Gut microbial metabolites of amino acids in liver diseases

Mengyao Hu; Yi Xu; Hongwei Zhou; Xiaolong He

doi:10.1080/19490976.2025.2586328

. 2025 Nov 24;17(1):2586328. doi: 10.1080/19490976.2025.2586328

Gut microbial metabolites of amino acids in liver diseases

Mengyao Hu ^a,¹, Yi Xu ^a,¹, Hongwei Zhou ^a,^b,^c,^d, Xiaolong He ^a,^b,^e,^*

PMCID: PMC12645865 PMID: 41277458

ABSTRACT

Due to the unique anatomical connection between the gut and liver, metabolites derived from gut microbiota are closely linked to hepatic health and disease. Among these microbial metabolites, amino acid derivatives have emerged as crucial mediators in gut-liver communication, influencing liver pathophysiology through their bioactive properties. Accumulating evidence demonstrates that amino acid metabolites, including amines, indoles, aromatic derivatives, branched-chain fatty acids (BCFAs), and sulphur-containing compounds (SCCs), function as critical signaling molecules within the gut-liver axis. These metabolites modulate immune responses, inflammation, and metabolic homeostasis, thus affecting the progression and severity of liver diseases. Understanding the specific microbial metabolic pathways responsible for producing these metabolites is essential to reveal novel pathological mechanisms and identify promising biomarkers and therapeutic targets. In this review, we summarize recent advances in microbial amino acid metabolism and highlight the diverse roles of amino acid-derived metabolites in liver disease progression. Furthermore, we discuss the translational potential and current challenges associated with targeting microbial amino acid metabolism in clinical settings. A deeper understanding of these metabolic interactions may ultimately facilitate the development of innovative diagnostic tools and effective therapeutic strategies for liver diseases.

Keywords: Amino acids metabolism, gut microbiota, microbial metabolites, liver diseases

1. Introduction

The gut and liver engage in extensive bidirectional communication primarily via the biliary tract, portal vein, and systemic circulation, a dynamic interplay referred to as the gut-liver axis. A central component of gut-liver axis is the gut microbiota, a rich and diverse microbial ecosystem that has co-evolved with the host. In recent years, it has been increasingly recognised as a “metabolic organ” capable of generating a wide range of bioactive molecules.¹ Among these, short-chain fatty acids (SCFAs) and bile acids have been extensively reviewed for their profound effects on host physiology and pathophysiology. Meanwhile, microbial amino acid metabolites have emerged as a novel and increasingly studied class of signalling molecules.

Proteins that escape digestion in the small intestine reach the colonic lumen, where they undergo microbial proteolysis and are degraded into amino acids. The resulting amino acids are subsequently metabolised through a series of microbial biochemical reactions, including fission, deamination, decarboxylation, oxidation, and reduction, leading to a diverse array of structurally related end products.² These metabolites exhibit considerable chemical and functional diversity, and many have been identified as important mediators of host-microbiota crosstalk within the gut-liver axis. Although previous reviews have discussed specific types of amino acid metabolism by the gut microbiota or its roles in certain diseases, a comprehensive and systematic overview of its relevance to liver health is still lacking.^3-7 This review aims to integrate current research advances by outlining the microbial catabolic pathways of amino acids and their metabolites, further elucidating the roles of key amino acid metabolites in liver-related diseases, and exploring the translational potential of targeting microbial amino acid metabolism for therapeutic applications. The gut microbiota includes bacteria, fungi, and other microorganisms. Given that fungal amino acid metabolism is less well characterised and its metabolites have rarely been linked to liver diseases, this review focuses on bacterial metabolism.

2. Regulation of gut microbiota on amino acid metabolism

Gut microbiota metabolise dietary and endogenous amino acids through enzymatic pathways that are often specific to certain amino acids and enriched in particular microbial taxa.⁸ For example, aromatic amino acid (AAA) aminotransferases and arginine deiminases are predominantly found in Firmicutes and Actinomycetota, whereas branched-chain amino acid (BCAA) aminotransferases are primarily observed in Bacteroidota and Firmicutes.⁹ Different bacterial genera have been reported to participate in the metabolism of various amino acid types, including AAAs, BCAAs, sulphur-containing amino acids (SAAs), and basic amino acids (BAAs), producing numerous metabolites that influence host health and disease.¹⁰

2.1. Aromatic amino acids

AAAs, including phenylalanine, tyrosine, and tryptophan, are among the most actively metabolised substrates of the gut microbiota and undergo a series of conserved biochemical transformations (Figure 1). Their shared structural feature, consisting of an aromatic ring linked to the universal amino acid backbone, predisposes them to common microbial pathways such as decarboxylation, transamination, and redox reactions. AAA decarboxylases catalyse the conversion of phenylalanine, tyrosine, and tryptophan into phenylethylamine (PEA), tyramine, and tryptamine, respectively. Although these enzymes are widely distributed among gut bacteria, their substrate specificities differ across taxa. Evidence from strain-level in vitro studies indicates that Morganella morganii predominantly produces PEA, whereas Clostridium asparagiforme and Enterococcus faecalis favour the formation of tyramine. Tryptamine production is more characteristic of Clostridium sporogenes, Tyzzerella nexilis, and Blautia hansenii. In Ruminococcus gnavus, the levels of PEA and tryptamine are considerably higher than that of tyramine.^11-14 Another shared route of AAA metabolism is transamination catalysed by aromatic amino acid transaminase (AroAT), which generates the keto acid intermediates phenylpyruvic acid, 4-hydroxyphenylpyruvic acid, and indole−3-pyruvic acid (IPyA). These intermediates, together with trace amines derived from decarboxylation, can undergo subsequent oxidative and reductive reactions that yield a wide range of downstream products, including acetic, propionic, and aldehyde derivatives. Several gut commensals such as Bacteroides thetaiotaomicron, Bacteroides eggerthii, Bacteroides ovatus, Bacteroides fragilis, Parabacteroides distasonis, Eubacterium hallii, and Clostridium bartlettii are capable of fermenting all three AAAs, collectively producing phenylacetic acid (PAA), 4-hydroxyphenylacetic acid (4-HPAA), and indole−3-acetic acid (IAA). Notably, Clostridium bartlettii showed 100 times higher IAA production than the other species tested.¹⁵ In addition, many Clostridium species have been reported to synthesise a diverse array of aromatic derivatives, although the specific metabolic end products depended upon the species.¹⁶ Other taxa also contribute, with certain Lactobacillus strains produce phenyllactic acid (PLA), while Peptostreptococcus species generate indole−3-propionic acid (IPA), indole−3-acrylic acid (IA), and 4-hydroxyphenylpropionic acid (4-HPPA).¹⁷^,¹⁸

Apart from the shared pathways, several distinct microbial conversions of AAAs have been reported (Figure 1). In tyrosine metabolism, Clostridium, Fusobacterium, Enterobacter, Morganella, Citrobacter, Klebsiella, and Olsenella have been shown to convert tyrosine to phenol, whereas Blautia, Clostridium, Romboutsia, and Olsenella can further metabolise 4-HPAA into p-cresol.¹² IAA, recognised as one of the most extensively studied indole derivatives, is generated not only through the IPyA and tryptamine pathways but also via the indole−3-acetamide (IAM) pathway catalysed by tryptophan 2-monooxygenase (TMO). While this route is well established in plant- and soil-associated microorganisms, its presence in gut microbiota has rarely been documented.¹⁹ IAA can subsequently be converted by Lactobacillus murinus, Lactobacillus acidophilus, and Lactobacillus reuteri into indole−3-aldehyde (IAld),²⁰^,²¹ or by Bacteroides, Clostridium, and Lactobacillus into skatole.¹⁵^,²²^,²³ Furthermore, multiple Gram-positive and Gram-negative taxa encode TnaA tryptophanase, enabling the production of large quantities of indole, a metabolite that plays a pivotal role in microbial consortia and in human health.²⁴^,²⁵ Collectively, these observations indicate that taxonomic differences, including strain-level variation, shape the specific metabolite profiles, and that metabolic exchange among coexisting bacteria further expands the repertoire of aromatic derivatives in the gut.

2.2. Branched-chain amino acids

BCAAs, including leucine, isoleucine, and valine, undergo characteristic microbial transformations within the gut in addition to host metabolism (Figure 2A). Their microbial catabolism is initiated by branched-chain amino acid transaminase (BCAT), which converts BCAAs into the corresponding branched-chain α-keto acids. These intermediates are then oxidatively decarboxylated by branched-chain keto acid dehydrogenase (BCKDH) to generate the respective acyl-CoA derivatives. These two reactions constitute the common pathway of BCAA degradation, after which the branched-chain metabolites are further processed through three distinct enzymatic systems to ultimately generate BCFAs. Several Clostridium species, as well as Parabacteroides merdae have been reported to metabolise leucine, isoleucine, and valine into isovalerate, 2-methylbutyrate, and isobutyrate, respectively.²⁶^,²⁷ In Clostridium porogenes and Parabacteroides merdae, this metabolic capacity has been experimentally confirmed to be mediated by the porA gene.²⁸^,²⁹

2.3. Sulphur-containing amino acids

SAAs, primarily cysteine and methionine, undergo microbial transformations that produce sulphur metabolites (Figure 2B). A well-characterised route is the cleavage of cysteine by cysteine desulfhydrase (CDS), releasing hydrogen sulphide (H₂S). CDS activity has been demonstrated in Salmonella enterica serovar Typhimurium and Escherichia coli.³⁰ It has also been identified in oral microorganisms such as Fusobacterium nucleatum, Prevotella intermedia, and Streptococcus anginosus, where it drives substantial H₂S production that contributes to oral malodor and periodontal disease.^31-33 Notably, these species are also common commensals of the human colon. In addition to CDS, earlier studies have shown that bacteria can utilise cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and mercaptopyruvate sulfurtransferase (MST) to convert cysteine into H₂S. Functional analyses in pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus confirmed the involvement of these enzymes in H₂S production,³⁴ suggesting that multiple enzymatic strategies for sulphide generation exist in bacteria, although these pathways remain poorly characterised in commensal taxa. Cysteine can also enter the transsulfuration pathway via cystathionine γ-synthase (CGS) and cystathionine β-lyase (CBL), generating cystathionine and subsequently homocysteine, which functions both as a direct precursor for methionine biosynthesis and as a substrate for the reverse transsulfuration pathway to produce cysteine. Methionine degradation provides another important microbial source of sulphur metabolites. Methionine γ-lyase (MGL) catalyses the conversion of methionine into methanethiol, which can be further transformed by methanethiol oxidase (MTO) to yield H₂S. Comparative enzymatic studies have shown that Pseudomonas ovalis exhibits the highest MGL activity, and the enzyme is inducibly formed upon addition of methionine to the medium.³⁵

2.4. Basic amino acids

BAAs, including arginine, histidine and lysine, function as critical metabolic precursors for the intestinal polyamine pool (Figure 2C). The catabolism of arginine in bacteria is mediated through several well-characterised pathways: the arginine deiminase (ADI) pathway, the arginase (ARG) pathway, the arginine succinyltransferase (AST) pathway, the arginine oxidase (AO) pathway, and the arginine decarboxylase (ADC) pathway.³⁶^,³⁷ Here we focus on the ADC pathway, which generates agmatine and supports microbial polyamine biosynthesis. In Enterococcus faecalis, agmatine deiminase (AgDI) converts agmatine to N-carbamoylputrescine, which is then further metabolised into putrescine by putrescine carbamoyltransferase (PCT). This route provides ATP and confers resistance to acid stress.³⁸ In Bacteroides thetaiotaomicron, N-carbamoylputrescine is hydrolysed by N-carbamoylputrescine amidohydrolase (NCPAH) to produce putrescine, a distinct step recently validated and kinetically characterised through genetic and biochemical analyses.³⁹ In addition to proceeding via agmatine, Escherichia coli synthesises putrescine by decarboxylating ornithine, and this putrescine is subsequently converted to spermidine by spermidine synthase (SPDS).⁴⁰ This general mode of spermidine biosynthesis is widespread among bacteria, although pathway specifics differ. In the key gut commensal Bacteroides thetaiotaomicron, the carboxyspermidine dehydrogenase/decarboxylase (CASDH/CASDC) system has been shown to be essential for spermidine production.⁴¹ In comparison, only a few gut commensals produce spermine. Parabacteroides distasonis, for example, has been reported to synthesise spermine via spermine synthase (SPMS) and to protect against testicular injury.⁴² Notably, a second spermine pathway involving carboxyspermine has recently been identified in Clostridium leptum, underscoring that additional bacterial routes of polyamine biosynthetic pathways likely remain to be discovered.⁴³

Histidine is processed by microbes along two principal routes and one emerging side pathway. The first route is decarboxylation to histamine catalysed by histidine decarboxylase (HDC). The probiotic Lactobacillus reuteri has repeatedly been shown to convert dietary histidine to histamine which signals through epithelial histamine type−2 receptor (H2R) to suppress colitis and attenuate tumour necrosis factor (TNF), highlighting a distinct immunomodulatory role for histamine.⁴⁴^,⁴⁵ The second route is the classical histidine utilisation pathway in which histidine is deaminated by histidine ammonia-lyase (HAL) to urocanate, then transformed by urocanase (UCH) to 4-imidazolone−5-propionate, and then converted by imidazolonepropionase (IPase) to N-formimino-L-glutamate (FIGLU). Downstream processing of FIGLU varies across taxa. In genera such as Klebsiella and Bacillus, FIGLU can be hydrolysed directly to L-glutamate, whereas in others such as Pseudomonas and Streptomyces the formimino group is first removed to generate N-formyl-L-glutamate (NFGLU), which is then hydrolysed to formate and L-glutamate that enter glutamate metabolism.⁴⁶ In parallel, a side pathway yielding imidazole propionate (ImP) has gained attention. Certain gut bacteria encode urocanate reductase (UrdA), for which no Enzyme Commission number has yet been assigned, that reduces urocanate to ImP. Levels of ImP are elevated in individuals with type 2 diabetes (T2D), and ImP impairs glucose tolerance and insulin signalling when administered to mice. The species Streptococcus mutans and Eggerthella lenta have been implicated in this association.⁴⁷ Recent studies further implicate ImP in atherosclerosis, highlighting that many microbially derived amino acid metabolites with important biological functions have yet to be identified.⁴⁸ Beyond these signature products, colonic fermentation of histidine contributes SCFAs including acetate and propionate.

Lysine is also an important substrate in bacterial polyamine metabolism and is the principal precursor of cadaverine. In Escherichia coli and Lactobacillus, lysine decarboxylase (LDC) converts L-lysine to cadaverine, and lysine/cadaverine antiporter exchange extracellular lysine for intracellular cadaverine to support acid tolerance.⁴⁹^,⁵⁰ Beyond polyamine formation, lysine also serves as a significant source of microbial butyrate in the gut. The lysine route is one of the four main bacterial pathways for butyrate formation, alongside the acetyl-CoA, 4-aminobutyrate, and glutarate pathways.⁵¹ In addition, cadaverine undergoes transamination and dehydrogenation to yield 5-aminovalerate (5-AVA), which is subsequently oxidised to glutarate, thereby intersecting with the butyrate biosynthetic pathway.⁵² Aside from butyrate, lysine can also be metabolised to acetate, which modulates the efficiency of butyrate formation.⁵³ This capacity for SCFA production has been demonstrated for both BAAs and SAAs in a faecal microbiota fermentation study (Figure 2B, C).⁵⁴

Together, microbial amino acid metabolism is highly complex, involving numerous intermediate products, side reactions, and enzymatic pathways that may vary across taxa. Certain metabolites can be produced through multiple, overlapping routes involving different microbial species or enzyme isoforms. For example, phenylacetic acid can be generated either via the oxidative deamination of PEA, a decarboxylation product of phenylalanine,⁵⁵ or through the conversion of phenylpyruvate, a transamination product of the same amino acid.⁵⁶ Such metabolic flexibility illustrates the redundancy and interconnectedness of microbial pathways. Beyond this complexity, microbial amino acid metabolism also harbours considerable unknowns. Recent studies have revealed that gut bacteria can convert tyrosine into homovanillic acid, a compound previously thought to arise predominantly from host dopamine metabolism, suggesting that many microbial products remain undiscovered.⁵⁷ Continued exploration of these pathways will be essential for fully understanding the contribution of microbial amino acid metabolism to host physiology and disease.

3. Microbial amino acid metabolites as signalling molecules in the gut-liver crosstalk

Growing evidence indicates that microbial amino acid metabolites act as important signalling molecules within the gut-liver axis. These metabolites primarily include amines, indoles, aromatic derivatives, BCFAs, SCCs, and ammonia (Table 1 and 2). Among them, ammonia, a well-recognised microbial byproduct of amino acid deamination, plays a significant role in hepatic encephalopathy (HE) and other liver diseases, and its underlying mechanisms have been extensively reviewed elsewhere.⁵⁸ Thus, in this section, we focus on the roles and mechanisms of the other five classes of metabolites in metabolic disorders such as insulin resistance (IR) and obesity, as well as in liver diseases including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), alcohol-associated liver disease (ALD), acute liver failure (ALF), cirrhosis, and hepatocellular carcinoma (HCC) (Figure 3).

Table 1.

Human gut microbial amino acid-derived metabolite signatures in liver diseases.

Metabolites	Related liver disease	Study objects	Sample types	Trends in disease	References
Amines
Phenylethylamine (PEA)	HE	Patients with cirrhosis vs patients with HE	Serum	Increase	[59]
Tyramine	MASLD	Children with simple obesity vs children with obesity accompanied by MASLD	Serum	Increase	[60]
Cadaverine	MASLD	Subjects with normal liver vs subjects with MASLD	Faeces	Increase	[61]
Histamine	Biliary atresia	Normal controls vs infants with biliary atresia	Liver tissues	Increase	[62]
Putrescine	MASLD	Healthy controls vs patients with MASLD	Liver tissues	Increase	[63]
Spermine	HCC	Healthy controls vs patients with HCC	Serum	Increase	[64]
Indoles
Indole	MASLD	Lean subjects vs overweight subjects vs obese subjects	Serum	Decrease	[65]
Indole−3-acetic acid (IAA)	MASLD	Healthy controls vs patients with MASLD	Faeces	Decrease	[66]
	ALD	Healthy controls vs patients with alcoholic hepatitis	Faeces	Decrease	[67]
Indole−3-acrylic acid (IA)	Obesity	Healthy controls vs patients with obesity	Serum	Decrease	[68]
Indole−3-propionic acid (IPA)	Obesity	Lean controls vs obese T2D subjects	Plasma	Decrease	[69]
	Obesity	Normal-weight subjects vs overweight subjects	Serum, follicular fluid	Decrease	[70]
	Obesity	Average weight subjects vs overweight subjects vs obese subjects	Serum, colonic mucosa	Decrease	[71]
	MASLD	Healthy controls vs patients with MASLD	Faeces	Decrease	[66]
	Liver fibrosis	Bariatric surgery subjects with fibrosis vs those without fibrosis	Serum	Decrease	[72]
Aromatic Derivatives
4-Hydroxyphenyllactic acid (4-HPLA)	MASLD	Individuals without MASLD vs individuals with MASLD in twins and families (discovery cohort)Biopsy-proven MASLD patients without advanced fibrosis vs those with advanced fibrosis (validation cohort)	Serum	Increase	[73]
Phenylacetic acid (PAA)	MASLD	Non-diabetic women with morbid obesity	Plasma	Increase	[74]
Phenyllactic acid (PLA)	HCC	Healthy controls vs patients with HCC	Portal vein serum, liver tissues	Increase	[75]
Branched-chain fatty acids (BCFAs)
2-Methylbutyrate	Obesity	Normal-weight subjects vs obese subjects	Faeces	Increase	[76]
	MASLD	T2D patients with vs without MASLD	Serum	Decrease	[77]
	MASLD	Healthy controls vs patients with MASLD	Plasma	Increase	[78]
Isobutyrate	Obesity	Normal-weight controls vs women with morbid obesity	Plasma	Decrease	[79]
	Hypercholesterolaemia	Subjects with normocholesterolemia vs subjects with hypercholesterolaemia	Faeces	Increase	[80]
	MASLD	T2D patients with vs without MASLD	Serum	Decrease	[77]
	MASLD	Healthy controls vs patients with MASLD	Faeces	Increase	[81]
	MASLD	Lean healthy controls vs patients with lean MASLD	Serum	Increase	[82]
	Obesity	Normal-weight controls vs women with morbid obesity	Plasma	Increase	[79]
	Obesity	Normal-weight subjects vs obese subjects	Faeces	Increase	[76]
	Hypercholesterolaemia	Subjects with normocholesterolemia vs subjects with hypercholesterolaemia	Faeces	Increase	[80]
Sulphur-containing compounds (SCCs)
Methanethiol (MT)	HE	Healthy controls vs cirrhotic patients without overt HE vs those with overt HE	Serum	Increase	[83]
Methanethiol (MT)	HE	Healthy controls vs patients with different grades of HE	Serum	Increase	[84]

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Abbreviations: ALD, alcohol-associated liver disease; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; MASLD, metabolic dysfunction-associated steatotic liver disease; T2D, type 2 diabetes.

Table 2.

Roles of gut microbial amino acid-derived metabolites in preclinical models of liver diseases.

Metabolites	Related liver disease	Study objects	Effects	Related signalling pathway	References
Amines
Phenylethylamine (PEA)	IR	Monkeys and mice 3T3-L1 adipocytes	Detrimental	TAAR1/ERK	[85]
	HE	CCl₄-treated mice	Detrimental	/	[59]
Tryptamine	Obesity	HFD-fed mice3T3-L1 adipocytes	Protective	/	[86]
	IR	Monkeys and mice3T3-L1 adipocytes	Detrimental	TAAR1/ERK	[85]
	MASLD	HFD-fed micePA and LPS-treated RAW 264.7 cells	Protective	/	[87]
Tyramine	IR	HFD-fed DrosophilaHFD-fed mice	Protective	TyrR1/Ca²⁺/CRTC/CREB	[88]
	MASLD	HFD-fed miceHepG2 and THLE3 cells	Detrimental	PPAR-γ	[60]
Agmatine	Obesity	Olanzapine-treated rats	Protective	/	[89]
	MASLD	HFD-fed apoE^-/- mice	Protective	/	[90]
	HE	BDL-treated rats	Protective	/	[91]
	ALF	D-GalN/LPS-treated mice	Protective	/	[92]
	Cholestatic liver injury	BDL-treated rats	Protective	/	[93]
	LIRI	Liver ischaemia reperfusion injured miceCobalt chloride-treated AML12 cells	Protective	Wnt/β-catenin	[94]
	DILI	Sodium valproate-treated mice	Protective	NF-κB/iNOS	[95]
	Hepatocyte apoptosis	Primary rat hepatocytes	Detrimental	/	[96]
Histamine	MASLD	High-cholesterol diet-fed H2R^-/- mice	Protective	H2R	[97]
	MASH	HFHC diet-fed H1R^-/- and H2R^-/- mice	Protective	H1R/H2R	[98]
	ALD	Alcoholic diet-fed rat	Protective	H2R	[99]
Putrescine	MASLD	HFCF diet-fed micePA-induced HepG2	Detrimental	/	[63]
	ALF	D-GalN-treated ratsCCl₄-treated ratsCadmium-treated rats	Protective	/	[100-103]
Spermidine	Obesity	HFD-fed miceHIB-1B preadipocytes or C2C12 myotubes	Protective	/	[104]
	Obesity	HFD-fed mice	Protective	/	[105,106]
	Metabolic syndrome	HFD-fed mice3T3-L1 adipocytes	Protective	/	[107]
	MASLD	WD-fed miceFAA-induced AML12 hepatocytes	Protective	DHPS/DOHH/EIF5A	[108]
	MASLD	HFD-fed micePrimary mouse hepatocytes	Protective	AMPK	[109]
	MASLD	WD-fed miceOA and PA-induced HepG2 cells	Protective	THRSP	[110]
	ALD	Alcoholic diet-fed miceLPS-treated mice	Protective	NF-κB	[111]
	Autoimmune Hepatitis	ConA-treated mice	Protective	/	[112]
	Liver fibrosis	CCl4-treated micePrimary mouse HSCs	Protective	MAP1S/NRF2	[113,114]
	Liver fibrosis-HCC	CCl₄-treated miceDiethylnitrosamine-treated mice	Protective	MAP1S-mediated autophagy	[115]
Spermine	ALF	TAA-treated miceTAA-treated mouse kupffer cells	Protective	ATG5-mediated autophagy	[116]
	HCC	Hepa1−6 xenograft in mice	Detrimental	PI3K/AKT/mTOR/S6K	[64]
Indoles
Indole	Obesity	ob/ob mice	Protective	/	[117]
	MASLD	HFD-fed micePA and LPS-treated primary hepatocytesLPS-treated RAW264.7 cells and BMDM	Protective	PFKFB3	[65]
	MASLD	LPS-injected miceLPS-treated precision-cut liver slices	Protective	NF-κB	[118]
	MASLD	HFD-fed micePA-treated HepG2 cells	Protective	ACE2	[119]
	Portal hypertension	TAA-treated rats	Detrimental	/	[120]
Indole−3-acetaldehyde (IAAld)	HSOS	Monocrotaline-treated rats Rat primary liver sinusoidal endothelial cells	Protective	AHR/Nrf2	[121]
Indole−3-acetamide (IAM)	ALD	Alcoholic diet-fed miceAlcohol-treated HepG2 cells	Protective	AHR	[122]
Indole−3-acetic acid (IAA)	MASLD	HFD-fed mice	Protective	/	[123]
	MASLD	HFD-fed micePA and LPS-treated RAW 264.7 cells FAA and TNF-α-treated HepG2 and AML12 cells	Protective	AHR/Fasn/SREBP1c	[87]
	MASLD	WD-fed micePA and LPS-induced RAW 264.7 cells	Protective	AMPK	[124]
	MASLD	WD-fed mice	Protective	NF-κB	[66]
	ALD	Alcoholic diet-fed mice	Protective	AHR/IL22/REG3G	[67]
	ALF	D-GalN/LPS-treated mice	Detrimental	TLR2/NF-κB	[125]
Indole−3-acrylic acid (IA)	Obesity	HFD-fed zebrafishHuman primary visceral preadipocytes	Protective	STAT1/PPARγ	[68]
Indole−3-aldehyde (IAld)	Hypercholesterolaemia	HFD-fed mice	Protective	/	[126]
	MASLD	HFD-fed miceOA-induced HepG2 cells	Protective	AHR	[127]
	MASLD	HFD-fed mice	Protective	AHR	[128]
	PSC	DDC diet-fed mice	Protective	AHR/IL22	[129]
Indole−3-lactic acid (ILA)	MASLD	HFD-fed miceFFA-induced AML12 hepatocytes	Detrimental	/	[130]
	ALF	D-GalN/LPS-treated mice	Detrimental	/	[125]
	DILI	APAP-treated mice	Protective	AHR/Nrf2	[131]
Indole−3-propionic acid (IPA)	Obesity	HFD-fed miceIFN-γ and TNF-α-treated T84 cells	Protective	/	[69]
	Obesity	HFD-fed miceOrganoidsNIH3T3 cells	Protective	/	[71]
	Obesity	Standard diet-fed rats	Protective	/	[132]
	MASLD	WD-fed mice	Protective	NF-κB	[66]
	MASH	HFD-fed ratsLPS-treated J774A.1 cells	Protective	NF-κB	[133]
	MASLD-HCC	HFHC-fed miceCholesterol-treated HKCI−2 and HKCI−10 cells	Protective	/	[134]
	Liver fibrosis	CCl4-treated mice	Detrimental	TGF-β1/Smads	[135]
	Liver fibrosis	TGF-β1-treated LX−2 cells	Protective	/	[72]
	ALF	D-GalN/LPS-treated mice	Detrimental	/	[125]
skatole	MASLD	PA-induced HepG2, SNU−449, and Huh7 cells	Protective	/	[136]
Aromatic Derivatives
4-Hydroxyphenylacetic acid (4-HPAA)	Obesity	HFD-fed mice	Protective	/	[137]
	Obesity	HFD-fed mice	Protective	SIRT1	[138]
	MASLD	HFD-fed mice	Protective	AMPK	[139]
	ALD	Alcohol diet-fed Ppara-null mice	Protective	/	[140]
	DILI	APAP-treated mice	Protective	Nrf2	[141]
4-Hydroxyphenylpropionic acid (4-HPPA)	MASLD	HFD-fed mice	Protective	/	[142]
Cinnamic acid (CA)	MASLD	db/db miceOA-stimulated HepG2 cells	Protective	/	[143]
	ALD	Alcohol-treated mice	Protective	/	[144]
p-Cresol (PC)	MASLD	HFD-fed mice	Detrimental	/	[145]
Phenylacetic acid (PAA)	MASLD	Human primary hepatocytesMice	Detrimental	/	[74]
Phenyllactic acid (PLA)	Obesity	HFD-fed with low dose penicillin treated miceOrganoids	Protective	PPAR-γ	[17]
Phenylpropionic acid (PPA)	DILI	APAP- or CCl₄-treated mice	Protective	/	[146]
Branched-chain fatty acids (BCFAs)
Isobutyrate	Obesity	FAO rat hepatocytes cells	Detrimental	mTORC1/S6K1	[147]
	MASLD	Primary human hepatocyte spheroid	Detrimental	/	[82]
	Liver injury in IBD	DSS-induced colitis liver injury piglets	Protective	TLR4/MyD88/NF-κB	[148]
Isovalerate	Obesity	FAO rat hepatocytes cells	Detrimental	mTORC1/S6K1	[147]
	Liver fibrosis	CCl₄-treated miceTNFα-stimulated HepG2 cells	Detrimental	/	[149]
Sulphur-containing compounds (SCCs)
Hydrogen sulphide (H₂S)	Hepatitis	ConA-induced hepatitis mice	Protective	/	[150]
	MASLD	HFD-fed mice	Protective	/	[151]
	MASLD	HFD-fed miceFat-emulsion-treated L02 and HepG2 cells	Protective	AMPK/mTOR	[152]
	MASH	MCD diet-fed rats	Protective	/	[153]
	Liver fibrosis	CCl₄-treated rats	Protective	/	[154]
	Liver fibrosis	CCl₄-treated mice	Protective	/	[155]
	Liver fibrosis	Streptozotocin + HFD-treated LDLr^-/- miceCCl₄-treated mice	Protective	Keap1/Nrf2/Lrp1	[156]
	Liver fibrosis	Primary rat HSCsBDL-treated rats	Detrimental	/	[157]
	LIRI	Anoxia/reoxygenation injured primary mouse hepatocytesLiver ischaemia/reperfusion injured mice	Protective	PI3K/AKT1	[158]
	Portal hypertension	TAA-treated rats	Detrimental	/	[159]
	Portal hypertension	BDL-treated rats	Protective	/	[160]
	HCC	L02, SMMC−7721 and Huh−7 cellsSMMC−7721 and Huh−7 xenograft tumours in nude mice	Detrimental (low-dose)Protective (high-dose)	EGFR/ERK/MMP-2PTEN/PI3K/AKT	[161]
	HCC	PLC/PRF/5 and L02 cells	Detrimental	NF-κBSTAT3/COX−2	[162]
	HCC	TNFα-stimulated HEK293 cells	Detrimental	NF-κB	[163]
	HCC	HepG2 and HLE cells	Protective	PI3K/AKT/mTOR	[164]
	HCC	HepG2 and Bel7402 cellsHepG2 xenograft in mice	Protective	STAT3	[165]

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Abbreviations: ACE2, angiotensin-converting enzyme 2; AHR, aryl hydrocarbon receptor; AKT, protein kinase-B; ALD, alcohol-associated liver disease; ALF, acute liver failure; AMPK, AMP-activated protein kinase; APAP, acetaminophen; apoE, apolipoprotein E; BDL, bile duct ligation; COX-2, cyclooxygenase-2; CREB, cAMP response element-binding protein; CRTC, CREB-regulated transcription coactivator; DCC, 3,5-diethoxycarbonyl-1,4-dihydrocollidine; D-GalN, D-galactosamine; DHPS, deoxyhypusine synthase; DILI, drug-induced liver injury; DOHH, deoxyhypusine hydroxylase; DSS, dextran sulphate sodium; EGFR, epidermal growth factor receptor; EIF5A, eukaryotic initiation factor 5A; ERK, extracellular signal-regulated kinase; FAA, fatty acid; Fasn, fatty acid synthase; H1R, histamine type-1 receptor; H2R, histamine type-2 receptor; HCC, hepatocellular carcinoma; HE, hepatic encephalopathy; HFCF, high-fat, cholesterol, and fructose; HFD, high-fat diet; HFHC, high-fat/high-cholesterol; HSC, hepatic stellate cell; HSOS, hepatic sinusoidal obstruction syndrome; IBD, inflammatory bowel disease; iNOS, inducible nitric oxide synthetase; IR, insulin resistance; Keap1, kelch-like ECN-associated protein 1; LIRI, liver ischaemia reperfusion injury; LPS, lipopolysaccharides; Lrp1, low-density lipoprotein receptor-related protein 1; MAP1S, microtubule associated protein 1S; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MCD, methionine- and choline-deficient; MMP-2, matrix metalloproteinase 2; mTOR, mammalian target of rapamycin; MyD88, myeloid differentiation primary response 88; NF-κB, nuclear factor-κB; Nrf2, nuclear factor (erythroid-derived 2)-like 2; OA, oleic acid; PA, palmitic acid; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PI3K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor γ PSC, primary sclerosing cholangitis; PtdIns3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten; REG3G, regenerating islet-derived 3 gamma; S6K, ribosomal protein S6 kinase; SIRT1, sirtuin 1; SREBP1c, sterol regulatory element-binding protein-1c; STAT, signal transducer and activator of transcription; T2D, type 2 diabetes; TAA, thioacetamide; TAAR1, trace amine-associated receptor 1; TGF-β1, transforming growth factor-β1; THRSP, thyroid hormone-responsive protein; TLR, toll-like receptor; TyrR1, tyramine receptor 1; WD, western diet.

Figure 3. — Microbial amino acid metabolism and its representative signalling pathways in the gut-liver axis. Gut microbiota metabolise AAAs, BCAAs, SAAs, and BAAs into a variety of bioactive compounds, including monoamines, indoles, aromatic derivatives, BCFAs, SCCs, and polyamines. These microbial metabolites can translocate to the liver via the portal circulation and contribute to the pathogenesis and progression of liver diseases, including ALD, MASLD, MASH, cirrhosis, HCC, DILI, LIRI, ALF, PSC, and HSOS. Regular arrows indicate gene activation and detrimental effects on disease, while blunt arrows indicate gene inhibition and protective effects on disease. Figure created in BioRender. Abbreviations: 4-HPAA, 4-hydroxyphenylacetic acid; AAAs, aromatic amino acids; AHR, aryl hydrocarbon receptor; AKT, protein kinase-B; ALD, alcohol-associated liver disease; ALF, acute liver failure; AMPK, AMP-activated protein kinase; ATG5, autophagy-related 5; BAAs, basic amino acids; BCAAs, branched-chain amino acids; BCFAs, branched-chain fatty acids; DILI, drug-induced liver injury; H2R, histamine type−2 receptor; H₂S, hydrogen sulphide; HCC, hepatocellular carcinoma; HSOS, hepatic sinusoidal obstruction syndrome; IAA, indole−3-acetic acid; IAM, indole−3-acetamide; IPA, indole−3-propionic acid; Keap1, kelch-like ECH-associated protein 1; LIRI, liver ischaemia reperfusion injury; MAP1S, microtubule-associated protein 1S; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PEA, phenylethylamine; PI3K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator-activated receptor γ PSC, primary sclerosing cholangitis; SAAs, sulphur-containing amino acids; SCCs, sulphur-containing compounds; STAT3, signal transducer and activator of transcription 3; TGF-β1, transforming growth factor-β1; TLR, toll-like receptor.

3.1. Amines

Amines represent a chemically diverse group of nitrogen-containing compounds that are primarily produced in the gut through microbial decarboxylation of amino acids. This group includes monoamines such as PEA, tyramine, and tryptamine, which are derived respectively from phenylalanine, tyrosine, and tryptophan through direct decarboxylation. Polyamines such as cadaverine, agmatine, putrescine, spermidine, spermine, and histamine originate from amino acid precursors including lysine, arginine, ornithine, and histidine, often involving multistep biosynthetic pathways. While certain polyamines can also be synthesised by host cells, the gut microbiota, particularly in the colon, is considered a major source under physiological conditions. In healthy adults, colonic luminal concentrations of polyamines range from the micro- to millimolar level, with putrescine being the most abundant, followed sequentially by spermine, spermidine, and cadaverine.¹⁶⁶^,¹⁶⁷

PEA, tyramine, and tryptamine are classified as trace amines capable of influencing neurotransmission even at low tissue concentrations. Under physiological conditions, they are rapidly degraded by liver monoamine oxidases, thereby limiting their systemic accumulation and neuroactive effects.⁵⁵ However, our recent study suggests that under cirrhotic conditions, reduced monoamine oxidase-B activity in the liver and circulation impairs the clearance of PEA, primarily produced by Ruminococcus gnavus, leading to its accumulation in the brain and contributing to the neurological symptoms characteristic of HE.⁵⁹ Beyond their classical roles in the nervous system, these microbial amines have recently gained attention for their emerging involvement in metabolic disorders. Among them, tyramine has been found to be elevated in children with MASLD and positively associated with clinical indicators of hepatic steatosis. Experimental studies further demonstrate that Enterococcus faecium B6-derived tyramine promotes MASLD progression via activation of peroxisome proliferator-activated receptor γ (PPAR-γ) signalling.⁶⁰ Interestingly, in parallel studies using high-fat diet (HFD) models in both Drosophila and mice, tyramine was shown to alleviate IR, which is considered an early initiating factor in the development of MASLD.⁸⁸ Tryptamine, another trace amine, is reported to be reduced in HFD-fed mice, and in vitro studies suggest that tryptamine supplementation attenuates macrophage inflammation, indicating a potential protective role in fatty liver disease.⁸⁷ Similarly, in HFD models, tryptamine improves obesity and IR by directly modulating lipogenesis and lipolysis in white adipose tissue.⁸⁶ However, under physiological conditions, tryptamine has been reported to impair insulin signalling through activation of the trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signalling axis, suggesting that its metabolic effects may be context dependent.⁸⁵ Given the multifaceted roles of trace amines in metabolic regulation, further research is warranted to elucidate the underlying mechanisms and assess the clinical relevance of trace amines in MASLD.

Histamine, a biogenic amine derived from the decarboxylation of histidine, has been implicated in a range of liver diseases. Clinical studies have reported elevated histamine levels in patients with advanced liver diseases. In individuals with advanced chronic liver disease, high plasma histamine is associated with circulatory dysfunction and independently associated with increased risks of acute-on-chronic liver failure and liver-related mortality.¹⁶⁸ Similarly, hepatic histamine levels are markedly increased in infants with biliary atresia and correlate positively with the severity of liver fibrosis, suggesting a potential link between histamine accumulation and disease progression.⁶² In contrast, experimental animal models suggest a protective role for histamine in the early stages of liver injury. In alcohol-fed rats, histamine confers protection against hepatic damage via H2R signalling.⁹⁹ Likewise, in dietary models of MASLD and MASH, histamine signalling through histamine type−1 receptor (H1R) and H2R has been shown to regulate glucose and lipid metabolism and attenuate steatohepatitis progression.⁹⁷^,⁹⁸ These findings suggest stage-specific roles for histamine in liver disease. While elevated levels in patients may result from reduced hepatic clearance, receptor-dependent effects observed in animal models point to potential metabolic benefits. However, the pathological significance of histamine accumulation in advanced liver disease remains unclear and requires further elucidation.

Cadaverine, a polyamine derived from lysine decarboxylation, has been less extensively studied within the gut-liver axis. Limited clinical evidence indicates that faecal cadaverine levels are elevated in patients with MASLD compared to obese individuals with normal liver histology, suggesting a possible association with disease progression.⁶¹ Further studies are needed to clarify its mechanistic role and clinical significance in liver diseases.

Another subset of polyamines is derived from microbial arginine metabolism. Among them, agmatine is generated through the decarboxylation of arginine and acts as both a precursor and a regulator of downstream polyamines, including putrescine, spermidine, and spermine. These metabolites are involved in diverse physiological and pathological pathways. Notably, agmatine and spermidine have been extensively investigated in experimental models of liver injury. In models of D-galactosamine and lipopolysaccharide (D-GalN/LPS)-induced liver failure, bile duct ligation-induced cholestasis, ischaemia-reperfusion injury, and sodium valproate-induced hepatotoxicity, agmatine administration mitigates hepatic injury by exerting anti-inflammatory, antioxidant, and cytoprotective effects.^92-95 Additionally, in HFD-fed apolipoprotein E-knockout mice, agmatine reduces hepatic steatosis, suggesting a beneficial role in metabolic liver disease.⁹⁰ Similarly, spermidine has demonstrated beneficial effects in obesity, MASLD, and metabolic syndrome. It improves hepatic lipid metabolism, reduces steatosis, and alleviates systemic metabolic dysfunction through multiple mechanisms, including AMP-activated protein kinase (AMPK) activation, enhancement of mitochondrial function, and gut microbiota-mediated modulation of bile acid metabolism.^104-110 Additionally, spermidine has been shown to protects against alcohol- and LPS-induced liver injury by reducing oxidative stress and inflammation,¹¹¹ mitigates hepatic fibrosis through Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent pathways,¹¹³ and prevents fibrosis-associated hepatocellular carcinoma via MAP1S (Microtubule-associated protein 1S)-mediated autophagy.¹¹⁵ Collectively, these findings underscore the broad hepatoprotective properties of agmatine and spermidine and support their therapeutic potential in liver disease management. Further human studies are warranted to evaluate their clinical relevance. Unlike the broadly protective effects observed with agmatine and spermidine, putrescine and spermine exhibit more variable roles across different liver disease contexts. Putrescine has been reported to alleviate hepatic injury in several acute liver damage models.^100-103 However, its levels are elevated in hepatic tissue of both diet-induced MASH mice and patients with MASH, and in vitro studies suggest that putrescine may exacerbate palmitic acid-induced lipotoxicity in hepatocytes.⁶³ Spermine similarly exerts protective effects in thioacetamide-induced acute liver injury by attenuating inflammatory responses in liver-resident macrophages through ATG5-dependent autophagy.¹¹⁶ In contrast, increased spermine levels have been detected in the serum of patients with HCC compared to healthy individuals, and mechanistic studies indicate that spermine facilitates M2 macrophage polarisation, thereby impairing antitumor immunity.⁶⁴ These findings indicate that while putrescine and spermine may confer protection in acute liver injury, their accumulation in chronic liver disease may contribute to pathogenesis. Further studies are warranted to delineate their mechanistic roles and to evaluate their potential as biomarkers or therapeutic targets.

3.2. Indoles

Tryptophan, an essential aromatic amino acid, is metabolised through three major pathways in the gastrointestinal tract: the kynurenine pathway mediated by indoleamine 2,3-dioxygenase 1, the serotonin biosynthesis pathway via tryptophan hydroxylase 1, and the direct transformation by the gut microbiota into various bioactive molecules.³ Metabolites directly derived from microbial tryptophan metabolism, including indole and its derivatives, have emerged as important regulators of host physiology and disease.¹⁶⁹ Several bacterial genera, including Clostridium, Lactobacillus, and Blautia, have been reported to produce high levels of indole-related substances.¹⁷⁰ Multiple studies have quantified the levels of indole derivatives in the faeces of healthy adults.^171-174 However, reported concentrations vary considerably due to differences in analytical methods and interindividual variability. Despite these discrepancies, indole is generally recognised as the most abundant microbial tryptophan catabolite in adults, followed by IAA and IPA. In contrast, the concentrations of several other tryptophan-derived metabolites, such as indole-lactic acid (ILA), IA, IAM, IAld, and indole−3-acetaldehyde (IAAld), have not yet been comprehensively assessed in the human gut.

Indole and several of its derivatives, including ILA, IA, IPA, IAAld, IAld, and IAA are considered endogenous ligands of the aryl hydrocarbon receptor (AHR).²¹^,^175-177 AHR signalling is a critical regulator of intestinal and hepatic immune responses, playing an important role in intestinal homoeostasis and liver diseases.^178-181 A recent study demonstrated that metabolic syndrome is linked to a reduced microbial capacity to produce AHR-activating tryptophan metabolites, and restoring this function through AHR agonists or a Lactobacillus strain with high ligand-producing capacity improves glucose metabolism and liver steatosis by enhancing intestinal barrier function and stimulating GLP−1 secretion.¹⁸² Similar to AHR, pregnane X receptor (PXR) is capable of sensing certain microbial tryptophan catabolites. Among them, IPA has been identified as a ligand for PXR, particularly in the presence of indole, contributing to the regulation of intestinal barrier function.¹⁸³ Importantly, PXR has been recognised as a key regulator in metabolic disorders and chronic liver diseases.¹⁸⁴^,¹⁸⁵ These findings underscore the critical role of bacterial tryptophan catabolites in modulating host metabolic homoeostasis and highlight their potential as therapeutic targets in metabolic disorders and liver diseases. Indole has also been identified as a microbial signalling molecule capable of stimulating the secretion of glucagon-like peptide−1 (GLP−1) from colonic enteroendocrine L cells, a hormone involved in regulating insulin secretion, appetite, and energy balance.¹⁸⁶ In both animal models and in vitro studies, indole has been shown to attenuate hepatic steatosis, suppress inflammatory responses, and modulate cholesterol metabolism.⁶⁵^,^117-119 Additionally, circulating indole levels are reversely associated with body mass index in human subjects, further supporting its potential role in metabolic regulation.⁶⁵

ILA has been shown to alleviate drug-induced liver injury by activating hepatic AHR/Nrf2 signalling pathway.¹³¹ In contrast, ILA exacerbates hepatic steatosis in the in vitro and in vivo model of MASLD, suggesting a potential pathogenic role under certain metabolic conditions.¹³⁰ Previous studies have indicated that microbiota-regulated AHR signalling exhibits considerable complexity across different liver diseases, and further research is needed to elucidate the mechanisms underlying these diverse effects.¹⁸⁷ Reduced levels of IPA have been consistently observed in overweight and obese individuals, indicating its potential protective role in metabolic health. Supporting evidence from both animal and in vitro studies shows that IPA supplementation mitigates weight gain, improves intestinal barrier function, and attenuates obesity-related metabolic disorders.^69-71^,¹³² In addition to its role in obesity, IPA has demonstrated beneficial effects in MASLD. A recent study showed that IPA levels are decreased in the stool of patients with MASLD. In a mouse model of Western diet-induced MASLD, administration of IPA effectively alleviated hepatic steatosis and inflammation by suppressing the nuclear factor κB (NF-κB) signalling pathway through a reduction in endotoxin levels and inactivation of macrophages.⁶⁶ Consistently, another study reported that IPA supplementation attenuated MASH progression in rats by enhancing gut barrier function and reducing both systemic and hepatic inflammatory responses.¹³³ Notably, in a cholesterol-driven MASLD-HCC model, a high-fat/high-cholesterol diet induced gut microbial dysbiosis and disrupted microbial tryptophan metabolism, resulting in significantly reduced serum levels of IPA compared to a high-fat/low-cholesterol diet. Functional assays further demonstrated that IPA inhibited cholesterol-induced lipid accumulation and hepatocyte proliferation, suggesting a protective role microbiota-derived IPA depletion in the pathogenesis of cholesterol-driven MASLD-HCC. Despite its beneficial effects in metabolic liver diseases, the role of IPA in hepatic fibrosis has yielded conflicting results. In a murine model, IPA was shown to exacerbate carbon tetrachloride (CCl₄)-induced liver injury and fibrosis by promoting hepatic stellate cell (HSC) activation via the transforming growth factor-β1 (TGF-β1)/Smads pathway.¹³⁵ Conversely, clinical data revealed significantly reduced circulating IPA levels in individuals with liver fibrosis, and in vitro studies demonstrated that IPA inhibited TGF-β1-induced adhesion and migration of LX−2 cells, suggesting a potential antifibrotic effect.⁷² These inconsistent findings may be attributed to differences in experimental models and study designs, highlighting the need for further investigation to clarify the role of IPA in hepatic fibrogenesis.

As an endogenous ligand of the AHR, IAld has demonstrated hepatoprotective effects through AHR-mediated signalling in several studies. IAld, produced by Lactobacillus acidophilus KLDS1.0901, was shown to alleviate HFD-induced MASLD in mice, accompanied by reduced hepatic lipid accumulation and increased glycogen content in oleic acid-treated hepatocytes.¹²⁷ Moreover, IAld was found to restore HFD-induced intestinal barrier dysfunction by promoting AHR-mediated intestinal stem cell proliferation, thereby reducing systemic inflammation.¹²⁸ In a murine model of primary sclerosing cholangitis (PSC), localised delivery of IAld to the gut attenuated hepatic inflammation and fibrosis by modulating the gut microbiota and activating the AHR-IL−22 signalling axis, underscoring its therapeutic potential in gut-liver axis-related liver diseases.¹²⁹ Another indole derivative, IAA, has demonstrated consistent hepatoprotective effects in liver diseases. Faecal levels of IAA were significantly reduced in patients with MASLD compared to healthy controls, and IAA supplementation effectively alleviated hepatic steatosis and inflammation in an animal model of MASLD.⁶⁶ Several studies have further shown that IAA reduces hepatic lipid accumulation, oxidative stress, and inflammatory responses through mechanisms involving activation of the AHR and AMPK, underscoring its potential as a multifactorial regulator of hepatic metabolic homoeostasis.⁸⁷^,¹²³^,¹²⁴ Moreover, faecal levels of IAA are significantly reduced in both patients with alcoholic hepatitis and mice fed a chronic-binge ethanol diet, leading to impaired AHR activation and downregulation of IL−22 and REG3G expression in the gut. Supplementation with IAA restores this signalling pathway, strengthens intestinal barrier function, prevents bacterial translocation, and attenuates ethanol-induced liver injury.⁶⁷

3.3. Aromatic derivatives

Aromatic derivatives are gut microbial metabolites primarily produced through the fermentation of aromatic amino acids, such as phenylalanine and tyrosine, via transamination followed by a series of oxidative and reductive reactions.⁵⁶ This class includes compounds such as PAA, PLA, phenylpropionic acid (PPA), cinnamic acid (CA), 4-HPAA, 4-HPPA, 4-hydroxyphenylactic acid (4-HPLA), p-cresol (PC), phenol, and others. Many of these compounds are classified as phenolic acids, which have traditionally been regarded as plant-derived secondary metabolites. However, accumulating evidence indicates that microbial fermentation of amino acids also constitutes a significant source.¹⁵ These aromatic metabolites, despite their varying concentrations, have been extensively investigated for their regulatory roles in the pathogenesis and progression of liver diseases.¹⁸⁸

Among these, 4-HPAA generally exerts a protective role across various forms of liver disease. In HFD-induced mouse models, 4-HPAA and its analogues have been shown to mitigate obesity, hepatic steatosis, and glucose intolerance. Mechanistically, 4-HPAA exerts its beneficial effects by activating hepatic AMPK signalling, modulating intestinal immune responses, and reducing lipid uptake in the gut mucosa. It also enhances Sirtuin 1 (SIRT1) signalling and induces beige adipogenesis and thermogenesis-related gene expression in white adipose tissue, contributing to improved energy metabolism.^137-139 Beyond metabolic regulation, 4-HPAA has demonstrated hepatoprotective effects in both alcoholic and drug-induced liver injury models. In Acetaminophen (APAP)-treated mice, 4-HPAA promotes nuclear translocation of Nrf2 and enhances phase II detoxification and antioxidant enzyme activity, thereby attenuating hepatocellular injury.¹⁴¹ Similarly, in alcohol-fed peroxisome proliferator-activated receptor alpha knockout (Ppara-null) mice, 4-HPAA ameliorates liver damage by reducing inflammation and modulating hepatic lipid metabolism.¹⁴⁰ Collectively, these findings suggest that 4-HPAA may serve as a multifunctional microbial metabolite with therapeutic potential across a range of liver and metabolic disorders.

Another extensively studied metabolite is PLA, which exhibits context-dependent effects depending on disease stage and host status. In early metabolic disorders such as obesity and MASLD, PLA appears to play a protective role. Clinical observations have shown that circulating PLA levels are negatively correlated with hepatic steatosis,¹⁸⁹ and in experimental models, Lactobacillus-derived PLA was found to upregulate intestinal PPAR-γ expression and mitigate metabolic dysfunction caused by early-life antibiotic exposure and HFD feeding.¹⁷ These findings suggest that PLA may support gut epithelial homoeostasis and metabolic regulation, thereby indirectly benefiting liver health. However, in more advanced liver disease states, PLA may shift from a protective to a detrimental marker. In patients with HCC, PLA was significantly elevated in portal vein and liver tissues, correlating with impaired hepatic function and poor prognosis, raising the possibility that PLA accumulation reflects or contributes to disease progression.⁷⁵ Additionally, in alcohol-related liver injury, PLA has been identified as a conserved urinary biomarker in Ppara-null mice across different genetic backgrounds, highlighting its potential value for disease monitoring.¹⁹⁰

In addition, PAA has emerged as a microbial metabolite of interest due to robust evidence from human studies linking it to liver disease pathogenesis. In a multi-omics analysis of obese women with varying degrees of hepatic steatosis, higher levels of microbial gene pathways for PAA production were observed in patients with steatosis, and circulating PAA levels were significantly associated with hepatic triglyceride accumulation. Functional studies further confirmed that chronic PAA administration and faecal microbiota transplantation from steatotic individuals induced hepatic lipid accumulation and disrupted branched-chain amino acid metabolism in mice, supporting a causative role of PAA in MASLD progression.⁷⁴ In contrast, a Mendelian randomisation study suggested that PAA might exert a protective effect against ALD.¹⁸⁹ This discrepancy may be attributed to the fact that ALD pathogenesis involves alcohol-induced oxidative stress and immune activation rather than lipid metabolism. Further mechanistic and longitudinal studies are needed to clarify the role of PAA in distinct forms of liver disease and its potential as a therapeutic target.

Several less-characterised aromatic microbial metabolites have also been implicated in liver health. PPA, 4-HPPA, and CA have consistently shown hepatoprotective effects in preclinical models. These compounds have been reported to alleviate hepatic steatosis, oxidative stress, or inflammation in different experimental settings, including high-fat diet feeding, alcohol exposure, and chemically induced liver injury.^142-144^,¹⁴⁶ In contrast, PC was shown to promote steatosis and hepatocellular damage. Notably, 4-HPLA, identified through twin-family genetic modelling, showed a significant genetic correlation with hepatic steatosis and fibrosis, and was linked to specific gut microbial taxa, suggesting a host-microbe co-regulatory mechanism in disease susceptibility.⁷³

3.4. Branched-chain fatty acids

BCFAs, including isovalerate, 2-methylbutyrate, and isobutyrate, are a type of SCFAs characterised by their unique branched molecular structure. Unlike straight-chain SCFAs, such as acetate, propionate, and butyrate, which are primarily produced through carbohydrates catabolism of intestinal microbes, BCFAs originate from the bacterial catabolism of branched-chain amino acids.¹⁹¹ In the human gut, BCFAs represent a minor fraction of total SCFAs, with colonic concentrations averaging 4.6 mmol/kg in the proximal colon and 6.3 mmol/kg in the distal colon, which correspond to approximately 3.4% and 7.5% of total SCFAs, respectively.¹⁹² While straight-chain SCFAs are widely acknowledged as crucial mediators of the gut-X axis and protect against multiple organ injuries,¹⁹³ the physiological functions of BCFAs remain comparatively underexplored. Therefore, this section focuses on current insights into the roles of BCFAs in the gut-liver axis.

In patients with MASLD, circulating levels of BCFAs have shown inconsistent trends across studies. In a cohort of T2D patients with MASLD, serum concentrations of 2-methylbutyrate and isobutyrate were significantly reduced and negatively correlated with disease severity, suggesting a potential protective role.⁷⁷ However, conflicting findings have been reported in other studies. For instance, one investigation found that serum isobutyrate levels were elevated in lean individuals with MASLD,⁸² while another reported increased plasma levels of 2-methylbutyrate in patients with MASLD, which were positively associated with the degree of hepatic fibrosis.⁷⁸ These discrepancies may reflect differences in host metabolic phenotypes, including obesity status, along with variation in gut microbiota composition and dietary protein intake, all of which may influence BCFA production. Given that obesity, hypercholesterolaemia, and other metabolic disorders are recognised as major risk factors for the development and progression of MASLD, it is important to consider their association with BCFA levels. Elevated faecal concentrations of isovalerate and isobutyrate have been reported in patients with hypercholesterolaemia.⁸⁰ Similarly, in a study of individuals with obesity, faecal levels of both 2-methylbutyrate and isovalerate were found to be elevated compared to normal-weight controls.⁷⁶ In parallel, a female obesity cohort showed that plasma isovalerate levels were significantly increased, whereas isobutyrate levels were decreased in women with morbid obesity. However, this pattern did not exhibit a progressive trend along the histological spectrum from simple steatosis to steatohepatitis, suggesting that these changes may reflect systemic metabolic alterations associated with obesity rather than liver-specific pathology.⁷⁹ Mechanistically, both isobutyrate and isovalerate have been shown to stimulate hepatic glucose production in hepatocyte models, with isovalerate demonstrating a greater capacity to overcome insulin-mediated suppression. These effects are mediated through activation of the mammalian target of rapamycin complex 1/S6 kinase 1 (mTORC1/S6K1) signalling pathway,¹⁴⁷ which plays a central role in hepatic regulation of ketogenesis and lipogenesis.¹⁹⁴ In addition, isobutyrate has been reported to induce lipid accumulation in human 3D liver spheroids, potentially via modulation of lipogenesis-related genes, fatty acid metabolism, and bile acid signalling.⁸²

Beyond metabolic liver diseases, BCFAs have also been implicated in other forms of liver injury. For instance, isovalerate has been shown to exacerbate tumour necrosis factor alpha (TNF-α)-induced apoptosis in HepG2 cells, suggesting a detrimental role in liver damage.¹⁴⁹ In contrast, in a dextran sodium sulphate (DSS)-induced colitis model in piglets, preventive supplementation with sodium isobutyrate alleviated colitis-associated liver injury, highlighting its hepatoprotective role. This protective effect was associated with the suppression of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/NF-κB signalling pathway, resulting in reduced expression of pro-inflammatory cytokines including TNF-α, IL-1β, and IL−6.¹⁴⁸ This pathway has been widely implicated in diverse inflammatory processes and thought to mediate the anti-inflammatory effects of butyrate in both the gut and the brain.^195-197 In addition, isobutyrate helped preserve mitochondrial function, thereby limiting oxidative stress and hepatocyte apoptosis.¹⁴⁸ Similar effects have also been reported for other SCFAs, including acetate and butyrate.¹⁹⁸ While this suggests a shared mechanism of action among SCFAs, it remains unclear whether BCFAs can confer comparable protective benefits at lower effective doses, warranting further investigation.

3.5. Sulphur-containing compounds

Amino acid-derived SCCs are primarily generated through desulfurization reactions of cysteine and methionine, which produce H₂S and methanethiol (MT). H₂S in the colon is produced by both gut microbiota and host cells. Its intracellular concentration is determined by multiple factors, including exogenous H₂S diffusion, endogenous synthesis from cysteine within the cells, and the cellular capacity for H₂S oxidation.¹⁹⁹ Studies have reported that the concentration of sulphide in the colonic contents and faeces of mammals ranges from approximately 0.17 to 3.38 mmol/kg.²⁰⁰ This broad variability underscores the complexity of H₂S homoeostasis and suggests that luminal levels are influenced by a multifactorial interplay involving the host metabolic state, dietary composition, and microbial community structure and activity.

Emerging evidence has highlighted the protective roles of H₂S in several liver diseases. In drug-induced hepatitis mouse models, gut microbiota-derived H₂S has been shown to exert hepatoprotective effects by mitigating oxidative stress-mediated liver injury.¹⁵⁰ In the context of MASLD, exogenous H₂S supplementation significantly improves hepatic lipid metabolism and enhances antioxidant capacity in HFD-fed mice.¹⁵¹ Furthermore, in models of MASH, H₂S prevents disease progression induced by MCD-diets in rats, possibly through abating oxidative stress and suppressing inflammation.¹⁵³ Mechanistically, it has been implicated in the activation of hepatic autophagy via the AMPK-mTOR signalling pathway, contributing to the reduction of serum triglyceride levels and subsequent improvement of steatotic liver phenotypes.¹⁵² Consistent with these findings, exogenous H₂S attenuates CCl₄-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cyto-protection and anti-fibrosis.¹⁵⁴ Cystathionine γ-lyase gene knockout mice showed exacerbated liver injury and fibrosis, while administration of H₂S donors reversed these changes.¹⁵⁵ Mechanistically, H₂S exerts its protective effects by inducing Keap1 (Kelch-like ECH-associated protein 1) Cys151-dependent S-sulfhydration, which activates the Nrf2 antioxidant pathway, promotes Nrf2 nuclear translocation, and upregulates antioxidant gene expression, thereby mitigating hepatocyte damage and fibrotic progression.¹⁵⁶ These observations suggest that exogenous H₂S, including that derived from the gut microbiota, may serve as a promising therapeutic target for liver fibrosis, in which antioxidative effects appear to play a central and repeatedly observed role.

However, the effects of H₂S are not uniformly beneficial across all hepatic cell types. In HSCs, exogenous H₂S has been shown to promote cell proliferation and upregulate fibrogenic gene expression in both primary rat HSCs and bile duct-ligated rat models.¹⁵⁷ This discrepancy may be explained by differences in experimental models, as well as the route and dosage of H₂S administration, and indicates the cell-type specific effects of H₂S within the hepatic microenvironment.

The role of H₂S in HCC remains controversial, with studies reporting both tumour-promoting and tumour-suppressive effects. On one hand, H₂S has been shown to promote proliferation, inhibit apoptosis, and enhance angiogenesis and migration of PLC/PRF/5 hepatoma cells via activation of the NF-κB or signal transducer and activator of transcription 3 (STAT3)-cyclooxygenase−2 (COX−2) signalling pathways.¹⁶²^,²⁰¹ Furthermore, H₂S supplementation facilitated the sulfhydration of the p65 subunit of NF-κB, thereby increasing its transcriptional activity at anti-apoptotic gene promoters in HEK293 cells.¹⁶³ In contrast, other studies have demonstrated that H₂S can induce autophagy and apoptosis by inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase-B (AKT)/mTOR signalling pathway.¹⁶⁴ Additionally, H₂S attenuates STAT3 activation, thereby contributing to reduced cell proliferation and tumour growth.¹⁶⁵ These contradictory results may be attributed to differences in the administered dose of H₂S, as well as the varying sensitivity of different cellular models to its concentration. As evidenced by prior studies, H₂S appears to exert a dose-dependent biphasic effect in HCC. Low concentrations (10−100 μM) of NaHS (an H₂S donor) stimulate tumour-promoting behaviours such as proliferation, migration, and angiogenesis, while higher concentrations (800−1000 μM) exert inhibitory effects on tumour growth. This dual action may be mediated through the epidermal growth factor receptor (EGFR)/extracellular signal-regulated protein kinases (ERK)/matrix metalloproteinase 2 (MMP−2) and phosphatase and tensin homologue deleted on chromosome ten (PTEN)/AKT pathways.¹⁶¹ Collectively, these studies highlight the complexity of H₂S -mediated signalling in HCC and underscore its dose-dependent effects.

MT, another sulphur-containing compound, is highly neurotoxic and can induce reversible coma even at low concentrations.²⁰² Early clinical studies have suggested a potential association between elevated circulating levels of MT and the occurrence of HE. In healthy individuals, MT concentration in the bloodstream is extremely low, approximately 400 pmol/mL. In patients with liver cirrhosis, the levels increase significantly, even in those without overt HE, and can reach around 1000 pmol/mL in patients with overt HE. Notably, MT levels increased further during HE episodes and exhibited dynamic changes that closely paralleled alterations in mental status. This correlation was stronger than that observed with ammonia levels,⁸³ suggesting that MT may contribute to the pathogenesis or progression of HE and could serve as a more sensitive biomarker for neurological deterioration in patients with cirrhosis. However, this interpretation remains contentious. A subsequent study found that although MT was elevated in patients with HE, its increase was the smallest among methionine and its related metabolites and showed no significant variation across different HE severity grades. In addition, the elevated MT levels may partly reflect impaired renal function,⁸⁴ raising doubts about its direct pathological role in HE. Research on MT in HE has remained limited in recent years.

4. Translational implications of targeting amino acid metabolism

4.1. Biomarker potential of amino acid metabolism

Alterations in amino acid metabolism have been observed across various pathological conditions, providing new opportunities for non-invasive risk assessment and early diagnosis. Accumulating clinical evidence has demonstrated significant associations between circulating amino acid profiles and liver-related diseases. Newgard et al. identified a positive association between elevated plasma levels of BCAAs and IR.²⁰³ Supporting this observation, subsequent findings from a study in overweight and obese individuals showed that circulating BCAA concentrations were independently linked to hepatic fat accumulation and IR.²⁰⁴ Moreover, a large-scale prospective study demonstrated that five amino acids, including both BCAAs (isoleucine, leucine, valine) and AAAs (tyrosine, phenylalanine), were significantly associated with an increased risk of developing T2D. Notably, a model incorporating isoleucine, tyrosine, and phenylalanine significantly improved risk prediction, with individuals in the highest quartile of the amino acid score exhibiting a five- to sevenfold higher risk of developing diabetes compared to those in the lowest quartile, highlighting the potential value of amino acid profiling in early risk assessment.²⁰⁵

An untargeted metabolomic analysis of fasting plasma samples from histologically confirmed patients with MASLD (including those with steatosis and MASH) and matched healthy controls revealed that individuals with MASH had significantly elevated circulating levels of phenylalanine, BCAAs (leucine, isoleucine, valine), glutamate, aspartate, and tyrosine. By contrast, patients with simple steatosis showed significant increases in fewer amino acids, including glutamate, lysine, tyrosine, and isoleucine. These metabolomic signatures were insufficient to distinguish hepatic steatosis from steatohepatitis.²⁰⁶ A metabolomic analysis of liver biopsy samples from patients with MASLD further confirmed elevated levels of BCAAs in individuals with MASH, aligning with findings from plasma-based profiling. Moreover, hepatic concentrations of BCAAs, tyrosine, and phenylalanine were significantly elevated during the transition from steatosis to MASH.²⁰⁷ However, as liver disease progresses, BCAA levels exhibit an opposite trend. In a study of 101 patients with chronic hepatitis and 20 with liver cirrhosis, both plasma BCAA concentrations and the BCAA-to-tyrosine ratio (BTR) progressively declined with increasing fibrosis severity, and were significantly lower in patients with cirrhosis. In contrast, tyrosine levels were elevated even at early stages and continued to rise as the disease advanced.²⁰⁸ Consistently, another study involving 137 biopsy-confirmed patients with MASLD also demonstrated that BCAA and BTR levels decreased with fibrosis progression, whereas tyrosine levels positively correlated with both fibrosis stage and IR.²⁰⁹ Collectively, these findings underscore a characteristic amino acid imbalance pattern in advanced liver disease, marked by a reduced BTR. This shift is thought to result from impaired hepatic catabolism of AAAs and enhanced peripheral utilisation of BCAAs for energy production and ammonia detoxification,²¹⁰ with important implications for disease staging, nutritional assessment, and metabolic support strategies. Indeed, the BTR has been established as a prognostic factor for early-stage HCC and the most reliable predictor of intrahepatic recurrence.²¹¹ Moreover, BTR is closely associated with HE and the prognosis of these patients.²¹²

Zhang et al. developed a noninvasive diagnostic index for liver fibrosis based on plasma amino acid profiles in patients with chronic hepatitis C. By analysing amino acid concentrations in 53 biopsy-confirmed cases, they derived an optimal index expressed as (Phenylalanine/Valine) + (Threonine + Methionine + Ornithine)/(Proline + Glycine). This composite “amino index” demonstrated strong diagnostic performance, with area under the receiver operating characteristic curve (AUC) values of 0.92 for advanced fibrosis (F3-F4) and 0.99 for cirrhosis. Both sensitivity and specificity exceeded 88% at optimal cut-off values.²¹³ A recent large-scale serum metabolomics study involving two independent cohorts of patients with chronic hepatitis B further demonstrated the potential of metabolic profiling for noninvasive fibrosis staging. Using data from 504 HBV-infected patients with liver fibrosis and 502 healthy controls, a panel of four metabolites comprising taurocholate, tyrosine, valine, and linoelaidic acid was identified, and three random forest models were constructed to stratify disease presence and severity. These models exhibited excellent classification performance, achieving AUCs of 0.997 for distinguishing chronic liver disease from healthy controls, 0.941 for differentiating cirrhosis from fibrosis, and 0.918 for staging early versus advanced fibrosis. Validation in an independent cohort of 300 patients with HBV-related chronic liver disease and 90 healthy individuals confirmed the robustness of the models and their superiority over conventional indices, including the aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratio, the AST to Platelet Ratio Index (APRI), and FIB−4 (patient age, AST, ALT, and platelet).²¹⁴ These findings underscore the diagnostic potential of targeted amino acid profiles, either individually or in combination with other metabolite panels, for the noninvasive assessment of liver fibrosis. Future studies should aim to extend these results to liver diseases of diverse etiologies and incorporate longitudinal designs to validate the predictive utility and clinical applicability of metabolite-based indices. Such efforts will be instrumental in facilitating the development of simplified and lower-cost diagnostic tools for routine clinical practice.

Notably, numerous microbial amino acid metabolites have been found to be altered in liver-related diseases (Table 1), with growing mechanistic and preclinical evidence supporting their pathogenic or protective roles (Table 2). Despite this strong biological foundation, large-scale, population-based studies assessing their value as early diagnostic or prognostic biomarkers remain limited. Nonetheless, these mechanistic insights are increasingly driving translational research aimed at developing clinically applicable, noninvasive biomarker strategies. In our recent longitudinal cohort study of patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), elevated baseline serum levels of PEA were independently associated with a sevenfold increased risk of developing HE within three months after the TIPS procedures. These findings suggest that PEA may represent a clinically relevant early warning biomarker for post-TIPS HE.⁵⁹ In addition, disruptions in aromatic and branched-chain amino acid metabolism have been implicated in hepatic steatosis among obese individuals, and PAA was identified as the metabolite most strongly associated with steatosis, highlighting its potential as a biomarker in obesity-related hepatic steatosis.⁷⁴ Collectively, these observations emphasise the emerging clinical relevance of microbial amino acid metabolites within the gut-liver axis. Their potential role in disease prediction underscores warrants further investigation and validation in large-scaler, well-characterised human cohorts to substantiate their robustness and translational value. In parallel, standardised detection technologies and analytical methodologies are needed to ensure consistency, comparability, and clinical applicability across studies.

4.2. Therapeutic strategies targeting amino acid metabolism

Emerging discoveries have highlighted amino acid metabolism as a critical axis linking nutrition, gut microbiota, and host pathophysiology. Although a wide range of microbial amino acid metabolites have been mechanistically implicated in the development and progression of liver diseases, clinical interventions directly targeting these metabolites remain largely unexplored. A growing body of preclinical and clinical evidence supports the feasibility of targeting amino acids, either through dietary restriction or supplementation, as a strategy to prevent or treat metabolic and liver-related diseases.

In recent years, multiple clinical studies have explored the impact of modifying dietary protein quantity and composition on the prognosis of liver-related diseases. In patients with MASLD, high-protein diets have shown greater effects in reducing hepatic steatosis compared to low-protein diets. In a randomised controlled trial, 19 patients with morbid obesity received isocaloric low-energy diets with either 10% or 30% of energy from protein. Intrahepatic lipid levels decreased significantly only in the high-protein group, despite similar weight loss. The high-protein diet also reduced hepatic expression of lipid uptake and synthesis genes and attenuated inflammatory signalling. These findings suggest that its benefits were mediated by suppression of hepatic lipid accumulation.²¹⁵ Another multicenter RCT involving 226 overweight or obese patients with MASLD further confirmed these findings. The intervention group followed a low carbohydrate, high protein calorie-restricted diet combined with exercise and intensive counselling from a dietitian. This group exhibited significantly greater reductions in liver fat attenuation parameter, body mass index, and multiple metabolic indexes, including ALT, AST, gamma-glutamyl transferase (GGT), triglycerides, and fasting glucose.²¹⁶ Emerging evidence also suggest that high protein intake may affect host metabolism via the gut microbiota. An intervention study in healthy individuals demonstrated that a high-protein diet enriched microbial species capable of producing secondary bile acids, which was associated with elevated levels of secondary bile acids and glucagon, enhanced amino acid catabolism, reduced visceral adiposity, and lower total cholesterol.²¹⁷ However, in contrast to these findings, protein restriction has shown metabolic benefits in various experimental models of metabolic disease. Protein-restricted diets have been reported to improve metabolic function, reduce the risk of chronic diseases, and promote healthy aging.^218-220 These contrasting findings suggest that the metabolic effects of dietary protein modulation may depend on factors such as baseline nutritional status, disease stage, and protein source, highlighting the need for personalised dietary strategies in liver disease management.

An important limitation of protein-based interventions is the lack of precision, as some amino acids have been shown to correlate positively with disease risk, while others in the same food source exert protective effects.²²¹ This highlights the need for more targeted strategies focusing on specific amino acid types for effective disease management. Among these, modulation of BCAA intake has drawn considerable attention due to its multifaceted effects on metabolic health and liver disease. However, clinical evidence regarding BCAA modulation has shown conflicting outcomes in different stages of liver disease. In MASLD, circulating levels of BCAAs are frequently elevated. Emerging evidence suggests that dietary restriction of BCAAs may confer metabolic benefits, including improved insulin sensitivity, enhanced fatty acid oxidation, and increased energy expenditure.^222-224 Consistently, a clinical study demonstrated that short term dietary restriction of BCAAs reduced postprandial insulin secretion, improved white adipose tissue metabolism, and modulated gut microbiota composition.²²⁴ However, comprehensive clinical trial evidence supporting the therapeutic benefits of BCAA restriction in liver diseases remains limited. Conversely, in advanced liver diseases such as liver cirrhosis and HCC, BCAA supplementation is recommended as an effective intervention by multiple clinical guidelines.²²⁵^,²²⁶ A recent systematic review and meta-analysis, comprising 28 studies, compared oral BCAA supplementation to control treatments in patients with liver cirrhosis. The results indicated that oral BCAA supplementation significantly reduced the incidence of HE and other liver-related complications, such as decompensation events. Notably, in a subgroup of patients undergoing surgical resection for HCC, BCAA supplementation further decreased the recurrence of HE and related liver complications.²²⁷ Although these findings support the role of BCAAs as an adjunct nutritional therapy in liver cirrhosis to reduce complications, an improvement in overall survival has not yet been clearly demonstrated. Additionally, a Cochrane review highlighted differential outcomes based on the route of administration, finding oral BCAA supplementation beneficial for HE, whereas intravenous BCAA did not yield similar benefits.²²⁸ Given the critical role of gut microbiota as a pathogenic factor in HE, the differential efficacy of oral versus intravenous BCAAs suggests that gut microbiota may mediate some beneficial effects of oral BCAA supplementation, a hypothesis that warrants further investigation.

Another commonly used class of amino acids in dietary interventions is the SAAs, including cysteine and methionine. Modulating SAA intake has been shown to influence diverse diseases. For instance, a randomised controlled trial found that restricting dietary SAAs may exert beneficial effects on systemic metabolic markers, including fibroblast growth factor 21 (FGF21).²²⁹ Additionally, SAA restriction was shown to protect against Desulfovibrio-induced liver injury by reinforcing hepatic antioxidant and detoxification capacity and restoring bile acid homoeostasis,²³⁰ suggesting a key role in gut-liver axis. When focusing on individual SAAs, cysteine restriction has been reported to enhance serine biosynthesis and attenuate hepatic triglyceride accumulation, thereby improving lipid metabolism in the liver.²³¹ Similarly, recent research has demonstrated that cysteine deficiency triggers systemic metabolic reprogramming, leading to rapid fat mobilisation and consequent weight loss.²³² This beneficial effect was further supported by an intervention study in obese individuals, where dietary restriction of SAA led to greater weight loss, reduced leptin levels, and increased ketone body production compared to controls. In contrast to restriction, supplementation of SAAs has also shown potential benefits. High-SAA diet resulted in post-translationally modified gut microbial tryptophanase activity, thereby reducing the production of uraemic toxins and attenuating chronic kidney disease progression in mice.²³³ This further underscores the critical role of the gut microbiota in mediating the effects of dietary amino acids on host health.

Engineered microbes represent one of the pivotal strategies for modulating gut microbiota-derived metabolites. Using synthetic biology, bacteria can be designed to produce or consume specific metabolites that precisely modulate specific host metabolic pathways, thereby intervening in disease progression. For instance, one study engineered the probiotic Escherichia coli Nissle 1917 (EcN) to efficiently produce AHR ligands, such as IAA and ILA. In an ethanol-induced liver injury model, these metabolites acted on intestinal IL−22-producing cells to activate AhR signalling and enhance IL−22 production, thereby limiting bacterial translocation to the liver and significantly ameliorated hepatic damage.²³⁴ In another study, an ILA-producing EcN strain also demonstrated beneficial effects in a DSS-induced colitis model.²³⁵^,²³⁶ Additionally, ammonia, a toxic byproduct of intestinal amino acid metabolism, has been targeted by engineering the EcN strain SYNB1020 to convert it to arginine. This strain significantly reduced hyperammonemia in a mouse model of liver injury. Furthermore, a phase 1 clinical study confirmed its safety and successful colonisation, supporting its potential for further clinical development.²³⁷ These findings collectively highlight the promising application of engineered microbes in therapies that target amino acid metabolism.

5. Conclusions and future perspectives

Microbial amino acid metabolism has emerged as a critical component of gut-liver communication, generating a wide array of bioactive metabolites that influence host physiology. Here, we summarise current knowledge regarding its roles in liver diseases, identify the key challenges, and outline prospective directions for future studies.

In basic research, future should address three fundamental questions: 1) What is the microbial contribution to amino acid metabolism in vivo? Many amino acid metabolites are generated through overlapping host and microbial pathways. Distinguishing microbial-derived from host-derived metabolites is essential for interpreting their functional roles. 2) Which microbially derived metabolites are truly relevant to liver disease? For those metabolites primarily produced by microbes, it is crucial to determine whether they are merely associated with liver pathology or actively involved in disease processes. This distinction determines whether a metabolite is better suited as a diagnostic marker, prognostic indicator, or therapeutic target. 3) What are the underlying mechanisms linking these metabolites to liver disease? When causal relationships are established, the next step is to uncover the molecular and cellular mechanisms through which these metabolites act, such as their effects on inflammation, metabolism, fibrosis, or immune signalling. Addressing these questions will require integrated strategies, including isotope tracing, gnotobiotic models, organoid systems, and multi-omics approaches to attribute metabolite origins and functions with precision.

Translationally, microbial amino acid metabolites show strong promise as non-invasive biomarkers and therapeutic targets. Early clinical studies suggest associations between metabolite profiles and disease stages, and emerging interventions, such as amino acid dietary modulation, engineered probiotics, and metabolite supplementation, have shown encouraging results in preclinical models. However, most findings remain preliminary. Moving toward clinical application will require: 1) Large-scale, diverse, and longitudinal human cohorts to validate diagnostic and prognostic utility. 2) Standardised, low-cost detection technologies for reliable metabolite quantification. 3) Stratified clinical trials that account for host genetics, microbiota composition, and dietary habits. With deeper mechanistic insights and robust validation, microbial amino acid metabolism may become a cornerstone of precision diagnostics and targeted interventions in liver disease management.

Funding Statement

This work was supported by the following funding: National Key R&D Programme of China (2022YFA0806400 to H.Z.). National Natural Science Foundation of China (82422051 to X.H.). (National Key Research and Development Program of China)

Disclosure statement

No potential conflict of interest was reported by the author(s).

References

1.Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22(10):1079–1089. doi: 10.1038/nm.4185. [DOI] [PubMed] [Google Scholar]
2.Davila AM, Blachier F, Gotteland M, Andriamihaja M, Benetti PH, Sanz Y, Tomé D. Intestinal luminal nitrogen metabolism: role of the gut microbiota and consequences for the host. Pharmacol Res. 2013;68(1):95–107. doi: 10.1016/j.phrs.2012.11.005. [DOI] [PubMed] [Google Scholar]
3.Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018;23(6):716–724. doi: 10.1016/j.chom.2018.05.003. [DOI] [PubMed] [Google Scholar]
4.Liu Y, Hou Y, Wang G, Zheng X, Hao H. Gut microbial metabolites of aromatic amino acids as signals in host-microbe interplay. Trends Endocrinol Metab. 2020;31(11):818–834. doi: 10.1016/j.tem.2020.02.012. [DOI] [PubMed] [Google Scholar]
5.Tuerhongjiang G, Guo M, Qiao X, Lou B, Wang C, Wu H, Wu Y, Yuan Z, She J. Interplay between gut microbiota and amino acid metabolism in heart failure. Front Cardiovasc Med. 2021;8:752241. doi: 10.3389/fcvm.2021.752241. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Wang W, Jiang S, Xu C, Tang L, Liang Y, Zhao Y, Zhu G. Interactions between gut microbiota and Parkinson's disease: the role of microbiota-derived amino acid metabolism. Front Aging Neurosci. 2022;14:976316. doi: 10.3389/fnagi.2022.976316. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Wu L, Tang Z, Chen H, Ren Z, Ding Q, Liang K, Sun Z. Mutual interaction between gut microbiota and protein/amino acid metabolism for host mucosal immunity and health. Anim Nutr. 2021;7(1):11–16. doi: 10.1016/j.aninu.2020.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Neis EP, Dejong CH, Rensen SS. The role of microbial amino acid metabolism in host metabolism. Nutrients. 2015;7(4):2930–2946. doi: 10.3390/nu7042930. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Li TT, Chen X, Huo D, Arifuzzaman M, Qiao S, Jin WB, Shi H, Li XV, Iliev ID, Artis D, et al. Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology. Cell Host Microbe. 2024;32(5):661–675. doi: 10.1016/j.chom.2024.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55–71. doi: 10.1038/s41579-020-0433-9. [DOI] [PubMed] [Google Scholar]
11.Chen H, Nwe PK, Yang Y, Rosen CE, Bielecka AA, Kuchroo M, Cline GW, Kruse AC, Ring AM, Crawford JM, et al. A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology. Cell. 2019;177(5):1217–1231. 10.1016/j.cell.2019.03.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Pessione E, Pessione A, Lamberti C, Coïsson DJ, Riedel K, Mazzoli R, Bonetta S, Eberl L, Giunta C. First evidence of a membrane-bound, tyramine and beta-phenylethylamine producing, tyrosine decarboxylase in Enterococcus faecalis: a two-dimensional electrophoresis proteomic study. Proteomics. 2009;9(10):2695–2710. doi: 10.1002/pmic.200800780. [DOI] [PubMed] [Google Scholar]
13.Sugiyama Y, Mori Y, Nara M, Kotani Y, Nagai E, Kawada H, Kitamura M, Hirano R, Shimokawa H, Nakagawa A, et al. Gut bacterial aromatic amine production: aromatic amino acid decarboxylase and its effects on peripheral serotonin production. Gut Microbes. 2022;14(1):2128605. doi: 10.1080/19490976.2022.2128605. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Williams BB, Van Benschoten AH, Cimermancic P, Donia MS, Zimmermann M, Taketani M, Ishihara A, Kashyap PC, Fraser JS, Fischbach MA. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16(4):495–503. doi: 10.1016/j.chom.2014.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE, Flint HJ. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res. 2013;57(3):523–535. doi: 10.1002/mnfr.201200594. [DOI] [PubMed] [Google Scholar]
16.Elsden SR, Hilton MG, Waller JM. The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol. 1976;107(3):283–288. doi: 10.1007/bf00425340. [DOI] [PubMed] [Google Scholar]
17.Shelton CD, Sing E, Mo J, Shealy NG, Yoo W, Thomas J, Fitz GN, Castro PR, Hickman TT, Torres TP, et al. An early-life microbiota metabolite protects against obesity by regulating intestinal lipid metabolism. Cell Host Microbe. 2023;31(10):1604–1619. 10.1016/j.chom.2023.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW, Heim CE, Krastel P, Schmitt EK, Omar AS, Creasey EA, et al. Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe. 2017;22(1):25–37. doi: 10.1016/j.chom.2017.06.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Tang J, Li Y, Zhang L, Mu J, Jiang Y, Fu H, Zhang Y, Cui H, Yu X, Ye Z. Biosynthetic Pathways and Functions of Indole-3-Acetic Acid in Microorganisms. Microorganisms. 2023;11(8):2077. doi: 10.3390/microorganisms11082077. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, Bartolomaeus H, Haase S, Mähler A, Balogh A, Markó L, et al. Salt-responsive gut commensal modulates T(H)17 axis and disease. Natur. 2017;551(7682):585–589. doi: 10.1038/nature24628. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39(2):372–385. doi: 10.1016/j.immuni.2013.08.003. [DOI] [PubMed] [Google Scholar]
22.Honeyfield DC, Carlson JR. Effect of indoleacetic acid and related indoles on lactobacillus sp. strain 11201 growth, indoleacetic acid catabolism, and 3-methylindole formation. Appl Environ Microbiol. 1990;56(5):1373–1377. doi: 10.1128/aem.56.5.1373-1377.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Whitehead TR, Price NP, Drake HL, Cotta MA. Catabolic pathway for the production of skatole and indoleacetic acid by the acetogen Clostridium drakei, Clostridium scatologenes, and swine manure. Appl Environ Microbiol. 2008;74(6):1950–1953. doi: 10.1128/aem.02458-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Lee JH, Wood TK, Lee J. Roles of indole as an interspecies and interkingdom signaling molecule. Trends Microbiol. 2015;23(11):707–718. doi: 10.1016/j.tim.2015.08.001. [DOI] [PubMed] [Google Scholar]
25.Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev. 2010;34(4):426–444. doi: 10.1111/j.1574-6976.2009.00204.x. [DOI] [PubMed] [Google Scholar]
26.Sr Fau E, Hilton MG, Hilton MG. Volatile acid production from threonine, valine, leucine and isoleucine by clostridia. (0:302–8933. (Print)). [DOI] [PubMed]
27.Wang HA-O, Feng L, Pei ZA-O, Zhao J, Lu S, Lu W. Gut microbiota metabolism of branched-chain amino acids and their metabolites can improve the physiological function of aging mice(1474- 9726 Electronic)). [DOI] [PMC free article] [PubMed]
28.Qiao S, Liu C, Sun L, Wang T, Dai H, Wang K, Bao L, Li H, Wang W, Liu SJ, et al. Gut Parabacteroides merdae protects against cardiovascular damage by enhancing branched-chain amino acid catabolism. Nat Metab. 2022;4(10):1271–1286. doi: 10.1038/s42255-022-00649-y. [DOI] [PubMed] [Google Scholar]
29.Guo CJ, Allen BM, Hiam KJ, Dodd D, Van Treuren W, Higginbottom S, Nagashima K, Fischer CR, Sonnenburg JL, Spitzer MH, et al. Depletion of microbiome-derived molecules in the host using Clostridium genetics. Sci. 2019;366(6471). doi: 10.1126/science.aav1282. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Awano N, Wada M, Mori H, Nakamori S, Takagi H. Identification and functional analysis of Escherichia coli cysteine desulfhydrases. Appl Environ Microbiol. 2005;71(7):4149–4152. doi: 10.1128/aem.71.7.4149-4152.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Yoshida Y, Ito S, Kamo M, Kezuka Y, Tamura H, Kunimatsu K, Kato H. Production of hydrogen sulfide by two enzymes associated with biosynthesis of homocysteine and lanthionine in Fusobacterium nucleatum subsp. nucleatum ATCC 25586. Microbiology. 2010;156(Pt 7):2260–2269. doi: 10.1099/mic.0.039180-0. [DOI] [PubMed] [Google Scholar]
32.Takahashi Y, Yoshida A, Nagata E, Hoshino T, Oho T, Awano S, Takehara T, Ansai T. Streptococcus anginosus l-cysteine desulfhydrase gene expression is associated with abscess formation in BALB/c mice. Mol Oral Microbiol. 2011;26(3):221–227. doi: 10.1111/j.2041-1014.2010.00599.x. [DOI] [PubMed] [Google Scholar]
33.Yano T, Fukamachi H, Yamamoto M, Igarashi T. Characterization of L-cysteine desulfhydrase from Prevotella intermedia. Oral Microbiol Immunol. 2009;24(6):485–492. doi: 10.1111/j.1399-302X.2009.00546.x. [DOI] [PubMed] [Google Scholar]
34.Shatalin K, Shatalina E, Mironov A, Nudler E. H2S: a universal defense against antibiotics in bacteria. Sci. 2011;334(6058):986–990. doi: 10.1126/science.1209855. [DOI] [PubMed] [Google Scholar]
35.Tanaka H Fau - Esaki N, Esaki N Fau - Soda K, Soda K. Properties of L-methionine gamma-lyase from Pseudomonas ovalis. (0006-2960 (Print)). [DOI] [PubMed]
36.Lu CD. Pathways and regulation of bacterial arginine metabolism and perspectives for obtaining arginine overproducing strains. Appl Microbiol Biotechnol. 2006;70(3):261–272. doi: 10.1007/s00253-005-0308-z. [DOI] [PubMed] [Google Scholar]
37.Nüse B, Holland T, Rauh M, Gerlach RG, Mattner J. L-arginine metabolism as pivotal interface of mutual host-microbe interactions in the gut. Gut Microbes. 2023;15(1):2222961. doi: 10.1080/19490976.2023.2222961. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Perez M, Calles-Enríquez M, Del Rio B, Redruello B, de Jong A, Kuipers OP, Kok J, Martin MC, Ladero V, Fernandez M, et al. Construction and characterization of a double mutant of Enterococcus faecalis that does not produce biogenic amines. Sci Rep. 2019;9(1):16881. doi: 10.1038/s41598-019-53175-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Shimokawa H, Sakanaka M, Fujisawa Y, Ohta H, Sugiyama Y, Kurihara S. N-Carbamoylputrescine amidohydrolase of bacteroides thetaiotaomicron, a dominant species of the human gut microbiota. Biomedicines. 2023;11(4):1123. doi: 10.3390/biomedicines11041123. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Sugiyama Y, Nakamura A, Matsumoto M, Kanbe A, Sakanaka M, Higashi K, Igarashi K, Katayama T, Suzuki H, Kurihara S. A novel putrescine exporter SapBCDF of Escherichia coli. J Biol Chem. 2016;291(51):26343–26351. doi: 10.1074/jbc.M116.762450. [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Sakanaka M, Sugiyama Y, Kitakata A, Katayama T, Kurihara S. Carboxyspermidine decarboxylase of the prominent intestinal microbiota species Bacteroides thetaiotaomicron is required for spermidine biosynthesis and contributes to normal growth. Amino Acids. 2016;48(10):2443–2451. doi: 10.1007/s00726-016-2233-0. [DOI] [PubMed] [Google Scholar]
42.Zhao Q, Huang JF, Cheng Y, Dai MY, Zhu WF, Yang XW, Gonzalez FJ, Li F. Polyamine metabolism links gut microbiota and testicular dysfunction. Microbiome. 2021;9(1):224. doi: 10.1186/s40168-021-01157-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Li B, Baniasadi HR, Liang J, Phillips MA, Michael AJ. New routes for spermine biosynthesis. J Biol Chem. 2025;301(4):108390. doi: 10.1016/j.jbc.2025.108390. [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Gao C, Major A, Rendon D, Lugo M, Jackson V, Shi Z, Mori-Akiyama Y, Versalovic J. Histamine H2 receptor-mediated suppression of intestinal inflammation by probiotic lactobacillus reuteri. mBio. 2015;6(6):e01358–01315. doi: 10.1128/mBio.01358-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Thomas CM, Hong T, van Pijkeren JP, Hemarajata P, Trinh DV, Hu W, Britton RA, Kalkum M, Versalovic J. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 2012;7(2):e31951. doi: 10.1371/journal.pone.0031951. [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Bender RA. Regulation of the histidine utilization (hut) system in bacteria. Microbiol Mol Biol Rev. 2012;76(3):565–584. doi: 10.1128/mmbr.00014-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Koh A, Molinaro A, Ståhlman M, Khan MT, Schmidt C, Mannerås-Holm L, Wu H, Carreras A, Jeong H, Olofsson LE, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. 2018;175(4):947–961. doi: 10.1016/j.cell.2018.09.055. [DOI] [PubMed] [Google Scholar]
48.Mastrangelo A, Robles-Vera I, Mañanes D, Galán M, Femenía-Muiña M, Redondo-Urzainqui A, Barrero-Rodríguez R, Papaioannou E, Amores-Iniesta J, Devesa A, et al. Imidazole propionate is a driver and therapeutic target in atherosclerosis. Natur. 2025;645(8079):254–261. doi: 10.1038/s41586-025-09263-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Schneider J, Wendisch VF. Biotechnological production of polyamines by bacteria: recent achievements and future perspectives. Appl Microbiol Biotechnol. 2011;91(1):17–30. doi: 10.1007/s00253-011-3252-0. [DOI] [PubMed] [Google Scholar]
50.Li Z, Huang Z, Gu P. Response of Escherichia coli to acid stress: mechanisms and applications-a narrative review. Microorganisms. 2024;12(9):1774. doi: 10.3390/microorganisms12091774. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. mBio. 2014;5(2):e00889. doi: 10.1128/mBio.00889-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Li W, Ma L, Shen X, Wang J, Feng Q, Liu L, Zheng G, Yan Y, Sun X, Yuan Q. Targeting metabolic driving and intermediate influx in lysine catabolism for high-level glutarate production. Nat Commun. 2019;10(1):3337. doi: 10.1038/s41467-019-11289-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
53.Bui TP, Ritari J, Boeren S, de Waard P, Plugge CM, de Vos WM. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. Nat Commun. 2015;6:10062. doi: 10.1038/ncomms10062. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Smith EA, Macfarlane GT. Dissimilatory amino acid metabolism in human colonic bacteria. Anaerobe. 1997;3(5):327–337. doi: 10.1006/anae.1997.0121. [DOI] [PubMed] [Google Scholar]
55.Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev. 2008;60(13-14):1527–1533. doi: 10.1016/j.addr.2008.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ, Higginbottom SK, Le A, Cowan TM, Nolan GP, Fischbach MA, et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Natur. 2017;551(7682):648–652. doi: 10.1038/nature24661. [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Zhao M, Ren Z, Zhao A, Tang Y, Kuang J, Li M, Chen T, Wang S, Wang J, Zhang H, et al. Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity. Cell Metab. 2024;36(5):1000–1012. 10.1016/j.cmet.2024.03.010. [DOI] [PubMed] [Google Scholar]
58.Gallego-Durán R, Hadjihambi A, Ampuero J, Rose CF, Jalan R, Romero-Gómez M. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2024;21(11):774–791. doi: 10.1038/s41575-024-00970-9. [DOI] [PubMed] [Google Scholar]
59.He X, Hu M, Xu Y, Xia F, Tan Y, Wang Y, Xiang H, Wu H, Ji T, Xu Q, et al. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nat Med. 2025;31(2):627–638. doi: 10.1038/s41591-024-03405-9. [DOI] [PubMed] [Google Scholar]
60.Wei J, Luo J, Yang F, Feng X, Zeng M, Dai W, Pan X, Yang Y, Li Y, Duan Y, et al. Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine. Gut Microbes. 2024;16(1):2351620. doi: 10.1080/19490976.2024.2351620. [DOI] [PMC free article] [PubMed] [Google Scholar]
61.Schwenger KJP, Sharma D, Ghorbani Y, Xu W, Lou W, Comelli EM, Fischer SE, Jackson TD, Okrainec A, Allard JP. Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients. Liver Int. 2024;44(5):1176–1188. doi: 10.1111/liv.15864. [DOI] [PubMed] [Google Scholar]
62.Zhou K, Xie G, Wen J, Wang J, Pan W, Zhou Y, Xiao Y, Wang Y, Jia W, Cai W. Histamine is correlated with liver fibrosis in biliary atresia. Dig Liver Dis. 2016;48(8):921–926. doi: 10.1016/j.dld.2016.05.001. [DOI] [PubMed] [Google Scholar]
63.Núñez-Sánchez M, Martínez-Sánchez MA, Sierra-Cruz M, Lambertos A, Rico-Chazarra S, Oliva-Bolarín A, Balaguer-Román A, Yuste JE, Martínez CM, Mika A, et al. Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease. J Pathol. 2024;264(1):101–111. doi: 10.1002/path.6330. [DOI] [PMC free article] [PubMed] [Google Scholar]
64.Sun Y, Zhou P, Qian J, Zeng Q, Wei G, Li Y, Liu Y, Lai Y, Zhan Y, Wu D, et al. Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma. Cell Death Differ. 2025;32(3):573–586. doi: 10.1038/s41418-024-01409-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Ma L, Li H, Hu J, Zheng J, Zhou J, Botchlett R, Matthews D, Zeng T, Chen L, Xiao X, et al. Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3. Hepatology. 2020;72(4):1191–1203. doi: 10.1002/hep.31115. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.Min BH, Devi S, Kwon GH, Gupta H, Jeong JJ, Sharma SP, Won SM, Oh KK, Yoon SJ, Park HJ, et al. Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation. Gut Microbes. 2024;16(1):2307568. doi: 10.1080/19490976.2024.2307568. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Hendrikx T, Duan Y, Wang Y, Oh JH, Alexander LM, Huang W, Stärkel P, Ho SB, Gao B, Fiehn O, et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut. 2019;68(8):1504–1515. doi: 10.1136/gutjnl-2018-317232. [DOI] [PMC free article] [PubMed] [Google Scholar]
68.Zhang L, Zhao J, Peng Z, Zhang Z, Huang S, Dong X, Gao J, Guo XA-O. Anti-adipogenesis effect of indole-3-acrylic acid on human preadipocytes and HFD-induced zebrafish. (1432-5233 (Electronic)). [DOI] [PubMed]
69.Jennis M, Cavanaugh CR, Leo GC, Mabus JR, Lenhard J, Hornby PJ. Microbiota-derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo. Neurogastroenterol Motil. 2018;30(2). doi: 10.1111/nmo.13178. [DOI] [PubMed] [Google Scholar]
70.Ruebel ML, Piccolo BD, Mercer KE, Pack L, Moutos D, Shankar K, Andres A. Obesity leads to distinct metabolomic signatures in follicular fluid of women undergoing in vitro fertilization. Am J Physiol Endocrinol Metab. 2019;316(3):e383–e396. doi: 10.1152/ajpendo.00401.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Chen L, Yang Y, Sun S, Xie Y, Pan C, Li M, Li C, Liu Y, Xu Z, Liu W, et al. Indolepropionic acid reduces obesity-induced metabolic dysfunction through colonic barrier restoration mediated via tuft cell-derived IL-25. Febs j. 2022;289(19):5985–6004. doi: 10.1111/febs.16470. [DOI] [PubMed] [Google Scholar]
72.Sehgal R, Ilha M, Vaittinen M, Kaminska D, Männistö V, Kärjä V, Tuomainen M, Hanhineva K, Romeo S, Pajukanta P, et al. Indole-3-propionic acid, a gut-derived tryptophan metabolite, associates with hepatic fibrosis. Nutrients. 2021;13(10):3509. doi: 10.3390/nu13103509. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, Bassirian S, Hooker J, Sy E, Richards L, et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology. 2018;68(3):918–932. doi: 10.1002/hep.29892. [DOI] [PMC free article] [PubMed] [Google Scholar]
74.Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Luque JL, Anthony E, Barton RH, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018;24(7):1070–1080. doi: 10.1038/s41591-018-0061-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
75.Liu J, Geng W, Sun H, Liu C, Huang F, Cao J, Xia L, Zhao H, Zhai J, Li Q, et al. Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma. Gut. 2022;71(6):1203–1213. doi: 10.1136/gutjnl-2021-325189. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Tiihonen K, Ouwehand AC, Rautonen N. Effect of overweight on gastrointestinal microbiology and immunology: correlation with blood biomarkers. Br J Nutr. 2010;103(7):1070–1078. doi: 10.1017/s0007114509992807. [DOI] [PubMed] [Google Scholar]
77.Tsai HJ, Hung WC, Hung WW, Lee YJ, Chen YC, Lee CY, Tsai YC, Dai CY. Circulating short-chain fatty acids and non-alcoholic fatty liver disease severity in patients with type 2 diabetes Mellitus. Nutrients. 2023;15(7):1712. doi: 10.3390/nu15071712. [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Thing M, Werge MP, Kimer N, Hetland LE, Rashu EB, Nabilou P, Junker AE, Galsgaard ED, Bendtsen F, Laupsa-Borge J, et al. Targeted metabolomics reveals plasma short-chain fatty acids are associated with metabolic dysfunction-associated steatotic liver disease. BMC Gastroenterol. 2024;24(1):43. doi: 10.1186/s12876-024-03129-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Aragonès G, Colom-Pellicer M, Aguilar C, Guiu-Jurado E, Martínez S, Sabench F, Antonio Porras J, Riesco D, Del Castillo D, Richart C, et al. Circulating microbiota-derived metabolites: a “liquid biopsy? Int J Obes (Lond). 2020;44(4):875–885. doi: 10.1038/s41366-019-0430-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
80.Granado-Serrano AB, Martín-Garí M, Sánchez V, Riart Solans M, Berdún R, Ludwig IA, Rubió L, Vilaprinyó E, Portero-Otín M, Serrano JCE. Faecal bacterial and short-chain fatty acids signature in hypercholesterolemia. Sci Rep. 2019;9(1):1772. doi: 10.1038/s41598-019-38874-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
81.Da Silva HE, Teterina A, Comelli EM, Taibi A, Arendt BM, Fischer SE, Lou W, Allard JP. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci Rep. 2018;8(1):1466. doi: 10.1038/s41598-018-19753-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
82.Haag M, Winter S, Kemas AM, Tevini J, Feldman A, Eder SK, Felder TK, Datz C, Paulweber B, Liebisch G, et al. Circulating metabolite signatures indicate differential gut-liver crosstalk in lean and obese MASLD. JCI Insight. 2025;10(8). doi: 10.1172/jci.insight.180943. [DOI] [PMC free article] [PubMed] [Google Scholar]
83.McClain CJ, Zieve L, Doizaki WM, Gilberstadt S, Onstad GR. Blood methanethiol in alcoholic liver disease with and without hepatic encephalopathy. Gut. 1980;21(4):318–323. doi: 10.1136/gut.21.4.318. [DOI] [PMC free article] [PubMed] [Google Scholar]
84.Blom HJ, Ferenci P, Grimm G, Yap SH, Tangerman A. The role of methanethiol in the pathogenesis of hepatic encephalopathy. Hepatology. 1991;13(3):445–454. doi: 10.1002/hep.1840130311. [DOI] [PubMed] [Google Scholar]
85.Zhai L, Xiao H, Lin C, Wong HLX, Lam YY, Gong M, Wu G, Ning Z, Huang C, Zhang Y, et al. Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome. Nat Commun. 2023;14(1):4986. doi: 10.1038/s41467-023-40552-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Lee J, Jang HR, Lee D, Lee Y, Lee HY. Gut bacteria-derived tryptamine ameliorates diet-induced obesity and insulin resistance in mice. Int J Mol Sci. 2025;26(3):1327. doi: 10.3390/ijms26031327. [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH, Yarmush ML, Alaniz RC, Jayaraman A, Lee K. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 2018;23(4):1099–1111. doi: 10.1016/j.celrep.2018.03.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
88.Ma P, Zhang Y, Yin Y, Wang S, Chen S, Liang X, Li Z, Deng H. Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca(2+) signaling. Embo j. 2024;43(16):3466–3493. doi: 10.1038/s44318-024-00162-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
89.Dixit MP, Sammeta SS, Dhokne MD, Mangrulkar S, Upadhya MA, Umekar MJ, Taksande BG, Kotagale NR. Chronic agmatine treatment prevents olanzapine-induced obesity and metabolic dysregulation in female rats. Brain Res Bull. 2022;191:69–77. doi: 10.1016/j.brainresbull.2022.10.013. [DOI] [PubMed] [Google Scholar]
90.Wiśniewska AA-, Stachowicz AA-O, Kuś K, Ulatowska-Białas M, Totoń-Żurańska JA-OX, Kiepura AA-O, Stachyra K, Suski MA-O, Gajda M, Jawień JA-O, et al. Inhibition of atherosclerosis and liver steatosis by agmatine in western diet-fed apoE-knockout mice is associated with decrease in hepatic de novo lipogenesis and reduction in Plasma triglyceride/high-density lipoprotein cholesterol ratio. LID. 2021;22(19):10688. 10.3390/ijms221910688. [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Ganjalikhan-Hakemi S, Asadi-Shekaari M, Pourjafari F, Asadikaram G, Nozari M. Agmatine improves liver function, balance performance, and neuronal damage in a hepatic encephalopathy induced by bile duct ligation. Brain Behav. 2023;13(9):e3124. doi: 10.1002/brb3.3124. [DOI] [PMC free article] [PubMed] [Google Scholar]
92.El-Agamy DS, Makled MN, Gamil NM. Protective effects of agmatine against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice. Inflammopharmacology. 2014;22(3):187–194. doi: 10.1007/s10787-013-0188-2. [DOI] [PubMed] [Google Scholar]
93.Ommati MM, Farshad O, Mousavi K, Taghavi R, Farajvajari S, Azarpira N, Moezi L, Heidari R. Agmatine alleviates hepatic and renal injury in a rat model of obstructive jaundice. PharmaNutrition. 2020;13:100212. doi: 10.1016/j.phanu.2020.100212. [DOI] [Google Scholar]
94.Han Z, Li Y, Yang B, Tan R, Wang M, Zhang B, Dai C, Wei L, Chen D, Chen Z. Agmatine Attenuates Liver Ischemia Reperfusion Injury by Activating Wnt/β-catenin Signaling in Mice (1534-6080 (Electronic)). [DOI] [PubMed]
95.Ahmed N, Aljuhani N, Al-Hujaili HS, Al-Hujaili MA, Elkablawy MA, Noah MM, Abo-Haded H. Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-κB/inducible nitric oxide synthetase pathway. (1099-0461(Electronic)). [DOI] [PubMed]
96.Gardini G, Cabella C, Cravanzola C, Vargiu C, Belliardo S, Testore G, Solinas SP, Toninello A, Grillo MA, Colombatto S. Agmatine induces apoptosis in rat hepatocyte cultures. J Hepatol. 2001;35(4):482–489. doi: 10.1016/s0168-8278(01)00153-2. [DOI] [PubMed] [Google Scholar]
97.Yamada S, Guo X, Wang KY, Tanimoto A, Sasaguri Y. Novel function of histamine signaling via histamine receptors in cholesterol and bile acid metabolism: Histamine H2 receptor protects against nonalcoholic fatty liver disease. Pathol Int. 2016;66(7):376–385. doi: 10.1111/pin.12423. [DOI] [PubMed] [Google Scholar]
98.Wang KY, Tanimoto A, Yamada S, Guo X, Ding Y, Watanabe T, Watanabe T, Kohno K, Hirano K, Tsukada H, et al. Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice. Am J Pathol. 2010;177(2):713–723. doi: 10.2353/ajpath.2010.091198. [DOI] [PMC free article] [PubMed] [Google Scholar]
99.Hornyak SC, Gehlsen KR, Haaparanta T. Histamine dihydrochloride protects against early alcohol-induced liver injury in a rat model. Inflammation. 2003;27(5):317–327. doi: 10.1023/a:1026032611643. [DOI] [PubMed] [Google Scholar]
100.Tzirogiannis KN, Panoutsopoulos GI, Demonakou MD, Papadimas GK, Kondyli VG, Kourentzi KT, Hereti RI, Mykoniatis MG. The hepatoprotective effect of putrescine against cadmium-induced acute liver injury. Arch Toxicol. 2004;78(6):321–329. doi: 10.1007/s00204-004-0549-0. [DOI] [PubMed] [Google Scholar]
101.Nagoshi S, Ohta Y, Matsui A, Fujiwara K. Protective action of putrescine against rat liver injury. Scand J Gastroenterol. 1994;29(2):166–171. doi: 10.3109/00365529409090457. [DOI] [PubMed] [Google Scholar]
102.Nishiguchi S, Kuroki T, Takeda T, Nakajima S, Shiomi S, Seki S, Matsui-Yuasa I, Otani S, Kobayashi K. Effects of putrescine on D-galactosamine-induced acute liver failure in rats. Hepatology. 1990;12(2):348–353. doi: 10.1002/hep.1840120224. [DOI] [PubMed] [Google Scholar]
103.Daikuhara Y, Tamada F, Takigawa M, Takeda Y, Mori Y. Changes in polyamine metabolism of rat liver after administration of D-galactosamine. Favorable effects of putrescine administration on galactosamine-induced hepatic injury. Gastroenterology. 1979;77(1):123–132. doi: 10.1016/S0016-5085(79)80022-0. [DOI] [PubMed] [Google Scholar]
104.Wang D, Yin J, Zhou Z, Tao Y, Jia Y, Jie H, Zhao J, Li R, Li Y, Guo C, et al. Oral spermidine targets brown fat and skeletal muscle to mitigate diet-induced obesity and metabolic disorders. Mol Nutr Food Res. 2021;65(19):e2100315. doi: 10.1002/mnfr.202100315. [DOI] [PubMed] [Google Scholar]
105.Ma L, Ni Y, Wang Z, Tu W, Ni L, Zhuge F, Zheng A, Hu L, Zhao Y, Zheng L, et al. Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes. 2020;12(1):1–19. doi: 10.1080/19490976.2020.1832857. [DOI] [PMC free article] [PubMed] [Google Scholar]
106.Ma L, Ni Y, Hu L, Zhao Y, Zheng L, Yang S, Ni L, Fu Z. Spermidine ameliorates high-fat diet-induced hepatic steatosis and adipose tissue inflammation in preexisting obese mice. Life Sci. 2021;265:118739. doi: 10.1016/j.lfs.2020.118739. [DOI] [PubMed] [Google Scholar]
107.Ma Y, Zhong Y, Tang W, Valencak TG, Liu J, Deng Z, Mao J, Liu D, Wang S, Wang Y, et al. Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine. Nat Commun. 2025;16(1):877. doi: 10.1038/s41467-025-56105-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
108.Zhou J, Pang J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Cook SA, Suzuki A, Diehl AM, Petretto E, et al. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. Nat Commun. 2022;13(1):5202. doi: 10.1038/s41467-022-32788-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
109.Gao M, Zhao W, Li C, Xie X, Li M, Bi Y, Fang F, Du Y, Liu X. Spermidine ameliorates non-alcoholic fatty liver disease through regulating lipid metabolism via AMPK. Biochem Biophys Res Commun. 2018;505(1):93–98. doi: 10.1016/j.bbrc.2018.09.078. [DOI] [PubMed] [Google Scholar]
110.Ni Y, Hu Y, Lou X, Rong N, Liu F, Yang C, Zheng A, Yang S, Bao J, Fu Z. Spermidine ameliorates nonalcoholic steatohepatitis through thyroid hormone-responsive protein signaling and the gut microbiota-mediated metabolism of bile acids. J Agric Food Chem. 2022;70(21):6478–6492. doi: 10.1021/acs.jafc.2c02729. [DOI] [PubMed] [Google Scholar]
111.Adhikari R, Shah R, Reyes-Gordillo K, Arellanes-Robledo J, Cheng Y, Ibrahim J, Tuma PL. Spermidine prevents ethanol and lipopolysaccharide-induced hepatic injury in mice. Molecules. 2021;26(6):1786. doi: 10.3390/molecules26061786. [DOI] [PMC free article] [PubMed] [Google Scholar]
112.Ando T, Ito D, Shiogama K, Sakai Y, Abe M, Ideta T, Kanbe A, Shimizu M, Ito H. Administration of spermidine attenuates concanavalin A-induced liver injury. Biochem Biophys Res Commun. 2023;648:44–49. doi: 10.1016/j.bbrc.2023.01.072. [DOI] [PubMed] [Google Scholar]
113.Liu P, de la Vega MR, Dodson M, Yue F, Shi B, Fang D, Chapman E, Liu L, Zhang DD. Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated noncanonical mechanism. Hepatology. 2019;70(1):372–388. doi: 10.1002/hep.30616. [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Shi B, Wang W, Ye M, Liang M, Yu Z, Zhang Y, Liu Z, Liang X, Ao J, Xu F, et al. Spermidine suppresses the activation of hepatic stellate cells to cure liver fibrosis through autophagy activator MAP1S. Liver Int. 2023;43(6):1307–1319. doi: 10.1111/liv.15558. [DOI] [PubMed] [Google Scholar]
115.Yue F, Li W, Zou J, Jiang X, Xu G, Huang H, Liu L. Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 2017;77(11):2938–2951. doi: 10.1158/0008-5472.Can-16-3462. [DOI] [PMC free article] [PubMed] [Google Scholar]
116.Zhou S, Gu J, Liu R, Wei S, Wang Q, Shen H, Dai Y, Zhou H, Zhang F, Lu L. Spermine alleviates acute liver injury by inhibiting liver-resident macrophage pro-inflammatory response through ATG5-dependent autophagy. Front Immunol. 2018;9:948. doi: 10.3389/fimmu.2018.00948. [DOI] [PMC free article] [PubMed] [Google Scholar]
117.Knudsen C, Neyrinck AM, Leyrolle Q, Baldin P, Leclercq S, Rodriguez J, Beaumont M, Cani PD, Bindels LB, Lanthier N, et al. Hepatoprotective effects of Indole, a gut microbial metabolite, in leptin-deficient obese mice. J Nutr. 2021;151(6):1507–1516. doi: 10.1093/jn/nxab032. [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Beaumont M, Neyrinck AM, Olivares M, Rodriguez J, de Rocca Serra A, Roumain M, Bindels LB, Cani PD, Evenepoel P, Muccioli GG, et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. Faseb j. 2018;32(12):6681–6693. doi: 10.1096/fj.201800544. [DOI] [PMC free article] [PubMed] [Google Scholar]
119.Gao Y, Chen Q, Yang S, Cao J, Li F, Li R, Wu Z, Wang Y, Yuan L. Indole alleviates nonalcoholic fatty liver disease in an ACE2-dependent manner. Faseb j. 2024;38(18):e70061. doi: 10.1096/fj.202401172RR. [DOI] [PubMed] [Google Scholar]
120.Huc T, Konop M, Onyszkiewicz M, Podsadni P, Szczepańska A, Turło J, Ufnal M. Colonic indole, gut bacteria metabolite of tryptophan, increases portal blood pressure in rats. Am J Physiol Regul Integr Comp Physiol. 2018;315(4):R646–R655. doi: 10.1152/ajpregu.00111.2018. [DOI] [PubMed] [Google Scholar]
121.Shang H, Huang C, Xiao Z, Yang P, Zhang S, Hou X, Zhang L. Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome. Cell Biosci. 2023;13(1):127. doi: 10.1186/s13578-023-01078-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
122.Wang M, Feng X, Zhao Y, Lan Y, Xu H. Indole-3-acetamide from gut microbiota activated hepatic AhR and mediated the remission effect of Lactiplantibacillus plantarum P101 on alcoholic liver injury in mice. Food Funct. 2023;14(23):10535–10548. doi: 10.1039/d3fo03585a. [DOI] [PubMed] [Google Scholar]
123.Ji Y, Gao Y, Chen H, Yin Y, Zhang W. Indole-3-acetic acid alleviates nonalcoholic fatty liver disease in mice via attenuation of hepatic lipogenesis, and oxidative and inflammatory stress. Nutrients. 2019;11(9):2062. doi: 10.3390/nu11092062. [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Ding Y, Yanagi K, Yang F, Callaway E, Cheng C, Hensel ME, Menon R, Alaniz RC, Lee K, Jayaraman A. Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice. eLife. 2024;12. doi: 10.7554/eLife.87458. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Zhou Z, Wang B, Pan X, Lv J, Lou Z, Han Y, Yao Y, Chen J, Wang Q, Li L. Microbial metabolites indole derivatives sensitize mice to D-GalN/LPS induced-acute liver failure via the Tlr2/NF-κB pathway. Front Microbiol. 2022;13:1103998. doi: 10.3389/fmicb.2022.1103998. [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Wang W, Li Q, Geng X, Zhou F, Wang Z, Wang Y, Tang X, Cheng X, Sun J, Qi C. Supplementing Limosilactobacillus reuteri FN041 alleviates hypercholesterolemia via promoting indole-3-carboxaldehyde production by gut microbiota in high-fat diet mice. Food Bioscience. 2025;68:106393. doi: 10.1016/j.fbio.2025.106393. [DOI] [Google Scholar]
127.Guo Z, Yang S, Qi L, Ma X, Wang Y, Li B, He J. Lactobacillus acidophilus KLDS1.0901 ameliorates non-alcoholic fatty liver disease by modulating the tryptophan metabolite indole-3-aldehyde and acting on its receptor AhR. Food Funct. 2025;16(12):4939–4957. doi: 10.1039/d4fo05280c. [DOI] [PubMed] [Google Scholar]
128.Zhang J, Zhang R, Chen Y, Guo X, Ren Y, Wang M, Li X, Huang Z, Zhu W, Yu K. Indole-3-aldehyde alleviates high-fat diet-induced gut barrier disruption by increasing intestinal stem cell expansion. J Agric Food Chem. 2024;72(34):18930–18941. doi: 10.1021/acs.jafc.4c02381. [DOI] [PubMed] [Google Scholar]
129.D'Onofrio F, Renga G, Puccetti M, Pariano M, Bellet MM, Santarelli I, Stincardini C, Mosci P, Ricci M, Giovagnoli S, et al. Indole-3-carboxaldehyde restores gut mucosal integrity and protects from liver fibrosis in murine sclerosing cholangitis. Cells. 2021;10(7):1622. doi: 10.3390/cells10071622. [DOI] [PMC free article] [PubMed] [Google Scholar]
130.Cheng WT, Pei SY, Wu J, Wang YJ, Yang YW, Xiao MF, Chen J, Wang YY, Wu L, Huang ZB. Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism. Acta Pharmacol Sin. 2025;46(6):1676–1691. doi: 10.1038/s41401-025-01495-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Pan H, Song D, Wang Z, Yang X, Luo P, Li W, Li Y, Gong M, Zhang C. Dietary modulation of gut microbiota affects susceptibility to drug-induced liver injury. Gut Microbes. 2024;16(1):2439534. doi: 10.1080/19490976.2024.2439534. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Konopelski P, Konop M, Gawrys-Kopczynska M, Podsadni P, Szczepanska A, Ufnal M. Indole-3-Propionic acid, a Tryptophan-derived bacterial metabolite, reduces weight gain in rats. Nutrients. 2019;11(3):591. doi: 10.3390/nu11030591. [DOI] [PMC free article] [PubMed] [Google Scholar]
133.Zhao ZH, Xin FZ, Xue Y, Hu Z, Han Y, Ma F, Zhou D, Liu XL, Cui A, Liu Z, et al. Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats. Exp Mol Med. 2019;51(9):1–14. doi: 10.1038/s12276-019-0304-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
134.Zhang X, Coker OO, Chu ES, Fu K, Lau HCH, Wang YX, Chan AWH, Wei H, Yang X, Sung JJY, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut. 2021;70(4):761–774. doi: 10.1136/gutjnl-2019-319664. [DOI] [PMC free article] [PubMed] [Google Scholar]
135.Liu F, Sun C, Chen Y, Du F, Yang Y, Wu G. Indole-3-propionic acid-aggravated CCl(4)-induced liver fibrosis via the TGF-β1/Smads Signaling Pathway. J Clin Transl Hepatol. 2021;9(6):917–930. doi: 10.14218/jcth.2021.00032. [DOI] [PMC free article] [PubMed] [Google Scholar]
136.Hong SA-O, Hong Y, Lee M, Keum BR, Kim GA-O. Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes. LID - 10.3390/nu15061490 [doi] LID - 1490. (2072-6643 (Electronic)). [DOI] [PMC free article] [PubMed]
137.Jiang Z, He L, Li D, Zhuo L, Chen L, Shi RQ, Luo J, Feng Y, Liang Y, Li D, et al. Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control. Nat Metab. 2025;7(4):808–822. doi: 10.1038/s42255-025-01246-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Wang P, Wang R, Zhao W, Zhao Y, Wang D, Zhao S, Ge Z, Ma Y, Zhao X. Gut microbiota-derived 4-hydroxyphenylacetic acid from resveratrol supplementation prevents obesity through SIRT1 signaling activation. Gut Microbes. 2025;17(1):2446391. doi: 10.1080/19490976.2024.2446391. [DOI] [PubMed] [Google Scholar]
139.Osborn LJ, Schultz K, Massey W, DeLucia B, Choucair I, Varadharajan V, Banerjee R, Fung K, Horak AJ, Orabi D, et al. A gut microbial metabolite of dietary polyphenols reverses obesity-driven hepatic steatosis. Proc Natl Acad Sci U S A. 2022;119(48):e2202934119. doi: 10.1073/pnas.2202934119. [DOI] [PMC free article] [PubMed] [Google Scholar]
140.Zhang T, Bao L, Zhao Q, Wu ZE, Dai M, Rao Q, Li F. Metabolomics reveals gut microbiota contribute to PPARα deficiency-induced alcoholic liver injury. J Proteome Res. 2023;22(7):2327–2338. doi: 10.1021/acs.jproteome.3c00093. [DOI] [PubMed] [Google Scholar]
141.Zhao H, Jiang Z, Chang X, Xue H, Yahefu W, Zhang X. 4-Hydroxyphenylacetic acid prevents acute APAP-induced liver injury by increasing phase II and antioxidant enzymes in mice. Front Pharmacol. 2018;9:653. doi: 10.3389/fphar.2018.00653. [DOI] [PMC free article] [PubMed] [Google Scholar]
142.Guo J, Wang P, Cui Y, Hu X, Chen F, Ma C. Protective effects of hydroxyphenyl propionic acids on lipid metabolism and gut microbiota in mice fed a high-fat diet. Nutrients. 2023;15(4):1043. doi: 10.3390/nu15041043. [DOI] [PMC free article] [PubMed] [Google Scholar]
143.Wu Y, Wang M, Yang T, Qin L, Hu Y, Zhao D, Wu L, Liu T. Cinnamic acid ameliorates nonalcoholic fatty liver disease by suppressing hepatic lipogenesis and promoting fatty acid oxidation. Evid Based Complement Alternat Med. 2021;2021:9561613. doi: 10.1155/2021/9561613. [DOI] [PMC free article] [PubMed] [Google Scholar]
144.Yan SL, Wang ZH, Yen HF, Lee YJ, Yin MC. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice. Food Chem Toxicol. 2016;98(Pt B):119–126. doi: 10.1016/j.fct.2016.10.025. [DOI] [PubMed] [Google Scholar]
145.Chaves LD, Abyad S, Honan AM, Bryniarski MA, McSkimming DI, Stahura CM, Wells SC, Ruszaj DM, Morris ME, Quigg RJ, et al. Unconjugated p-cresol activates macrophage macropinocytosis leading to increased LDL uptake. JCI Insight. 2021;6(11). doi: 10.1172/jci.insight.144410. [DOI] [PMC free article] [PubMed] [Google Scholar]
146.Cho S, Yang X, Won KJ, Leone VA, Chang EB, Guzman G, Ko Y, Bae ON, Lee H, Jeong H. Phenylpropionic acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity. Gut Microbes. 2023;15(1):2231590. doi: 10.1080/19490976.2023.2231590. [DOI] [PMC free article] [PubMed] [Google Scholar]
147.Choi BS, Daniel N, Houde VP, Ouellette A, Marcotte B, Varin TV, Vors C, Feutry P, Ilkayeva O, Ståhlman M, et al. Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice. Nat Commun. 2021;12(1):3377. doi: 10.1038/s41467-021-23782-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
148.Liu H, Du Y, Wang Z, Fang X, Sun H, Gao F, Shang T, Shi B. Isobutyrate exerts a protective effect against liver injury in a DSS-induced colitis by inhibiting inflammation and oxidative stress. J Sci Food Agric. 2025;105(4):2486–2496. doi: 10.1002/jsfa.14021. [DOI] [PubMed] [Google Scholar]
149.Wu Q, Zhu F, Yao Y, Chen L, Ding Y, Su Y, Ge C. Sini san regulates intestinal flora and short-chain fatty acids to ameliorate hepatocyte apoptosis and relieve CCl(4)-induced liver fibrosis in mice. Front Pharmacol. 2024;15:1408459. doi: 10.3389/fphar.2024.1408459. [DOI] [PMC free article] [PubMed] [Google Scholar]
150.Uchiyama J, Akiyama M, Hase K, Kumagai Y, Kim YG. Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species. Cell Rep. 2022;38(10):110479. doi: 10.1016/j.celrep.2022.110479. [DOI] [PubMed] [Google Scholar]
151.Wu D, Zheng N, Qi K, Cheng H, Sun Z, Gao B, Zhang Y, Pang W, Huangfu C, Ji S, et al. Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential. Med Gas Res. 2015;5(1):1. doi: 10.1186/s13618-014-0022-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
152.Sun L, Zhang S, Yu C, Pan Z, Liu Y, Zhao J, Wang X, Yun F, Zhao H, Yan S, et al. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab. 2015;309(11):E925–935. doi: 10.1152/ajpendo.00294.2015. [DOI] [PubMed] [Google Scholar]
153.Luo ZL, Tang LJ, Wang T, Dai RW, Ren JD, Cheng L, Xiang K, Tian FZ. Effects of treatment with hydrogen sulfide on methionine-choline deficient diet-induced non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol. 2014;29(1):215–222. doi: 10.1111/jgh.12389. [DOI] [PubMed] [Google Scholar]
154.Tan G, Pan S, Li J, Dong X, Kang K, Zhao M, Jiang X, Kanwar JR, Qiao H, Jiang H, et al. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats. PLoS One. 2011;6(10):e25943. doi: 10.1371/journal.pone.0025943. [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Ci L, Yang X, Gu X, Li Q, Guo Y, Zhou Z, Zhang M, Shi J, Yang H, Wang Z, et al. Cystathionine γ-Lyase deficiency exacerbates CCl(4)-induced acute hepatitis and fibrosis in the mouse liver. Antioxid Redox Signal. 2017;27(3):133–149. doi: 10.1089/ars.2016.6773. [DOI] [PubMed] [Google Scholar]
156.Zhao S, Song T, Gu Y, Zhang Y, Cao S, Miao Q, Zhang X, Chen H, Gao Y, Zhang L, et al. Hydrogen sulfide alleviates liver injury through the S-Sulfhydrated-Kelch-Like ECH-associated protein 1/nuclear erythroid 2-related factor 2/low-density lipoprotein receptor-related protein 1 pathway. Hepatology. 2021;73(1):282–302. doi: 10.1002/hep.31247. [DOI] [PubMed] [Google Scholar]
157.Damba T, Zhang M, Buist-Homan M, van Goor H, Faber KN, Moshage H. Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics. Nitric Oxide. 2019;92:26–33. doi: 10.1016/j.niox.2019.08.004. [DOI] [PubMed] [Google Scholar]
158.Wang D, Ma Y, Li Z, Kang K, Sun X, Pan S, Wang J, Pan H, Liu L, Liang D, et al. The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice. Autophagy. 2012;8(6):954–962. doi: 10.4161/auto.19927. [DOI] [PMC free article] [PubMed] [Google Scholar]
159.Huc T, Jurkowska H, Wróbel M, Jaworska K, Onyszkiewicz M, Ufnal M. Colonic hydrogen sulfide produces portal hypertension and systemic hypotension in rats. Exp Biol Med (Maywood). 2018;243(1):96–106. doi: 10.1177/1535370217741869. [DOI] [PMC free article] [PubMed] [Google Scholar]
160.Fiorucci S, Antonelli E, Mencarelli A, Orlandi S, Renga B, Rizzo G, Distrutti E, Shah V, Morelli A. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology. 2005;42(3):539–548. doi: 10.1002/hep.20817. [DOI] [PubMed] [Google Scholar]
161.Wu D, Li M, Tian W, Wang S, Cui L, Li H, Wang H, Ji A, Li Y. Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Sci Rep. 2017;7(1):5134. doi: 10.1038/s41598-017-05457-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
162.Zhen Y, Pan W, Hu F, Wu H, Feng J, Zhang Y, Chen J. Exogenous hydrogen sulfide exerts proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway in PLC/PRF/5 hepatoma cells. Int J Oncol. 2015;46(5):2194–2204. doi: 10.3892/ijo.2015.2914. [DOI] [PubMed] [Google Scholar]
163.Sen N, Paul BD, Gadalla MM, Mustafa AK, Sen T, Xu R, Kim S, Snyder SH. Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol Cell. 2012;45(1):13–24. doi: 10.1016/j.molcel.2011.10.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
164.Wang SS, Chen YH, Chen N, Wang LJ, Chen DX, Weng HL, Dooley S, Ding HG. Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway. Cell Death Dis. 2017;8(3):e2688–e2688. doi: 10.1038/cddis.2017.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
165.Lu S, Gao Y, Huang X, Wang X. GYY4137, a hydrogen sulfide (H₂S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway. Int J Oncol. 2014;44(4):1259–1267. doi: 10.3892/ijo.2014.2305. [DOI] [PubMed] [Google Scholar]
166.Bekebrede AF, Keijer J, Gerrits WJJ, Boer VCJ. The molecular and physiological effects of protein-derived polyamines in the intestine. Nutrients. 2020;12(1):197. doi: 10.3390/nu12010197. [DOI] [PMC free article] [PubMed] [Google Scholar]
167.Tofalo R, Cocchi S, Suzzi G. Polyamines and gut microbiota. Front Nutr. 2019;6:16. doi: 10.3389/fnut.2019.00016. [DOI] [PMC free article] [PubMed] [Google Scholar]
168.Schwarz M, Simbrunner B, Jachs M, Hartl L, Balcar L, Bauer DJM, Semmler G, Hofer BS, Scheiner B, Pinter M, et al. High histamine levels are associated with acute-on-chronic liver failure and liver-related death in patients with advanced chronic liver disease. Liver Int. 2024;44(11):2904–2914. doi: 10.1111/liv.16056. [DOI] [PubMed] [Google Scholar]
169.Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9(1):3294. doi: 10.1038/s41467-018-05470-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
170.Liu Y, Pei Z, Pan T, Wang H, Chen W, Lu W. Indole metabolites and colorectal cancer: Gut microbial tryptophan metabolism, host gut microbiome biomarkers, and potential intervention mechanisms. Microbiol Res. 2023;272:127392. doi: 10.1016/j.micres.2023.127392. [DOI] [PubMed] [Google Scholar]
171.De Filippis F, Pellegrini N, Vannini L, Jeffery IB, La Storia A, Laghi L, Serrazanetti DI, Di Cagno R, Ferrocino I, Lazzi C, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016;65(11):1812–1821. doi: 10.1136/gutjnl-2015-309957. [DOI] [PubMed] [Google Scholar]
172.Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu C, Ma J, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Sci. 2018;359(6380):1151–1156. doi: 10.1126/science.aao5774. [DOI] [PubMed] [Google Scholar]
173.Darkoh C, Chappell C, Gonzales C, Okhuysen P. A rapid and specific method for the detection of indole in complex biological samples. Appl Environ Microbiol. 2015;81(23):8093–8097. doi: 10.1128/aem.02787-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
174.Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22(6):598–605. doi: 10.1038/nm.4102. [DOI] [PMC free article] [PubMed] [Google Scholar]
175.Hubbard TD, Murray IA, Bisson WH, Lahoti TS, Gowda K, Amin SG, Patterson AD, Perdew GH. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci Rep. 2015;5:12689. doi: 10.1038/srep12689. [DOI] [PMC free article] [PubMed] [Google Scholar]
176.Dong F, Hao F, Murray IA, Smith PB, Koo I, Tindall AM, Kris-Etherton PM, Gowda K, Amin SG, Patterson AD, et al. Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity. Gut Microbes. 2020;12(1):1–24. doi: 10.1080/19490976.2020.1788899. [DOI] [PMC free article] [PubMed] [Google Scholar]
177.Hubbard TD, Murray IA, Perdew GH. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab Dispos. 2015;43(10):1522–1535. doi: 10.1124/dmd.115.064246. [DOI] [PMC free article] [PubMed] [Google Scholar]
178.Lamas B, Natividad JM, Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018;11(4):1024–1038. doi: 10.1038/s41385-018-0019-2. [DOI] [PubMed] [Google Scholar]
179.Carambia A, Schuran FA. The aryl hydrocarbon receptor in liver inflammation. Semin Immunopathol. 2021;43(4):563–575. doi: 10.1007/s00281-021-00867-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Yamazaki T, Kouno T, Hsu CL, Hartmann P, Mayo S, Zhang X, Stärkel P, Bosques-Padilla F, Verna EC, Abraldes JG, et al. Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis. Hepatology. 2024;80(2):403–417. doi: 10.1097/hep.0000000000000777. [DOI] [PMC free article] [PubMed] [Google Scholar]
181.Vuerich M, Harshe R, Frank LA, Mukherjee S, Gromova B, Csizmadia E, Nasser IAM, Ma Y, Bonder A, Patwardhan V, et al. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis. J Hepatol. 2021;74(1):48–57. doi: 10.1016/j.jhep.2020.06.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
182.Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC, Martin R, Michel ML, Chong-Nguyen C, Roussel R, Straube M, et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 2018;28(5):737–749. 10.1016/j.cmet.2018.07.001. [DOI] [PubMed] [Google Scholar]
183.Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, Qiu Z, Maher L, Redinbo MR, Phillips RS, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41(2):296–310. doi: 10.1016/j.immuni.2014.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
184.Sayaf K, Zanotto I, Russo FP, Gabbia D, De Martin S. The nuclear receptor PXR in chronic liver disease. Cells. 2021;11(1):61. doi: 10.3390/cells11010061. [DOI] [PMC free article] [PubMed] [Google Scholar]
185.Gao J, Xie W. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci. 2012;33(10):552–558. doi: 10.1016/j.tips.2012.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
186.Chimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 2014;9(4):1202–1208. doi: 10.1016/j.celrep.2014.10.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
187.Wang B, Zhou Z, Li L. Gut microbiota regulation of AHR signaling in liver disease. Biomolecules. 2022;12(9):1244. doi: 10.3390/biom12091244. [DOI] [PMC free article] [PubMed] [Google Scholar]
188.Gutiérrez-Díaz I, Fernández-Navarro T, Salazar N, Bartolomé B, Moreno-Arribas MV, López P, Suárez A, de Los Reyes-Gavilán CG, Gueimonde M, González S. Could fecal phenylacetic and phenylpropionic acids be used as indicators of health status? J Agric Food Chem. 2018;66(40):10438–10446. doi: 10.1021/acs.jafc.8b04102. [DOI] [PubMed] [Google Scholar]
189.Zhang L, Zi L, Kuang T, Wang K, Qiu Z, Wu Z, Liu L, Liu R, Wang P, Wang W. Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study. Front Endocrinol (Lausanne). 2023;14:1159148. doi: 10.3389/fendo.2023.1159148. [DOI] [PMC free article] [PubMed] [Google Scholar]
190.Manna SK, Patterson AD, Yang Q, Krausz KW, Idle JR, Fornace AJ, Gonzalez FJ. UPLC-MS-based urine metabolomics reveals indole-3-lactic acid and phenyllactic acid as conserved biomarkers for alcohol-induced liver disease in the Ppara-null mouse model. J Proteome Res. 2011;10(9):4120–4133. doi: 10.1021/pr200310s. [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilán CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185. doi: 10.3389/fmicb.2016.00185. [DOI] [PMC free article] [PubMed] [Google Scholar]
192.Macfarlane GT, Gibson GR, Beatty E, Cummings JH. Estimation of short-chain fatty acid production from protein by human intestinal bacteria based on branched-chain fatty acid measurements. FEMS Microbiol Ecol. 1992;10(2):81–88. doi: 10.1111/j.1574-6941.1992.tb00002.x. [DOI] [Google Scholar]
193.Lin X, Yu Z, Liu Y, Li C, Hu H, Hu JC, Liu M, Yang Q, Gu P, Li J, et al. Gut-X axis. Imeta. 2025;4(1):e270. doi: 10.1002/imt2.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
194.Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–293. doi: 10.1016/j.cell.2012.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
195.Sun J, Lu L, Lian Y, Xu S, Zhu Y, Wu Y, Lin Q, Hou J, Li Y, Yu Z. Sodium butyrate attenuates microglia-mediated neuroinflammation by modulating the TLR4/MyD88/NF-κB pathway and microbiome-gut-brain axis in cardiac arrest mice. Mol Brain. 2025;18(1):13. doi: 10.1186/s13041-025-01179-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
196.Zheng J, Ahmad AA, Yang C, Liang Z, Shen W, Liu J, Yan Z, Han J, Yang Y, Dong P, et al. Orally Administered Lactobacillus rhamnosus CY12 Alleviates DSS-Induced Colitis in Mice by Restoring the Intestinal Barrier and Inhibiting the TLR4-MyD88-NF-κB Pathway via Intestinal Microbiota Modulation. J Agric Food Chem. 2024. doi: 10.1021/acs.jafc.3c07279. [DOI] [PubMed] [Google Scholar]
197.Lu H, Xu X, Fu D, Gu Y, Fan R, Yi H, He X, Wang C, Ouyang B, Zhao P, et al. Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis. Cell Host Microbe. 2022;30(8):1139–1150. 10.1016/j.chom.2022.07.003. [DOI] [PubMed] [Google Scholar]
198.Hu S, Kuwabara R, de Haan BJ, Smink AM, de Vos P. Acetate and butyrate improve β-cell metabolism and mitochondrial respiration under oxidative stress. Int J Mol Sci. 2020;21(4):1542. doi: 10.3390/ijms21041542. [DOI] [PMC free article] [PubMed] [Google Scholar]
199.Blachier F, Andriamihaja M, Larraufie P, Ahn E, Lan A, Kim E. Production of hydrogen sulfide by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa. Am J Physiol Gastrointest Liver Physiol. 2021;320(2):G125–G135. doi: 10.1152/ajpgi.00261.2020. [DOI] [PubMed] [Google Scholar]
200.Blachier F, Davila AM, Mimoun S, Benetti PH, Atanasiu C, Andriamihaja M, Benamouzig R, Bouillaud F, Tomé D. Luminal sulfide and large intestine mucosa: friend or foe? Amino Acids. 2010;39(2):335–347. doi: 10.1007/s00726-009-0445-2. [DOI] [PubMed] [Google Scholar]
201.Zhen Y, Wu Q, Ding Y, Zhang W, Zhai Y, Lin X, Weng Y, Guo R, Zhang Y, Feng J, et al. Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway. Oncol Lett. 2018;15(5):6562–6570. doi: 10.3892/ol.2018.8154. [DOI] [PMC free article] [PubMed] [Google Scholar]
202.Zieve L, Doizaki WM, Zieve J. Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma. J Lab Clin Med. 1974;83(1):16–28. [PubMed] [Google Scholar]
203.Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9(4):311–326. doi: 10.1016/j.cmet.2009.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
204.Haufe S, Witt H, Engeli S, Kaminski J, Utz W, Fuhrmann JC, Rein D, Schulz-Menger J, Luft FC, Boschmann M, et al. Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects. Nutr Metab Cardiovasc Dis. 2016;26(7):637–642. doi: 10.1016/j.numecd.2016.03.013. [DOI] [PubMed] [Google Scholar]
205.Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17(4):448–453. doi: 10.1038/nm.2307. [DOI] [PMC free article] [PubMed] [Google Scholar]
206.Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, Milburn M. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism. 2011;60(3):404–413. doi: 10.1016/j.metabol.2010.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
207.Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids. 2015;47(3):603–615. doi: 10.1007/s00726-014-1894-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
208.Michitaka K, Hiraoka A, Kume M, Uehara T, Hidaka S, Ninomiya T, Hasebe A, Miyamoto Y, Ichiryu M, Tanihira T, et al. Amino acid imbalance in patients with chronic liver diseases. Hepatol Res. 2010;40(4):393–398. doi: 10.1111/j.1872-034X.2009.00614.x. [DOI] [PubMed] [Google Scholar]
209.Kawanaka M, Nishino K, Oka T, Urata N, Nakamura J, Suehiro M, Kawamoto H, Chiba Y, Yamada G. Tyrosine levels are associated with insulin resistance in patients with nonalcoholic fatty liver disease. Hepat Med. 2015;7:29–35. doi: 10.2147/hmer.S79100. [DOI] [PMC free article] [PubMed] [Google Scholar]
210.Zhang Y, Zhan L, Zhang L, Shi Q, Li L. Branched-chain amino acids in liver diseases: complexity and controversy. Nutrients. 2024;16(12):1875. doi: 10.3390/nu16121875. [DOI] [PMC free article] [PubMed] [Google Scholar]
211.Ishikawa T, Kubota T, Horigome R, Kimura N, Honda H, Iwanaga A, Seki K, Honma T, Yoshida T. Branched-chain amino acids to tyrosine ratio (BTR) predicts intrahepatic distant recurrence and survival for early hepatocellular carcinoma. Hepatogastroenterology. 2013;60(128):2055–2059. doi: 10.5754/hge13488. [DOI] [PubMed] [Google Scholar]
212.Tajiri K. Shimizu Y. Branched-chain amino acids in liver diseases. World J Gastroenterol. 2013;19(43):7620–7629. doi: 10.3748/wjg.v19.i43.7620. [DOI] [PMC free article] [PubMed] [Google Scholar]
213.Zhang Q, Takahashi M, Noguchi Y, Sugimoto T, Kimura T, Okumura A, Ishikawa T, Kakumu S. Plasma amino acid profiles applied for diagnosis of advanced liver fibrosis in patients with chronic hepatitis C infection. Hepatol Res. 2006;34(3):170–177. doi: 10.1016/j.hepres.2005.12.006. [DOI] [PubMed] [Google Scholar]
214.Xie G, Wang X, Wei R, Wang J, Zhao A, Chen T, Wang Y, Zhang H, Xiao Z, Liu X, et al. Serum metabolite profiles are associated with the presence of advanced liver fibrosis in Chinese patients with chronic hepatitis B viral infection. BMC Med. 2020;18(1):144. doi: 10.1186/s12916-020-01595-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
215.Xu C, Markova M, Seebeck N, Loft A, Hornemann S, Gantert T, Kabisch S, Herz K, Loske J, Ost M, et al. High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels. Liver Int. 2020;40(12):2982–2997. doi: 10.1111/liv.14596. [DOI] [PubMed] [Google Scholar]
216.Liu Z, Jin P, Liu Y, Zhang Z, Wu X, Weng M, Cao S, Wang Y, Zeng C, Yang R, et al. A comprehensive approach to lifestyle intervention based on a calorie-restricted diet ameliorates liver fat in overweight/obese patients with NAFLD: a multicenter randomized controlled trial in China. Nutr J. 2024;23(1):64. doi: 10.1186/s12937-024-00968-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
217.Tobón-Cornejo S, Sanchez-Tapia M, Guizar-Heredia R, Velázquez Villegas L, Noriega LG, Furuzawa-Carballeda J, Hernández-Pando R, Vázquez-Manjarrez N, Granados-Portillo O, López-Barradas A, et al. Increased dietary protein stimulates amino acid catabolism via the gut microbiota and secondary bile acid production. Gut Microbes. 2025;17(1):2465896. doi: 10.1080/19490976.2025.2465896. [DOI] [PMC free article] [PubMed] [Google Scholar]
218.Hill CM, Albarado DC, Coco LG, Spann RA, Khan MS, Qualls-Creekmore E, Burk DH, Burke SJ, Collier JJ, Yu S, et al. FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice. Nat Commun. 2022;13(1):1897. doi: 10.1038/s41467-022-29499-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
219.Green CL, Lamming DW, Fontana L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2022;23(1):56–73. doi: 10.1038/s41580-021-00411-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
220.Zhang X, Sergin I, Evans TD, Jeong SJ, Rodriguez-Velez A, Kapoor D, Chen S, Song E, Holloway KB, Crowley JR, et al. High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy. Nat Metab. 2020;2(1):110–125. doi: 10.1038/s42255-019-0162-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
221.Dai Z, Zheng W, Locasale JW. Amino acid variability, tradeoffs and optimality in human diet. Nat Commun. 2022;13(1):6683. doi: 10.1038/s41467-022-34486-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
222.Richardson NE, Konon EN, Schuster HS, Mitchell AT, Boyle C, Rodgers AC, Finke M, Haider LR, Yu D, Flores V, et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice. Nat Aging. 2021;1(1):73–86. doi: 10.1038/s43587-020-00006-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
223.Green CL, Trautman ME, Chaiyakul K, Jain R, Alam YH, Babygirija R, Pak HH, Sonsalla MM, Calubag MF, Yeh CY, et al. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Cell Metab. 2023;35(11):1976–1995. 10.1016/j.cmet.2023.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
224.Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, Jang C, Kasza I, Nikodemova M, Wakai MH, et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab. 2021;33(5):905–922. 10.1016/j.cmet.2021.03.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
225.Plauth M, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, Bischoff SC. ESPEN guideline on clinical nutrition in liver disease. Clin Nutr. 2019;38(2):485–521. doi: 10.1016/j.clnu.2018.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
226.Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases . J Hepatol. 2014;61(3):642–659. doi: 10.1016/j.jhep.2014.05.042. [DOI] [PubMed] [Google Scholar]
227.Lee H, Yoo JJ, Ahn SH, Kim BK. New evidence of oral branched-chain amino acid supplementation on the prognosis of patients with advanced liver disease. Clin Transl Gastroenterol. 2022;13(12):e00542. doi: 10.14309/ctg.0000000000000542. [DOI] [PMC free article] [PubMed] [Google Scholar]
228.Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;5(5):Cd001939. doi: 10.1002/14651858.CD001939.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
229.Olsen T, Øvrebø B, Haj-Yasein N, Lee S, Svendsen K, Hjorth M, Bastani NE, Norheim F, Drevon CA, Refsum H, et al. Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study. J Transl Med. 2020;18(1):122. doi: 10.1186/s12967-020-02288-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
230.Zhou L, Lu G, Nie Y, Ren Y, Shi JS, Xue Y, Xu ZH, Geng Y. Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut-liver axis. Gut Microbes. 2024;16(1):2370634. doi: 10.1080/19490976.2024.2370634. [DOI] [PMC free article] [PubMed] [Google Scholar]
231.Nichenametla SN, Mattocks DAL, Cooke D, Midya V, Malloy VL, Mansilla W, Øvrebø B, Turner C, Bastani NE, Sokolová J, et al. Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism. Aging cell. 2022;21(12):e13739. doi: 10.1111/acel.13739. [DOI] [PMC free article] [PubMed] [Google Scholar]
232.Varghese A, Gusarov I, Gamallo-Lana B, Dolgonos D, Mankan Y, Shamovsky I, Phan M, Jones R, Gomez-Jenkins M, White E, et al. Unravelling cysteine-deficiency-associated rapid weight loss. Natur. 2025;643:776–784. doi: 10.1038/s41586-025-08996-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
233.Lobel L, Cao YG, Fenn K, Glickman JN, Garrett WS. Diet posttranslationally modifies the mouse gut microbial proteome to modulate renal function. Sci. 2020;369(6510):1518–1524. doi: 10.1126/science.abb3763. [DOI] [PMC free article] [PubMed] [Google Scholar]
234.Kouno T, Zeng S, Wang Y, Duan Y, Lang S, Gao B, Hartmann P, Cabré N, Llorente C, Galbert C, et al. Engineered bacteria producing aryl-hydrocarbon receptor agonists protect against ethanol-induced liver disease in mice. Alcohol Clin Exp Res (Hoboken). 2023;47(5):856–867. doi: 10.1111/acer.15048. [DOI] [PMC free article] [PubMed] [Google Scholar]
235.Dimopoulou C, Guerra PR, Mortensen MS, Kristensen KA, Pedersen M, Bahl MI, Sommer MAO, Licht TR, Laursen MF. Potential of using an engineered indole lactic acid producing Escherichia coli Nissle 1917 in a murine model of colitis. Sci Rep. 2024;14(1):17542. doi: 10.1038/s41598-024-68412-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
236.Dimopoulou C, Bongers M, Pedersen M, Bahl MI, Sommer MOA, Laursen MF, Licht TR. An engineered Escherichia coli Nissle 1917 increase the production of indole lactic acid in the gut. FEMS Microbiol Lett. 2023;370. doi: 10.1093/femsle/fnad027. [DOI] [PubMed] [Google Scholar]
237.Kurtz CB, Millet YA, Puurunen MK, Perreault M, Charbonneau MR, Isabella VM, Kotula JW, Antipov E, Dagon Y, Denney WS, et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci Transl Med. 2019;11(475). doi: 10.1126/scitranslmed.aau7975. [DOI] [PubMed] [Google Scholar]

[cit0001] 1.Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med. 2016;22(10):1079–1089. doi: 10.1038/nm.4185. [DOI] [PubMed] [Google Scholar]

[cit0002] 2.Davila AM, Blachier F, Gotteland M, Andriamihaja M, Benetti PH, Sanz Y, Tomé D. Intestinal luminal nitrogen metabolism: role of the gut microbiota and consequences for the host. Pharmacol Res. 2013;68(1):95–107. doi: 10.1016/j.phrs.2012.11.005. [DOI] [PubMed] [Google Scholar]

[cit0003] 3.Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018;23(6):716–724. doi: 10.1016/j.chom.2018.05.003. [DOI] [PubMed] [Google Scholar]

[cit0004] 4.Liu Y, Hou Y, Wang G, Zheng X, Hao H. Gut microbial metabolites of aromatic amino acids as signals in host-microbe interplay. Trends Endocrinol Metab. 2020;31(11):818–834. doi: 10.1016/j.tem.2020.02.012. [DOI] [PubMed] [Google Scholar]

[cit0005] 5.Tuerhongjiang G, Guo M, Qiao X, Lou B, Wang C, Wu H, Wu Y, Yuan Z, She J. Interplay between gut microbiota and amino acid metabolism in heart failure. Front Cardiovasc Med. 2021;8:752241. doi: 10.3389/fcvm.2021.752241. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0006] 6.Wang W, Jiang S, Xu C, Tang L, Liang Y, Zhao Y, Zhu G. Interactions between gut microbiota and Parkinson's disease: the role of microbiota-derived amino acid metabolism. Front Aging Neurosci. 2022;14:976316. doi: 10.3389/fnagi.2022.976316. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0007] 7.Wu L, Tang Z, Chen H, Ren Z, Ding Q, Liang K, Sun Z. Mutual interaction between gut microbiota and protein/amino acid metabolism for host mucosal immunity and health. Anim Nutr. 2021;7(1):11–16. doi: 10.1016/j.aninu.2020.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0008] 8.Neis EP, Dejong CH, Rensen SS. The role of microbial amino acid metabolism in host metabolism. Nutrients. 2015;7(4):2930–2946. doi: 10.3390/nu7042930. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0009] 9.Li TT, Chen X, Huo D, Arifuzzaman M, Qiao S, Jin WB, Shi H, Li XV, Iliev ID, Artis D, et al. Microbiota metabolism of intestinal amino acids impacts host nutrient homeostasis and physiology. Cell Host Microbe. 2024;32(5):661–675. doi: 10.1016/j.chom.2024.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0010] 10.Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55–71. doi: 10.1038/s41579-020-0433-9. [DOI] [PubMed] [Google Scholar]

[cit0011] 11.Chen H, Nwe PK, Yang Y, Rosen CE, Bielecka AA, Kuchroo M, Cline GW, Kruse AC, Ring AM, Crawford JM, et al. A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology. Cell. 2019;177(5):1217–1231. 10.1016/j.cell.2019.03.036. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0012] 12.Pessione E, Pessione A, Lamberti C, Coïsson DJ, Riedel K, Mazzoli R, Bonetta S, Eberl L, Giunta C. First evidence of a membrane-bound, tyramine and beta-phenylethylamine producing, tyrosine decarboxylase in Enterococcus faecalis: a two-dimensional electrophoresis proteomic study. Proteomics. 2009;9(10):2695–2710. doi: 10.1002/pmic.200800780. [DOI] [PubMed] [Google Scholar]

[cit0013] 13.Sugiyama Y, Mori Y, Nara M, Kotani Y, Nagai E, Kawada H, Kitamura M, Hirano R, Shimokawa H, Nakagawa A, et al. Gut bacterial aromatic amine production: aromatic amino acid decarboxylase and its effects on peripheral serotonin production. Gut Microbes. 2022;14(1):2128605. doi: 10.1080/19490976.2022.2128605. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0014] 14.Williams BB, Van Benschoten AH, Cimermancic P, Donia MS, Zimmermann M, Taketani M, Ishihara A, Kashyap PC, Fraser JS, Fischbach MA. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell Host Microbe. 2014;16(4):495–503. doi: 10.1016/j.chom.2014.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0015] 15.Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE, Flint HJ. Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res. 2013;57(3):523–535. doi: 10.1002/mnfr.201200594. [DOI] [PubMed] [Google Scholar]

[cit0016] 16.Elsden SR, Hilton MG, Waller JM. The end products of the metabolism of aromatic amino acids by Clostridia. Arch Microbiol. 1976;107(3):283–288. doi: 10.1007/bf00425340. [DOI] [PubMed] [Google Scholar]

[cit0017] 17.Shelton CD, Sing E, Mo J, Shealy NG, Yoo W, Thomas J, Fitz GN, Castro PR, Hickman TT, Torres TP, et al. An early-life microbiota metabolite protects against obesity by regulating intestinal lipid metabolism. Cell Host Microbe. 2023;31(10):1604–1619. 10.1016/j.chom.2023.09.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0018] 18.Wlodarska M, Luo C, Kolde R, d'Hennezel E, Annand JW, Heim CE, Krastel P, Schmitt EK, Omar AS, Creasey EA, et al. Indoleacrylic acid produced by commensal peptostreptococcus species suppresses inflammation. Cell Host Microbe. 2017;22(1):25–37. doi: 10.1016/j.chom.2017.06.007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0019] 19.Tang J, Li Y, Zhang L, Mu J, Jiang Y, Fu H, Zhang Y, Cui H, Yu X, Ye Z. Biosynthetic Pathways and Functions of Indole-3-Acetic Acid in Microorganisms. Microorganisms. 2023;11(8):2077. doi: 10.3390/microorganisms11082077. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0020] 20.Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, Bartolomaeus H, Haase S, Mähler A, Balogh A, Markó L, et al. Salt-responsive gut commensal modulates T(H)17 axis and disease. Natur. 2017;551(7682):585–589. doi: 10.1038/nature24628. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0021] 21.Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G, Pieraccini G, Zecchi R, D'Angelo C, Massi-Benedetti C, Fallarino F, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39(2):372–385. doi: 10.1016/j.immuni.2013.08.003. [DOI] [PubMed] [Google Scholar]

[cit0022] 22.Honeyfield DC, Carlson JR. Effect of indoleacetic acid and related indoles on lactobacillus sp. strain 11201 growth, indoleacetic acid catabolism, and 3-methylindole formation. Appl Environ Microbiol. 1990;56(5):1373–1377. doi: 10.1128/aem.56.5.1373-1377.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0023] 23.Whitehead TR, Price NP, Drake HL, Cotta MA. Catabolic pathway for the production of skatole and indoleacetic acid by the acetogen Clostridium drakei, Clostridium scatologenes, and swine manure. Appl Environ Microbiol. 2008;74(6):1950–1953. doi: 10.1128/aem.02458-07. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0024] 24.Lee JH, Wood TK, Lee J. Roles of indole as an interspecies and interkingdom signaling molecule. Trends Microbiol. 2015;23(11):707–718. doi: 10.1016/j.tim.2015.08.001. [DOI] [PubMed] [Google Scholar]

[cit0025] 25.Lee JH, Lee J. Indole as an intercellular signal in microbial communities. FEMS Microbiol Rev. 2010;34(4):426–444. doi: 10.1111/j.1574-6976.2009.00204.x. [DOI] [PubMed] [Google Scholar]

[cit0026] 26.Sr Fau E, Hilton MG, Hilton MG. Volatile acid production from threonine, valine, leucine and isoleucine by clostridia. (0:302–8933. (Print)). [DOI] [PubMed]

[cit0027] 27.Wang HA-O, Feng L, Pei ZA-O, Zhao J, Lu S, Lu W. Gut microbiota metabolism of branched-chain amino acids and their metabolites can improve the physiological function of aging mice(1474- 9726 Electronic)). [DOI] [PMC free article] [PubMed]

[cit0028] 28.Qiao S, Liu C, Sun L, Wang T, Dai H, Wang K, Bao L, Li H, Wang W, Liu SJ, et al. Gut Parabacteroides merdae protects against cardiovascular damage by enhancing branched-chain amino acid catabolism. Nat Metab. 2022;4(10):1271–1286. doi: 10.1038/s42255-022-00649-y. [DOI] [PubMed] [Google Scholar]

[cit0029] 29.Guo CJ, Allen BM, Hiam KJ, Dodd D, Van Treuren W, Higginbottom S, Nagashima K, Fischer CR, Sonnenburg JL, Spitzer MH, et al. Depletion of microbiome-derived molecules in the host using Clostridium genetics. Sci. 2019;366(6471). doi: 10.1126/science.aav1282. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0030] 30.Awano N, Wada M, Mori H, Nakamori S, Takagi H. Identification and functional analysis of Escherichia coli cysteine desulfhydrases. Appl Environ Microbiol. 2005;71(7):4149–4152. doi: 10.1128/aem.71.7.4149-4152.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0031] 31.Yoshida Y, Ito S, Kamo M, Kezuka Y, Tamura H, Kunimatsu K, Kato H. Production of hydrogen sulfide by two enzymes associated with biosynthesis of homocysteine and lanthionine in Fusobacterium nucleatum subsp. nucleatum ATCC 25586. Microbiology. 2010;156(Pt 7):2260–2269. doi: 10.1099/mic.0.039180-0. [DOI] [PubMed] [Google Scholar]

[cit0032] 32.Takahashi Y, Yoshida A, Nagata E, Hoshino T, Oho T, Awano S, Takehara T, Ansai T. Streptococcus anginosus l-cysteine desulfhydrase gene expression is associated with abscess formation in BALB/c mice. Mol Oral Microbiol. 2011;26(3):221–227. doi: 10.1111/j.2041-1014.2010.00599.x. [DOI] [PubMed] [Google Scholar]

[cit0033] 33.Yano T, Fukamachi H, Yamamoto M, Igarashi T. Characterization of L-cysteine desulfhydrase from Prevotella intermedia. Oral Microbiol Immunol. 2009;24(6):485–492. doi: 10.1111/j.1399-302X.2009.00546.x. [DOI] [PubMed] [Google Scholar]

[cit0034] 34.Shatalin K, Shatalina E, Mironov A, Nudler E. H2S: a universal defense against antibiotics in bacteria. Sci. 2011;334(6058):986–990. doi: 10.1126/science.1209855. [DOI] [PubMed] [Google Scholar]

[cit0035] 35.Tanaka H Fau - Esaki N, Esaki N Fau - Soda K, Soda K. Properties of L-methionine gamma-lyase from Pseudomonas ovalis. (0006-2960 (Print)). [DOI] [PubMed]

[cit0036] 36.Lu CD. Pathways and regulation of bacterial arginine metabolism and perspectives for obtaining arginine overproducing strains. Appl Microbiol Biotechnol. 2006;70(3):261–272. doi: 10.1007/s00253-005-0308-z. [DOI] [PubMed] [Google Scholar]

[cit0037] 37.Nüse B, Holland T, Rauh M, Gerlach RG, Mattner J. L-arginine metabolism as pivotal interface of mutual host-microbe interactions in the gut. Gut Microbes. 2023;15(1):2222961. doi: 10.1080/19490976.2023.2222961. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0038] 38.Perez M, Calles-Enríquez M, Del Rio B, Redruello B, de Jong A, Kuipers OP, Kok J, Martin MC, Ladero V, Fernandez M, et al. Construction and characterization of a double mutant of Enterococcus faecalis that does not produce biogenic amines. Sci Rep. 2019;9(1):16881. doi: 10.1038/s41598-019-53175-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0039] 39.Shimokawa H, Sakanaka M, Fujisawa Y, Ohta H, Sugiyama Y, Kurihara S. N-Carbamoylputrescine amidohydrolase of bacteroides thetaiotaomicron, a dominant species of the human gut microbiota. Biomedicines. 2023;11(4):1123. doi: 10.3390/biomedicines11041123. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0040] 40.Sugiyama Y, Nakamura A, Matsumoto M, Kanbe A, Sakanaka M, Higashi K, Igarashi K, Katayama T, Suzuki H, Kurihara S. A novel putrescine exporter SapBCDF of Escherichia coli. J Biol Chem. 2016;291(51):26343–26351. doi: 10.1074/jbc.M116.762450. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0041] 41.Sakanaka M, Sugiyama Y, Kitakata A, Katayama T, Kurihara S. Carboxyspermidine decarboxylase of the prominent intestinal microbiota species Bacteroides thetaiotaomicron is required for spermidine biosynthesis and contributes to normal growth. Amino Acids. 2016;48(10):2443–2451. doi: 10.1007/s00726-016-2233-0. [DOI] [PubMed] [Google Scholar]

[cit0042] 42.Zhao Q, Huang JF, Cheng Y, Dai MY, Zhu WF, Yang XW, Gonzalez FJ, Li F. Polyamine metabolism links gut microbiota and testicular dysfunction. Microbiome. 2021;9(1):224. doi: 10.1186/s40168-021-01157-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0043] 43.Li B, Baniasadi HR, Liang J, Phillips MA, Michael AJ. New routes for spermine biosynthesis. J Biol Chem. 2025;301(4):108390. doi: 10.1016/j.jbc.2025.108390. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0044] 44.Gao C, Major A, Rendon D, Lugo M, Jackson V, Shi Z, Mori-Akiyama Y, Versalovic J. Histamine H2 receptor-mediated suppression of intestinal inflammation by probiotic lactobacillus reuteri. mBio. 2015;6(6):e01358–01315. doi: 10.1128/mBio.01358-15. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0045] 45.Thomas CM, Hong T, van Pijkeren JP, Hemarajata P, Trinh DV, Hu W, Britton RA, Kalkum M, Versalovic J. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 2012;7(2):e31951. doi: 10.1371/journal.pone.0031951. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0046] 46.Bender RA. Regulation of the histidine utilization (hut) system in bacteria. Microbiol Mol Biol Rev. 2012;76(3):565–584. doi: 10.1128/mmbr.00014-12. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0047] 47.Koh A, Molinaro A, Ståhlman M, Khan MT, Schmidt C, Mannerås-Holm L, Wu H, Carreras A, Jeong H, Olofsson LE, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. 2018;175(4):947–961. doi: 10.1016/j.cell.2018.09.055. [DOI] [PubMed] [Google Scholar]

[cit0048] 48.Mastrangelo A, Robles-Vera I, Mañanes D, Galán M, Femenía-Muiña M, Redondo-Urzainqui A, Barrero-Rodríguez R, Papaioannou E, Amores-Iniesta J, Devesa A, et al. Imidazole propionate is a driver and therapeutic target in atherosclerosis. Natur. 2025;645(8079):254–261. doi: 10.1038/s41586-025-09263-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0049] 49.Schneider J, Wendisch VF. Biotechnological production of polyamines by bacteria: recent achievements and future perspectives. Appl Microbiol Biotechnol. 2011;91(1):17–30. doi: 10.1007/s00253-011-3252-0. [DOI] [PubMed] [Google Scholar]

[cit0050] 50.Li Z, Huang Z, Gu P. Response of Escherichia coli to acid stress: mechanisms and applications-a narrative review. Microorganisms. 2024;12(9):1774. doi: 10.3390/microorganisms12091774. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0051] 51.Vital M, Howe AC, Tiedje JM. Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. mBio. 2014;5(2):e00889. doi: 10.1128/mBio.00889-14. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0052] 52.Li W, Ma L, Shen X, Wang J, Feng Q, Liu L, Zheng G, Yan Y, Sun X, Yuan Q. Targeting metabolic driving and intermediate influx in lysine catabolism for high-level glutarate production. Nat Commun. 2019;10(1):3337. doi: 10.1038/s41467-019-11289-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0053] 53.Bui TP, Ritari J, Boeren S, de Waard P, Plugge CM, de Vos WM. Production of butyrate from lysine and the Amadori product fructoselysine by a human gut commensal. Nat Commun. 2015;6:10062. doi: 10.1038/ncomms10062. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0054] 54.Smith EA, Macfarlane GT. Dissimilatory amino acid metabolism in human colonic bacteria. Anaerobe. 1997;3(5):327–337. doi: 10.1006/anae.1997.0121. [DOI] [PubMed] [Google Scholar]

[cit0055] 55.Bortolato M, Chen K, Shih JC. Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev. 2008;60(13-14):1527–1533. doi: 10.1016/j.addr.2008.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0056] 56.Dodd D, Spitzer MH, Van Treuren W, Merrill BD, Hryckowian AJ, Higginbottom SK, Le A, Cowan TM, Nolan GP, Fischbach MA, et al. A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites. Natur. 2017;551(7682):648–652. doi: 10.1038/nature24661. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0057] 57.Zhao M, Ren Z, Zhao A, Tang Y, Kuang J, Li M, Chen T, Wang S, Wang J, Zhang H, et al. Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity. Cell Metab. 2024;36(5):1000–1012. 10.1016/j.cmet.2024.03.010. [DOI] [PubMed] [Google Scholar]

[cit0058] 58.Gallego-Durán R, Hadjihambi A, Ampuero J, Rose CF, Jalan R, Romero-Gómez M. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2024;21(11):774–791. doi: 10.1038/s41575-024-00970-9. [DOI] [PubMed] [Google Scholar]

[cit0059] 59.He X, Hu M, Xu Y, Xia F, Tan Y, Wang Y, Xiang H, Wu H, Ji T, Xu Q, et al. The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis. Nat Med. 2025;31(2):627–638. doi: 10.1038/s41591-024-03405-9. [DOI] [PubMed] [Google Scholar]

[cit0060] 60.Wei J, Luo J, Yang F, Feng X, Zeng M, Dai W, Pan X, Yang Y, Li Y, Duan Y, et al. Cultivated Enterococcus faecium B6 from children with obesity promotes nonalcoholic fatty liver disease by the bioactive metabolite tyramine. Gut Microbes. 2024;16(1):2351620. doi: 10.1080/19490976.2024.2351620. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0061] 61.Schwenger KJP, Sharma D, Ghorbani Y, Xu W, Lou W, Comelli EM, Fischer SE, Jackson TD, Okrainec A, Allard JP. Links between gut microbiome, metabolome, clinical variables and non-alcoholic fatty liver disease severity in bariatric patients. Liver Int. 2024;44(5):1176–1188. doi: 10.1111/liv.15864. [DOI] [PubMed] [Google Scholar]

[cit0062] 62.Zhou K, Xie G, Wen J, Wang J, Pan W, Zhou Y, Xiao Y, Wang Y, Jia W, Cai W. Histamine is correlated with liver fibrosis in biliary atresia. Dig Liver Dis. 2016;48(8):921–926. doi: 10.1016/j.dld.2016.05.001. [DOI] [PubMed] [Google Scholar]

[cit0063] 63.Núñez-Sánchez M, Martínez-Sánchez MA, Sierra-Cruz M, Lambertos A, Rico-Chazarra S, Oliva-Bolarín A, Balaguer-Román A, Yuste JE, Martínez CM, Mika A, et al. Increased hepatic putrescine levels as a new potential factor related to the progression of metabolic dysfunction-associated steatotic liver disease. J Pathol. 2024;264(1):101–111. doi: 10.1002/path.6330. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0064] 64.Sun Y, Zhou P, Qian J, Zeng Q, Wei G, Li Y, Liu Y, Lai Y, Zhan Y, Wu D, et al. Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma. Cell Death Differ. 2025;32(3):573–586. doi: 10.1038/s41418-024-01409-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0065] 65.Ma L, Li H, Hu J, Zheng J, Zhou J, Botchlett R, Matthews D, Zeng T, Chen L, Xiao X, et al. Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3. Hepatology. 2020;72(4):1191–1203. doi: 10.1002/hep.31115. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0066] 66.Min BH, Devi S, Kwon GH, Gupta H, Jeong JJ, Sharma SP, Won SM, Oh KK, Yoon SJ, Park HJ, et al. Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation. Gut Microbes. 2024;16(1):2307568. doi: 10.1080/19490976.2024.2307568. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0067] 67.Hendrikx T, Duan Y, Wang Y, Oh JH, Alexander LM, Huang W, Stärkel P, Ho SB, Gao B, Fiehn O, et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut. 2019;68(8):1504–1515. doi: 10.1136/gutjnl-2018-317232. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0068] 68.Zhang L, Zhao J, Peng Z, Zhang Z, Huang S, Dong X, Gao J, Guo XA-O. Anti-adipogenesis effect of indole-3-acrylic acid on human preadipocytes and HFD-induced zebrafish. (1432-5233 (Electronic)). [DOI] [PubMed]

[cit0069] 69.Jennis M, Cavanaugh CR, Leo GC, Mabus JR, Lenhard J, Hornby PJ. Microbiota-derived tryptophan indoles increase after gastric bypass surgery and reduce intestinal permeability in vitro and in vivo. Neurogastroenterol Motil. 2018;30(2). doi: 10.1111/nmo.13178. [DOI] [PubMed] [Google Scholar]

[cit0070] 70.Ruebel ML, Piccolo BD, Mercer KE, Pack L, Moutos D, Shankar K, Andres A. Obesity leads to distinct metabolomic signatures in follicular fluid of women undergoing in vitro fertilization. Am J Physiol Endocrinol Metab. 2019;316(3):e383–e396. doi: 10.1152/ajpendo.00401.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0071] 71.Chen L, Yang Y, Sun S, Xie Y, Pan C, Li M, Li C, Liu Y, Xu Z, Liu W, et al. Indolepropionic acid reduces obesity-induced metabolic dysfunction through colonic barrier restoration mediated via tuft cell-derived IL-25. Febs j. 2022;289(19):5985–6004. doi: 10.1111/febs.16470. [DOI] [PubMed] [Google Scholar]

[cit0072] 72.Sehgal R, Ilha M, Vaittinen M, Kaminska D, Männistö V, Kärjä V, Tuomainen M, Hanhineva K, Romeo S, Pajukanta P, et al. Indole-3-propionic acid, a gut-derived tryptophan metabolite, associates with hepatic fibrosis. Nutrients. 2021;13(10):3509. doi: 10.3390/nu13103509. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0073] 73.Caussy C, Hsu C, Lo MT, Liu A, Bettencourt R, Ajmera VH, Bassirian S, Hooker J, Sy E, Richards L, et al. Link between gut-microbiome derived metabolite and shared gene-effects with hepatic steatosis and fibrosis in NAFLD. Hepatology. 2018;68(3):918–932. doi: 10.1002/hep.29892. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0074] 74.Hoyles L, Fernández-Real JM, Federici M, Serino M, Abbott J, Charpentier J, Heymes C, Luque JL, Anthony E, Barton RH, et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat Med. 2018;24(7):1070–1080. doi: 10.1038/s41591-018-0061-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0075] 75.Liu J, Geng W, Sun H, Liu C, Huang F, Cao J, Xia L, Zhao H, Zhai J, Li Q, et al. Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma. Gut. 2022;71(6):1203–1213. doi: 10.1136/gutjnl-2021-325189. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0076] 76.Tiihonen K, Ouwehand AC, Rautonen N. Effect of overweight on gastrointestinal microbiology and immunology: correlation with blood biomarkers. Br J Nutr. 2010;103(7):1070–1078. doi: 10.1017/s0007114509992807. [DOI] [PubMed] [Google Scholar]

[cit0077] 77.Tsai HJ, Hung WC, Hung WW, Lee YJ, Chen YC, Lee CY, Tsai YC, Dai CY. Circulating short-chain fatty acids and non-alcoholic fatty liver disease severity in patients with type 2 diabetes Mellitus. Nutrients. 2023;15(7):1712. doi: 10.3390/nu15071712. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0078] 78.Thing M, Werge MP, Kimer N, Hetland LE, Rashu EB, Nabilou P, Junker AE, Galsgaard ED, Bendtsen F, Laupsa-Borge J, et al. Targeted metabolomics reveals plasma short-chain fatty acids are associated with metabolic dysfunction-associated steatotic liver disease. BMC Gastroenterol. 2024;24(1):43. doi: 10.1186/s12876-024-03129-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0079] 79.Aragonès G, Colom-Pellicer M, Aguilar C, Guiu-Jurado E, Martínez S, Sabench F, Antonio Porras J, Riesco D, Del Castillo D, Richart C, et al. Circulating microbiota-derived metabolites: a “liquid biopsy? Int J Obes (Lond). 2020;44(4):875–885. doi: 10.1038/s41366-019-0430-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0080] 80.Granado-Serrano AB, Martín-Garí M, Sánchez V, Riart Solans M, Berdún R, Ludwig IA, Rubió L, Vilaprinyó E, Portero-Otín M, Serrano JCE. Faecal bacterial and short-chain fatty acids signature in hypercholesterolemia. Sci Rep. 2019;9(1):1772. doi: 10.1038/s41598-019-38874-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0081] 81.Da Silva HE, Teterina A, Comelli EM, Taibi A, Arendt BM, Fischer SE, Lou W, Allard JP. Nonalcoholic fatty liver disease is associated with dysbiosis independent of body mass index and insulin resistance. Sci Rep. 2018;8(1):1466. doi: 10.1038/s41598-018-19753-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0082] 82.Haag M, Winter S, Kemas AM, Tevini J, Feldman A, Eder SK, Felder TK, Datz C, Paulweber B, Liebisch G, et al. Circulating metabolite signatures indicate differential gut-liver crosstalk in lean and obese MASLD. JCI Insight. 2025;10(8). doi: 10.1172/jci.insight.180943. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0083] 83.McClain CJ, Zieve L, Doizaki WM, Gilberstadt S, Onstad GR. Blood methanethiol in alcoholic liver disease with and without hepatic encephalopathy. Gut. 1980;21(4):318–323. doi: 10.1136/gut.21.4.318. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0084] 84.Blom HJ, Ferenci P, Grimm G, Yap SH, Tangerman A. The role of methanethiol in the pathogenesis of hepatic encephalopathy. Hepatology. 1991;13(3):445–454. doi: 10.1002/hep.1840130311. [DOI] [PubMed] [Google Scholar]

[cit0085] 85.Zhai L, Xiao H, Lin C, Wong HLX, Lam YY, Gong M, Wu G, Ning Z, Huang C, Zhang Y, et al. Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome. Nat Commun. 2023;14(1):4986. doi: 10.1038/s41467-023-40552-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0086] 86.Lee J, Jang HR, Lee D, Lee Y, Lee HY. Gut bacteria-derived tryptamine ameliorates diet-induced obesity and insulin resistance in mice. Int J Mol Sci. 2025;26(3):1327. doi: 10.3390/ijms26031327. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0087] 87.Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH, Yarmush ML, Alaniz RC, Jayaraman A, Lee K. Gut microbiota-derived tryptophan metabolites modulate inflammatory response in hepatocytes and macrophages. Cell Rep. 2018;23(4):1099–1111. doi: 10.1016/j.celrep.2018.03.109. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0088] 88.Ma P, Zhang Y, Yin Y, Wang S, Chen S, Liang X, Li Z, Deng H. Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca(2+) signaling. Embo j. 2024;43(16):3466–3493. doi: 10.1038/s44318-024-00162-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0089] 89.Dixit MP, Sammeta SS, Dhokne MD, Mangrulkar S, Upadhya MA, Umekar MJ, Taksande BG, Kotagale NR. Chronic agmatine treatment prevents olanzapine-induced obesity and metabolic dysregulation in female rats. Brain Res Bull. 2022;191:69–77. doi: 10.1016/j.brainresbull.2022.10.013. [DOI] [PubMed] [Google Scholar]

[cit0090] 90.Wiśniewska AA-, Stachowicz AA-O, Kuś K, Ulatowska-Białas M, Totoń-Żurańska JA-OX, Kiepura AA-O, Stachyra K, Suski MA-O, Gajda M, Jawień JA-O, et al. Inhibition of atherosclerosis and liver steatosis by agmatine in western diet-fed apoE-knockout mice is associated with decrease in hepatic de novo lipogenesis and reduction in Plasma triglyceride/high-density lipoprotein cholesterol ratio. LID. 2021;22(19):10688. 10.3390/ijms221910688. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0091] 91.Ganjalikhan-Hakemi S, Asadi-Shekaari M, Pourjafari F, Asadikaram G, Nozari M. Agmatine improves liver function, balance performance, and neuronal damage in a hepatic encephalopathy induced by bile duct ligation. Brain Behav. 2023;13(9):e3124. doi: 10.1002/brb3.3124. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0092] 92.El-Agamy DS, Makled MN, Gamil NM. Protective effects of agmatine against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice. Inflammopharmacology. 2014;22(3):187–194. doi: 10.1007/s10787-013-0188-2. [DOI] [PubMed] [Google Scholar]

[cit0093] 93.Ommati MM, Farshad O, Mousavi K, Taghavi R, Farajvajari S, Azarpira N, Moezi L, Heidari R. Agmatine alleviates hepatic and renal injury in a rat model of obstructive jaundice. PharmaNutrition. 2020;13:100212. doi: 10.1016/j.phanu.2020.100212. [DOI] [Google Scholar]

[cit0094] 94.Han Z, Li Y, Yang B, Tan R, Wang M, Zhang B, Dai C, Wei L, Chen D, Chen Z. Agmatine Attenuates Liver Ischemia Reperfusion Injury by Activating Wnt/β-catenin Signaling in Mice (1534-6080 (Electronic)). [DOI] [PubMed]

[cit0095] 95.Ahmed N, Aljuhani N, Al-Hujaili HS, Al-Hujaili MA, Elkablawy MA, Noah MM, Abo-Haded H. Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-κB/inducible nitric oxide synthetase pathway. (1099-0461(Electronic)). [DOI] [PubMed]

[cit0096] 96.Gardini G, Cabella C, Cravanzola C, Vargiu C, Belliardo S, Testore G, Solinas SP, Toninello A, Grillo MA, Colombatto S. Agmatine induces apoptosis in rat hepatocyte cultures. J Hepatol. 2001;35(4):482–489. doi: 10.1016/s0168-8278(01)00153-2. [DOI] [PubMed] [Google Scholar]

[cit0097] 97.Yamada S, Guo X, Wang KY, Tanimoto A, Sasaguri Y. Novel function of histamine signaling via histamine receptors in cholesterol and bile acid metabolism: Histamine H2 receptor protects against nonalcoholic fatty liver disease. Pathol Int. 2016;66(7):376–385. doi: 10.1111/pin.12423. [DOI] [PubMed] [Google Scholar]

[cit0098] 98.Wang KY, Tanimoto A, Yamada S, Guo X, Ding Y, Watanabe T, Watanabe T, Kohno K, Hirano K, Tsukada H, et al. Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice. Am J Pathol. 2010;177(2):713–723. doi: 10.2353/ajpath.2010.091198. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0099] 99.Hornyak SC, Gehlsen KR, Haaparanta T. Histamine dihydrochloride protects against early alcohol-induced liver injury in a rat model. Inflammation. 2003;27(5):317–327. doi: 10.1023/a:1026032611643. [DOI] [PubMed] [Google Scholar]

[cit0100] 100.Tzirogiannis KN, Panoutsopoulos GI, Demonakou MD, Papadimas GK, Kondyli VG, Kourentzi KT, Hereti RI, Mykoniatis MG. The hepatoprotective effect of putrescine against cadmium-induced acute liver injury. Arch Toxicol. 2004;78(6):321–329. doi: 10.1007/s00204-004-0549-0. [DOI] [PubMed] [Google Scholar]

[cit0101] 101.Nagoshi S, Ohta Y, Matsui A, Fujiwara K. Protective action of putrescine against rat liver injury. Scand J Gastroenterol. 1994;29(2):166–171. doi: 10.3109/00365529409090457. [DOI] [PubMed] [Google Scholar]

[cit0102] 102.Nishiguchi S, Kuroki T, Takeda T, Nakajima S, Shiomi S, Seki S, Matsui-Yuasa I, Otani S, Kobayashi K. Effects of putrescine on D-galactosamine-induced acute liver failure in rats. Hepatology. 1990;12(2):348–353. doi: 10.1002/hep.1840120224. [DOI] [PubMed] [Google Scholar]

[cit0103] 103.Daikuhara Y, Tamada F, Takigawa M, Takeda Y, Mori Y. Changes in polyamine metabolism of rat liver after administration of D-galactosamine. Favorable effects of putrescine administration on galactosamine-induced hepatic injury. Gastroenterology. 1979;77(1):123–132. doi: 10.1016/S0016-5085(79)80022-0. [DOI] [PubMed] [Google Scholar]

[cit0104] 104.Wang D, Yin J, Zhou Z, Tao Y, Jia Y, Jie H, Zhao J, Li R, Li Y, Guo C, et al. Oral spermidine targets brown fat and skeletal muscle to mitigate diet-induced obesity and metabolic disorders. Mol Nutr Food Res. 2021;65(19):e2100315. doi: 10.1002/mnfr.202100315. [DOI] [PubMed] [Google Scholar]

[cit0105] 105.Ma L, Ni Y, Wang Z, Tu W, Ni L, Zhuge F, Zheng A, Hu L, Zhao Y, Zheng L, et al. Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes. 2020;12(1):1–19. doi: 10.1080/19490976.2020.1832857. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0106] 106.Ma L, Ni Y, Hu L, Zhao Y, Zheng L, Yang S, Ni L, Fu Z. Spermidine ameliorates high-fat diet-induced hepatic steatosis and adipose tissue inflammation in preexisting obese mice. Life Sci. 2021;265:118739. doi: 10.1016/j.lfs.2020.118739. [DOI] [PubMed] [Google Scholar]

[cit0107] 107.Ma Y, Zhong Y, Tang W, Valencak TG, Liu J, Deng Z, Mao J, Liu D, Wang S, Wang Y, et al. Lactobacillus reuteri ZJ617 attenuates metabolic syndrome via microbiota-derived spermidine. Nat Commun. 2025;16(1):877. doi: 10.1038/s41467-025-56105-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0108] 108.Zhou J, Pang J, Tripathi M, Ho JP, Widjaja AA, Shekeran SG, Cook SA, Suzuki A, Diehl AM, Petretto E, et al. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. Nat Commun. 2022;13(1):5202. doi: 10.1038/s41467-022-32788-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0109] 109.Gao M, Zhao W, Li C, Xie X, Li M, Bi Y, Fang F, Du Y, Liu X. Spermidine ameliorates non-alcoholic fatty liver disease through regulating lipid metabolism via AMPK. Biochem Biophys Res Commun. 2018;505(1):93–98. doi: 10.1016/j.bbrc.2018.09.078. [DOI] [PubMed] [Google Scholar]

[cit0110] 110.Ni Y, Hu Y, Lou X, Rong N, Liu F, Yang C, Zheng A, Yang S, Bao J, Fu Z. Spermidine ameliorates nonalcoholic steatohepatitis through thyroid hormone-responsive protein signaling and the gut microbiota-mediated metabolism of bile acids. J Agric Food Chem. 2022;70(21):6478–6492. doi: 10.1021/acs.jafc.2c02729. [DOI] [PubMed] [Google Scholar]

[cit0111] 111.Adhikari R, Shah R, Reyes-Gordillo K, Arellanes-Robledo J, Cheng Y, Ibrahim J, Tuma PL. Spermidine prevents ethanol and lipopolysaccharide-induced hepatic injury in mice. Molecules. 2021;26(6):1786. doi: 10.3390/molecules26061786. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0112] 112.Ando T, Ito D, Shiogama K, Sakai Y, Abe M, Ideta T, Kanbe A, Shimizu M, Ito H. Administration of spermidine attenuates concanavalin A-induced liver injury. Biochem Biophys Res Commun. 2023;648:44–49. doi: 10.1016/j.bbrc.2023.01.072. [DOI] [PubMed] [Google Scholar]

[cit0113] 113.Liu P, de la Vega MR, Dodson M, Yue F, Shi B, Fang D, Chapman E, Liu L, Zhang DD. Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated noncanonical mechanism. Hepatology. 2019;70(1):372–388. doi: 10.1002/hep.30616. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0114] 114.Shi B, Wang W, Ye M, Liang M, Yu Z, Zhang Y, Liu Z, Liang X, Ao J, Xu F, et al. Spermidine suppresses the activation of hepatic stellate cells to cure liver fibrosis through autophagy activator MAP1S. Liver Int. 2023;43(6):1307–1319. doi: 10.1111/liv.15558. [DOI] [PubMed] [Google Scholar]

[cit0115] 115.Yue F, Li W, Zou J, Jiang X, Xu G, Huang H, Liu L. Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 2017;77(11):2938–2951. doi: 10.1158/0008-5472.Can-16-3462. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0116] 116.Zhou S, Gu J, Liu R, Wei S, Wang Q, Shen H, Dai Y, Zhou H, Zhang F, Lu L. Spermine alleviates acute liver injury by inhibiting liver-resident macrophage pro-inflammatory response through ATG5-dependent autophagy. Front Immunol. 2018;9:948. doi: 10.3389/fimmu.2018.00948. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0117] 117.Knudsen C, Neyrinck AM, Leyrolle Q, Baldin P, Leclercq S, Rodriguez J, Beaumont M, Cani PD, Bindels LB, Lanthier N, et al. Hepatoprotective effects of Indole, a gut microbial metabolite, in leptin-deficient obese mice. J Nutr. 2021;151(6):1507–1516. doi: 10.1093/jn/nxab032. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0118] 118.Beaumont M, Neyrinck AM, Olivares M, Rodriguez J, de Rocca Serra A, Roumain M, Bindels LB, Cani PD, Evenepoel P, Muccioli GG, et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. Faseb j. 2018;32(12):6681–6693. doi: 10.1096/fj.201800544. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0119] 119.Gao Y, Chen Q, Yang S, Cao J, Li F, Li R, Wu Z, Wang Y, Yuan L. Indole alleviates nonalcoholic fatty liver disease in an ACE2-dependent manner. Faseb j. 2024;38(18):e70061. doi: 10.1096/fj.202401172RR. [DOI] [PubMed] [Google Scholar]

[cit0120] 120.Huc T, Konop M, Onyszkiewicz M, Podsadni P, Szczepańska A, Turło J, Ufnal M. Colonic indole, gut bacteria metabolite of tryptophan, increases portal blood pressure in rats. Am J Physiol Regul Integr Comp Physiol. 2018;315(4):R646–R655. doi: 10.1152/ajpregu.00111.2018. [DOI] [PubMed] [Google Scholar]

[cit0121] 121.Shang H, Huang C, Xiao Z, Yang P, Zhang S, Hou X, Zhang L. Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome. Cell Biosci. 2023;13(1):127. doi: 10.1186/s13578-023-01078-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0122] 122.Wang M, Feng X, Zhao Y, Lan Y, Xu H. Indole-3-acetamide from gut microbiota activated hepatic AhR and mediated the remission effect of Lactiplantibacillus plantarum P101 on alcoholic liver injury in mice. Food Funct. 2023;14(23):10535–10548. doi: 10.1039/d3fo03585a. [DOI] [PubMed] [Google Scholar]

[cit0123] 123.Ji Y, Gao Y, Chen H, Yin Y, Zhang W. Indole-3-acetic acid alleviates nonalcoholic fatty liver disease in mice via attenuation of hepatic lipogenesis, and oxidative and inflammatory stress. Nutrients. 2019;11(9):2062. doi: 10.3390/nu11092062. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0124] 124.Ding Y, Yanagi K, Yang F, Callaway E, Cheng C, Hensel ME, Menon R, Alaniz RC, Lee K, Jayaraman A. Oral supplementation of gut microbial metabolite indole-3-acetate alleviates diet-induced steatosis and inflammation in mice. eLife. 2024;12. doi: 10.7554/eLife.87458. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0125] 125.Zhou Z, Wang B, Pan X, Lv J, Lou Z, Han Y, Yao Y, Chen J, Wang Q, Li L. Microbial metabolites indole derivatives sensitize mice to D-GalN/LPS induced-acute liver failure via the Tlr2/NF-κB pathway. Front Microbiol. 2022;13:1103998. doi: 10.3389/fmicb.2022.1103998. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0126] 126.Wang W, Li Q, Geng X, Zhou F, Wang Z, Wang Y, Tang X, Cheng X, Sun J, Qi C. Supplementing Limosilactobacillus reuteri FN041 alleviates hypercholesterolemia via promoting indole-3-carboxaldehyde production by gut microbiota in high-fat diet mice. Food Bioscience. 2025;68:106393. doi: 10.1016/j.fbio.2025.106393. [DOI] [Google Scholar]

[cit0127] 127.Guo Z, Yang S, Qi L, Ma X, Wang Y, Li B, He J. Lactobacillus acidophilus KLDS1.0901 ameliorates non-alcoholic fatty liver disease by modulating the tryptophan metabolite indole-3-aldehyde and acting on its receptor AhR. Food Funct. 2025;16(12):4939–4957. doi: 10.1039/d4fo05280c. [DOI] [PubMed] [Google Scholar]

[cit0128] 128.Zhang J, Zhang R, Chen Y, Guo X, Ren Y, Wang M, Li X, Huang Z, Zhu W, Yu K. Indole-3-aldehyde alleviates high-fat diet-induced gut barrier disruption by increasing intestinal stem cell expansion. J Agric Food Chem. 2024;72(34):18930–18941. doi: 10.1021/acs.jafc.4c02381. [DOI] [PubMed] [Google Scholar]

[cit0129] 129.D'Onofrio F, Renga G, Puccetti M, Pariano M, Bellet MM, Santarelli I, Stincardini C, Mosci P, Ricci M, Giovagnoli S, et al. Indole-3-carboxaldehyde restores gut mucosal integrity and protects from liver fibrosis in murine sclerosing cholangitis. Cells. 2021;10(7):1622. doi: 10.3390/cells10071622. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0130] 130.Cheng WT, Pei SY, Wu J, Wang YJ, Yang YW, Xiao MF, Chen J, Wang YY, Wu L, Huang ZB. Cannabinoid-2 receptor depletion promotes non-alcoholic fatty liver disease in mice via disturbing gut microbiota and tryptophan metabolism. Acta Pharmacol Sin. 2025;46(6):1676–1691. doi: 10.1038/s41401-025-01495-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0131] 131.Pan H, Song D, Wang Z, Yang X, Luo P, Li W, Li Y, Gong M, Zhang C. Dietary modulation of gut microbiota affects susceptibility to drug-induced liver injury. Gut Microbes. 2024;16(1):2439534. doi: 10.1080/19490976.2024.2439534. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0132] 132.Konopelski P, Konop M, Gawrys-Kopczynska M, Podsadni P, Szczepanska A, Ufnal M. Indole-3-Propionic acid, a Tryptophan-derived bacterial metabolite, reduces weight gain in rats. Nutrients. 2019;11(3):591. doi: 10.3390/nu11030591. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0133] 133.Zhao ZH, Xin FZ, Xue Y, Hu Z, Han Y, Ma F, Zhou D, Liu XL, Cui A, Liu Z, et al. Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats. Exp Mol Med. 2019;51(9):1–14. doi: 10.1038/s12276-019-0304-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0134] 134.Zhang X, Coker OO, Chu ES, Fu K, Lau HCH, Wang YX, Chan AWH, Wei H, Yang X, Sung JJY, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut. 2021;70(4):761–774. doi: 10.1136/gutjnl-2019-319664. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0135] 135.Liu F, Sun C, Chen Y, Du F, Yang Y, Wu G. Indole-3-propionic acid-aggravated CCl(4)-induced liver fibrosis via the TGF-β1/Smads Signaling Pathway. J Clin Transl Hepatol. 2021;9(6):917–930. doi: 10.14218/jcth.2021.00032. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0136] 136.Hong SA-O, Hong Y, Lee M, Keum BR, Kim GA-O. Natural Product Skatole Ameliorates Lipotoxicity-Induced Multiple Hepatic Damage under Hyperlipidemic Conditions in Hepatocytes. LID - 10.3390/nu15061490 [doi] LID - 1490. (2072-6643 (Electronic)). [DOI] [PMC free article] [PubMed]

[cit0137] 137.Jiang Z, He L, Li D, Zhuo L, Chen L, Shi RQ, Luo J, Feng Y, Liang Y, Li D, et al. Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control. Nat Metab. 2025;7(4):808–822. doi: 10.1038/s42255-025-01246-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0138] 138.Wang P, Wang R, Zhao W, Zhao Y, Wang D, Zhao S, Ge Z, Ma Y, Zhao X. Gut microbiota-derived 4-hydroxyphenylacetic acid from resveratrol supplementation prevents obesity through SIRT1 signaling activation. Gut Microbes. 2025;17(1):2446391. doi: 10.1080/19490976.2024.2446391. [DOI] [PubMed] [Google Scholar]

[cit0139] 139.Osborn LJ, Schultz K, Massey W, DeLucia B, Choucair I, Varadharajan V, Banerjee R, Fung K, Horak AJ, Orabi D, et al. A gut microbial metabolite of dietary polyphenols reverses obesity-driven hepatic steatosis. Proc Natl Acad Sci U S A. 2022;119(48):e2202934119. doi: 10.1073/pnas.2202934119. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0140] 140.Zhang T, Bao L, Zhao Q, Wu ZE, Dai M, Rao Q, Li F. Metabolomics reveals gut microbiota contribute to PPARα deficiency-induced alcoholic liver injury. J Proteome Res. 2023;22(7):2327–2338. doi: 10.1021/acs.jproteome.3c00093. [DOI] [PubMed] [Google Scholar]

[cit0141] 141.Zhao H, Jiang Z, Chang X, Xue H, Yahefu W, Zhang X. 4-Hydroxyphenylacetic acid prevents acute APAP-induced liver injury by increasing phase II and antioxidant enzymes in mice. Front Pharmacol. 2018;9:653. doi: 10.3389/fphar.2018.00653. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0142] 142.Guo J, Wang P, Cui Y, Hu X, Chen F, Ma C. Protective effects of hydroxyphenyl propionic acids on lipid metabolism and gut microbiota in mice fed a high-fat diet. Nutrients. 2023;15(4):1043. doi: 10.3390/nu15041043. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0143] 143.Wu Y, Wang M, Yang T, Qin L, Hu Y, Zhao D, Wu L, Liu T. Cinnamic acid ameliorates nonalcoholic fatty liver disease by suppressing hepatic lipogenesis and promoting fatty acid oxidation. Evid Based Complement Alternat Med. 2021;2021:9561613. doi: 10.1155/2021/9561613. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0144] 144.Yan SL, Wang ZH, Yen HF, Lee YJ, Yin MC. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice. Food Chem Toxicol. 2016;98(Pt B):119–126. doi: 10.1016/j.fct.2016.10.025. [DOI] [PubMed] [Google Scholar]

[cit0145] 145.Chaves LD, Abyad S, Honan AM, Bryniarski MA, McSkimming DI, Stahura CM, Wells SC, Ruszaj DM, Morris ME, Quigg RJ, et al. Unconjugated p-cresol activates macrophage macropinocytosis leading to increased LDL uptake. JCI Insight. 2021;6(11). doi: 10.1172/jci.insight.144410. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0146] 146.Cho S, Yang X, Won KJ, Leone VA, Chang EB, Guzman G, Ko Y, Bae ON, Lee H, Jeong H. Phenylpropionic acid produced by gut microbiota alleviates acetaminophen-induced hepatotoxicity. Gut Microbes. 2023;15(1):2231590. doi: 10.1080/19490976.2023.2231590. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0147] 147.Choi BS, Daniel N, Houde VP, Ouellette A, Marcotte B, Varin TV, Vors C, Feutry P, Ilkayeva O, Ståhlman M, et al. Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice. Nat Commun. 2021;12(1):3377. doi: 10.1038/s41467-021-23782-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0148] 148.Liu H, Du Y, Wang Z, Fang X, Sun H, Gao F, Shang T, Shi B. Isobutyrate exerts a protective effect against liver injury in a DSS-induced colitis by inhibiting inflammation and oxidative stress. J Sci Food Agric. 2025;105(4):2486–2496. doi: 10.1002/jsfa.14021. [DOI] [PubMed] [Google Scholar]

[cit0149] 149.Wu Q, Zhu F, Yao Y, Chen L, Ding Y, Su Y, Ge C. Sini san regulates intestinal flora and short-chain fatty acids to ameliorate hepatocyte apoptosis and relieve CCl(4)-induced liver fibrosis in mice. Front Pharmacol. 2024;15:1408459. doi: 10.3389/fphar.2024.1408459. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0150] 150.Uchiyama J, Akiyama M, Hase K, Kumagai Y, Kim YG. Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species. Cell Rep. 2022;38(10):110479. doi: 10.1016/j.celrep.2022.110479. [DOI] [PubMed] [Google Scholar]

[cit0151] 151.Wu D, Zheng N, Qi K, Cheng H, Sun Z, Gao B, Zhang Y, Pang W, Huangfu C, Ji S, et al. Exogenous hydrogen sulfide mitigates the fatty liver in obese mice through improving lipid metabolism and antioxidant potential. Med Gas Res. 2015;5(1):1. doi: 10.1186/s13618-014-0022-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0152] 152.Sun L, Zhang S, Yu C, Pan Z, Liu Y, Zhao J, Wang X, Yun F, Zhao H, Yan S, et al. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab. 2015;309(11):E925–935. doi: 10.1152/ajpendo.00294.2015. [DOI] [PubMed] [Google Scholar]

[cit0153] 153.Luo ZL, Tang LJ, Wang T, Dai RW, Ren JD, Cheng L, Xiang K, Tian FZ. Effects of treatment with hydrogen sulfide on methionine-choline deficient diet-induced non-alcoholic steatohepatitis in rats. J Gastroenterol Hepatol. 2014;29(1):215–222. doi: 10.1111/jgh.12389. [DOI] [PubMed] [Google Scholar]

[cit0154] 154.Tan G, Pan S, Li J, Dong X, Kang K, Zhao M, Jiang X, Kanwar JR, Qiao H, Jiang H, et al. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats. PLoS One. 2011;6(10):e25943. doi: 10.1371/journal.pone.0025943. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0155] 155.Ci L, Yang X, Gu X, Li Q, Guo Y, Zhou Z, Zhang M, Shi J, Yang H, Wang Z, et al. Cystathionine γ-Lyase deficiency exacerbates CCl(4)-induced acute hepatitis and fibrosis in the mouse liver. Antioxid Redox Signal. 2017;27(3):133–149. doi: 10.1089/ars.2016.6773. [DOI] [PubMed] [Google Scholar]

[cit0156] 156.Zhao S, Song T, Gu Y, Zhang Y, Cao S, Miao Q, Zhang X, Chen H, Gao Y, Zhang L, et al. Hydrogen sulfide alleviates liver injury through the S-Sulfhydrated-Kelch-Like ECH-associated protein 1/nuclear erythroid 2-related factor 2/low-density lipoprotein receptor-related protein 1 pathway. Hepatology. 2021;73(1):282–302. doi: 10.1002/hep.31247. [DOI] [PubMed] [Google Scholar]

[cit0157] 157.Damba T, Zhang M, Buist-Homan M, van Goor H, Faber KN, Moshage H. Hydrogen sulfide stimulates activation of hepatic stellate cells through increased cellular bio-energetics. Nitric Oxide. 2019;92:26–33. doi: 10.1016/j.niox.2019.08.004. [DOI] [PubMed] [Google Scholar]

[cit0158] 158.Wang D, Ma Y, Li Z, Kang K, Sun X, Pan S, Wang J, Pan H, Liu L, Liang D, et al. The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice. Autophagy. 2012;8(6):954–962. doi: 10.4161/auto.19927. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0159] 159.Huc T, Jurkowska H, Wróbel M, Jaworska K, Onyszkiewicz M, Ufnal M. Colonic hydrogen sulfide produces portal hypertension and systemic hypotension in rats. Exp Biol Med (Maywood). 2018;243(1):96–106. doi: 10.1177/1535370217741869. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0160] 160.Fiorucci S, Antonelli E, Mencarelli A, Orlandi S, Renga B, Rizzo G, Distrutti E, Shah V, Morelli A. The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. Hepatology. 2005;42(3):539–548. doi: 10.1002/hep.20817. [DOI] [PubMed] [Google Scholar]

[cit0161] 161.Wu D, Li M, Tian W, Wang S, Cui L, Li H, Wang H, Ji A, Li Y. Hydrogen sulfide acts as a double-edged sword in human hepatocellular carcinoma cells through EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Sci Rep. 2017;7(1):5134. doi: 10.1038/s41598-017-05457-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0162] 162.Zhen Y, Pan W, Hu F, Wu H, Feng J, Zhang Y, Chen J. Exogenous hydrogen sulfide exerts proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway in PLC/PRF/5 hepatoma cells. Int J Oncol. 2015;46(5):2194–2204. doi: 10.3892/ijo.2015.2914. [DOI] [PubMed] [Google Scholar]

[cit0163] 163.Sen N, Paul BD, Gadalla MM, Mustafa AK, Sen T, Xu R, Kim S, Snyder SH. Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol Cell. 2012;45(1):13–24. doi: 10.1016/j.molcel.2011.10.021. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0164] 164.Wang SS, Chen YH, Chen N, Wang LJ, Chen DX, Weng HL, Dooley S, Ding HG. Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway. Cell Death Dis. 2017;8(3):e2688–e2688. doi: 10.1038/cddis.2017.18. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0165] 165.Lu S, Gao Y, Huang X, Wang X. GYY4137, a hydrogen sulfide (H₂S) donor, shows potent anti-hepatocellular carcinoma activity through blocking the STAT3 pathway. Int J Oncol. 2014;44(4):1259–1267. doi: 10.3892/ijo.2014.2305. [DOI] [PubMed] [Google Scholar]

[cit0166] 166.Bekebrede AF, Keijer J, Gerrits WJJ, Boer VCJ. The molecular and physiological effects of protein-derived polyamines in the intestine. Nutrients. 2020;12(1):197. doi: 10.3390/nu12010197. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0167] 167.Tofalo R, Cocchi S, Suzzi G. Polyamines and gut microbiota. Front Nutr. 2019;6:16. doi: 10.3389/fnut.2019.00016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0168] 168.Schwarz M, Simbrunner B, Jachs M, Hartl L, Balcar L, Bauer DJM, Semmler G, Hofer BS, Scheiner B, Pinter M, et al. High histamine levels are associated with acute-on-chronic liver failure and liver-related death in patients with advanced chronic liver disease. Liver Int. 2024;44(11):2904–2914. doi: 10.1111/liv.16056. [DOI] [PubMed] [Google Scholar]

[cit0169] 169.Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9(1):3294. doi: 10.1038/s41467-018-05470-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0170] 170.Liu Y, Pei Z, Pan T, Wang H, Chen W, Lu W. Indole metabolites and colorectal cancer: Gut microbial tryptophan metabolism, host gut microbiome biomarkers, and potential intervention mechanisms. Microbiol Res. 2023;272:127392. doi: 10.1016/j.micres.2023.127392. [DOI] [PubMed] [Google Scholar]

[cit0171] 171.De Filippis F, Pellegrini N, Vannini L, Jeffery IB, La Storia A, Laghi L, Serrazanetti DI, Di Cagno R, Ferrocino I, Lazzi C, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016;65(11):1812–1821. doi: 10.1136/gutjnl-2015-309957. [DOI] [PubMed] [Google Scholar]

[cit0172] 172.Zhao L, Zhang F, Ding X, Wu G, Lam YY, Wang X, Fu H, Xue X, Lu C, Ma J, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Sci. 2018;359(6380):1151–1156. doi: 10.1126/science.aao5774. [DOI] [PubMed] [Google Scholar]

[cit0173] 173.Darkoh C, Chappell C, Gonzales C, Okhuysen P. A rapid and specific method for the detection of indole in complex biological samples. Appl Environ Microbiol. 2015;81(23):8093–8097. doi: 10.1128/aem.02787-15. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0174] 174.Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, Da Costa G, Bridonneau C, Jegou S, Hoffmann TW, Natividad JM, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22(6):598–605. doi: 10.1038/nm.4102. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0175] 175.Hubbard TD, Murray IA, Bisson WH, Lahoti TS, Gowda K, Amin SG, Patterson AD, Perdew GH. Adaptation of the human aryl hydrocarbon receptor to sense microbiota-derived indoles. Sci Rep. 2015;5:12689. doi: 10.1038/srep12689. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0176] 176.Dong F, Hao F, Murray IA, Smith PB, Koo I, Tindall AM, Kris-Etherton PM, Gowda K, Amin SG, Patterson AD, et al. Intestinal microbiota-derived tryptophan metabolites are predictive of Ah receptor activity. Gut Microbes. 2020;12(1):1–24. doi: 10.1080/19490976.2020.1788899. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0177] 177.Hubbard TD, Murray IA, Perdew GH. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab Dispos. 2015;43(10):1522–1535. doi: 10.1124/dmd.115.064246. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0178] 178.Lamas B, Natividad JM, Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018;11(4):1024–1038. doi: 10.1038/s41385-018-0019-2. [DOI] [PubMed] [Google Scholar]

[cit0179] 179.Carambia A, Schuran FA. The aryl hydrocarbon receptor in liver inflammation. Semin Immunopathol. 2021;43(4):563–575. doi: 10.1007/s00281-021-00867-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0180] 180.Yamazaki T, Kouno T, Hsu CL, Hartmann P, Mayo S, Zhang X, Stärkel P, Bosques-Padilla F, Verna EC, Abraldes JG, et al. Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis. Hepatology. 2024;80(2):403–417. doi: 10.1097/hep.0000000000000777. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0181] 181.Vuerich M, Harshe R, Frank LA, Mukherjee S, Gromova B, Csizmadia E, Nasser IAM, Ma Y, Bonder A, Patwardhan V, et al. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis. J Hepatol. 2021;74(1):48–57. doi: 10.1016/j.jhep.2020.06.044. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0182] 182.Natividad JM, Agus A, Planchais J, Lamas B, Jarry AC, Martin R, Michel ML, Chong-Nguyen C, Roussel R, Straube M, et al. Impaired aryl hydrocarbon receptor ligand production by the gut microbiota is a key factor in metabolic syndrome. Cell Metab. 2018;28(5):737–749. 10.1016/j.cmet.2018.07.001. [DOI] [PubMed] [Google Scholar]

[cit0183] 183.Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, Qiu Z, Maher L, Redinbo MR, Phillips RS, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity. 2014;41(2):296–310. doi: 10.1016/j.immuni.2014.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0184] 184.Sayaf K, Zanotto I, Russo FP, Gabbia D, De Martin S. The nuclear receptor PXR in chronic liver disease. Cells. 2021;11(1):61. doi: 10.3390/cells11010061. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0185] 185.Gao J, Xie W. Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends Pharmacol Sci. 2012;33(10):552–558. doi: 10.1016/j.tips.2012.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0186] 186.Chimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 2014;9(4):1202–1208. doi: 10.1016/j.celrep.2014.10.032. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0187] 187.Wang B, Zhou Z, Li L. Gut microbiota regulation of AHR signaling in liver disease. Biomolecules. 2022;12(9):1244. doi: 10.3390/biom12091244. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0188] 188.Gutiérrez-Díaz I, Fernández-Navarro T, Salazar N, Bartolomé B, Moreno-Arribas MV, López P, Suárez A, de Los Reyes-Gavilán CG, Gueimonde M, González S. Could fecal phenylacetic and phenylpropionic acids be used as indicators of health status? J Agric Food Chem. 2018;66(40):10438–10446. doi: 10.1021/acs.jafc.8b04102. [DOI] [PubMed] [Google Scholar]

[cit0189] 189.Zhang L, Zi L, Kuang T, Wang K, Qiu Z, Wu Z, Liu L, Liu R, Wang P, Wang W. Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study. Front Endocrinol (Lausanne). 2023;14:1159148. doi: 10.3389/fendo.2023.1159148. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0190] 190.Manna SK, Patterson AD, Yang Q, Krausz KW, Idle JR, Fornace AJ, Gonzalez FJ. UPLC-MS-based urine metabolomics reveals indole-3-lactic acid and phenyllactic acid as conserved biomarkers for alcohol-induced liver disease in the Ppara-null mouse model. J Proteome Res. 2011;10(9):4120–4133. doi: 10.1021/pr200310s. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0191] 191.Ríos-Covián D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilán CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol. 2016;7:185. doi: 10.3389/fmicb.2016.00185. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0192] 192.Macfarlane GT, Gibson GR, Beatty E, Cummings JH. Estimation of short-chain fatty acid production from protein by human intestinal bacteria based on branched-chain fatty acid measurements. FEMS Microbiol Ecol. 1992;10(2):81–88. doi: 10.1111/j.1574-6941.1992.tb00002.x. [DOI] [Google Scholar]

[cit0193] 193.Lin X, Yu Z, Liu Y, Li C, Hu H, Hu JC, Liu M, Yang Q, Gu P, Li J, et al. Gut-X axis. Imeta. 2025;4(1):e270. doi: 10.1002/imt2.270. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0194] 194.Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274–293. doi: 10.1016/j.cell.2012.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0195] 195.Sun J, Lu L, Lian Y, Xu S, Zhu Y, Wu Y, Lin Q, Hou J, Li Y, Yu Z. Sodium butyrate attenuates microglia-mediated neuroinflammation by modulating the TLR4/MyD88/NF-κB pathway and microbiome-gut-brain axis in cardiac arrest mice. Mol Brain. 2025;18(1):13. doi: 10.1186/s13041-025-01179-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0196] 196.Zheng J, Ahmad AA, Yang C, Liang Z, Shen W, Liu J, Yan Z, Han J, Yang Y, Dong P, et al. Orally Administered Lactobacillus rhamnosus CY12 Alleviates DSS-Induced Colitis in Mice by Restoring the Intestinal Barrier and Inhibiting the TLR4-MyD88-NF-κB Pathway via Intestinal Microbiota Modulation. J Agric Food Chem. 2024. doi: 10.1021/acs.jafc.3c07279. [DOI] [PubMed] [Google Scholar]

[cit0197] 197.Lu H, Xu X, Fu D, Gu Y, Fan R, Yi H, He X, Wang C, Ouyang B, Zhao P, et al. Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis. Cell Host Microbe. 2022;30(8):1139–1150. 10.1016/j.chom.2022.07.003. [DOI] [PubMed] [Google Scholar]

[cit0198] 198.Hu S, Kuwabara R, de Haan BJ, Smink AM, de Vos P. Acetate and butyrate improve β-cell metabolism and mitochondrial respiration under oxidative stress. Int J Mol Sci. 2020;21(4):1542. doi: 10.3390/ijms21041542. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0199] 199.Blachier F, Andriamihaja M, Larraufie P, Ahn E, Lan A, Kim E. Production of hydrogen sulfide by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa. Am J Physiol Gastrointest Liver Physiol. 2021;320(2):G125–G135. doi: 10.1152/ajpgi.00261.2020. [DOI] [PubMed] [Google Scholar]

[cit0200] 200.Blachier F, Davila AM, Mimoun S, Benetti PH, Atanasiu C, Andriamihaja M, Benamouzig R, Bouillaud F, Tomé D. Luminal sulfide and large intestine mucosa: friend or foe? Amino Acids. 2010;39(2):335–347. doi: 10.1007/s00726-009-0445-2. [DOI] [PubMed] [Google Scholar]

[cit0201] 201.Zhen Y, Wu Q, Ding Y, Zhang W, Zhai Y, Lin X, Weng Y, Guo R, Zhang Y, Feng J, et al. Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway. Oncol Lett. 2018;15(5):6562–6570. doi: 10.3892/ol.2018.8154. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0202] 202.Zieve L, Doizaki WM, Zieve J. Synergism between mercaptans and ammonia or fatty acids in the production of coma: a possible role for mercaptans in the pathogenesis of hepatic coma. J Lab Clin Med. 1974;83(1):16–28. [PubMed] [Google Scholar]

[cit0203] 203.Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9(4):311–326. doi: 10.1016/j.cmet.2009.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0204] 204.Haufe S, Witt H, Engeli S, Kaminski J, Utz W, Fuhrmann JC, Rein D, Schulz-Menger J, Luft FC, Boschmann M, et al. Branched-chain and aromatic amino acids, insulin resistance and liver specific ectopic fat storage in overweight to obese subjects. Nutr Metab Cardiovasc Dis. 2016;26(7):637–642. doi: 10.1016/j.numecd.2016.03.013. [DOI] [PubMed] [Google Scholar]

[cit0205] 205.Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17(4):448–453. doi: 10.1038/nm.2307. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0206] 206.Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, Milburn M. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism. 2011;60(3):404–413. doi: 10.1016/j.metabol.2010.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0207] 207.Lake AD, Novak P, Shipkova P, Aranibar N, Robertson DG, Reily MD, Lehman-McKeeman LD, Vaillancourt RR, Cherrington NJ. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids. 2015;47(3):603–615. doi: 10.1007/s00726-014-1894-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0208] 208.Michitaka K, Hiraoka A, Kume M, Uehara T, Hidaka S, Ninomiya T, Hasebe A, Miyamoto Y, Ichiryu M, Tanihira T, et al. Amino acid imbalance in patients with chronic liver diseases. Hepatol Res. 2010;40(4):393–398. doi: 10.1111/j.1872-034X.2009.00614.x. [DOI] [PubMed] [Google Scholar]

[cit0209] 209.Kawanaka M, Nishino K, Oka T, Urata N, Nakamura J, Suehiro M, Kawamoto H, Chiba Y, Yamada G. Tyrosine levels are associated with insulin resistance in patients with nonalcoholic fatty liver disease. Hepat Med. 2015;7:29–35. doi: 10.2147/hmer.S79100. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0210] 210.Zhang Y, Zhan L, Zhang L, Shi Q, Li L. Branched-chain amino acids in liver diseases: complexity and controversy. Nutrients. 2024;16(12):1875. doi: 10.3390/nu16121875. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0211] 211.Ishikawa T, Kubota T, Horigome R, Kimura N, Honda H, Iwanaga A, Seki K, Honma T, Yoshida T. Branched-chain amino acids to tyrosine ratio (BTR) predicts intrahepatic distant recurrence and survival for early hepatocellular carcinoma. Hepatogastroenterology. 2013;60(128):2055–2059. doi: 10.5754/hge13488. [DOI] [PubMed] [Google Scholar]

[cit0212] 212.Tajiri K. Shimizu Y. Branched-chain amino acids in liver diseases. World J Gastroenterol. 2013;19(43):7620–7629. doi: 10.3748/wjg.v19.i43.7620. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0213] 213.Zhang Q, Takahashi M, Noguchi Y, Sugimoto T, Kimura T, Okumura A, Ishikawa T, Kakumu S. Plasma amino acid profiles applied for diagnosis of advanced liver fibrosis in patients with chronic hepatitis C infection. Hepatol Res. 2006;34(3):170–177. doi: 10.1016/j.hepres.2005.12.006. [DOI] [PubMed] [Google Scholar]

[cit0214] 214.Xie G, Wang X, Wei R, Wang J, Zhao A, Chen T, Wang Y, Zhang H, Xiao Z, Liu X, et al. Serum metabolite profiles are associated with the presence of advanced liver fibrosis in Chinese patients with chronic hepatitis B viral infection. BMC Med. 2020;18(1):144. doi: 10.1186/s12916-020-01595-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0215] 215.Xu C, Markova M, Seebeck N, Loft A, Hornemann S, Gantert T, Kabisch S, Herz K, Loske J, Ost M, et al. High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels. Liver Int. 2020;40(12):2982–2997. doi: 10.1111/liv.14596. [DOI] [PubMed] [Google Scholar]

[cit0216] 216.Liu Z, Jin P, Liu Y, Zhang Z, Wu X, Weng M, Cao S, Wang Y, Zeng C, Yang R, et al. A comprehensive approach to lifestyle intervention based on a calorie-restricted diet ameliorates liver fat in overweight/obese patients with NAFLD: a multicenter randomized controlled trial in China. Nutr J. 2024;23(1):64. doi: 10.1186/s12937-024-00968-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0217] 217.Tobón-Cornejo S, Sanchez-Tapia M, Guizar-Heredia R, Velázquez Villegas L, Noriega LG, Furuzawa-Carballeda J, Hernández-Pando R, Vázquez-Manjarrez N, Granados-Portillo O, López-Barradas A, et al. Increased dietary protein stimulates amino acid catabolism via the gut microbiota and secondary bile acid production. Gut Microbes. 2025;17(1):2465896. doi: 10.1080/19490976.2025.2465896. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0218] 218.Hill CM, Albarado DC, Coco LG, Spann RA, Khan MS, Qualls-Creekmore E, Burk DH, Burke SJ, Collier JJ, Yu S, et al. FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice. Nat Commun. 2022;13(1):1897. doi: 10.1038/s41467-022-29499-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0219] 219.Green CL, Lamming DW, Fontana L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat Rev Mol Cell Biol. 2022;23(1):56–73. doi: 10.1038/s41580-021-00411-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0220] 220.Zhang X, Sergin I, Evans TD, Jeong SJ, Rodriguez-Velez A, Kapoor D, Chen S, Song E, Holloway KB, Crowley JR, et al. High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy. Nat Metab. 2020;2(1):110–125. doi: 10.1038/s42255-019-0162-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0221] 221.Dai Z, Zheng W, Locasale JW. Amino acid variability, tradeoffs and optimality in human diet. Nat Commun. 2022;13(1):6683. doi: 10.1038/s41467-022-34486-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0222] 222.Richardson NE, Konon EN, Schuster HS, Mitchell AT, Boyle C, Rodgers AC, Finke M, Haider LR, Yu D, Flores V, et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and lifespan in mice. Nat Aging. 2021;1(1):73–86. doi: 10.1038/s43587-020-00006-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0223] 223.Green CL, Trautman ME, Chaiyakul K, Jain R, Alam YH, Babygirija R, Pak HH, Sonsalla MM, Calubag MF, Yeh CY, et al. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Cell Metab. 2023;35(11):1976–1995. 10.1016/j.cmet.2023.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0224] 224.Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, Jang C, Kasza I, Nikodemova M, Wakai MH, et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab. 2021;33(5):905–922. 10.1016/j.cmet.2021.03.025. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0225] 225.Plauth M, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, Bischoff SC. ESPEN guideline on clinical nutrition in liver disease. Clin Nutr. 2019;38(2):485–521. doi: 10.1016/j.clnu.2018.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0226] 226.Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases . J Hepatol. 2014;61(3):642–659. doi: 10.1016/j.jhep.2014.05.042. [DOI] [PubMed] [Google Scholar]

[cit0227] 227.Lee H, Yoo JJ, Ahn SH, Kim BK. New evidence of oral branched-chain amino acid supplementation on the prognosis of patients with advanced liver disease. Clin Transl Gastroenterol. 2022;13(12):e00542. doi: 10.14309/ctg.0000000000000542. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0228] 228.Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;5(5):Cd001939. doi: 10.1002/14651858.CD001939.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0229] 229.Olsen T, Øvrebø B, Haj-Yasein N, Lee S, Svendsen K, Hjorth M, Bastani NE, Norheim F, Drevon CA, Refsum H, et al. Effects of dietary methionine and cysteine restriction on plasma biomarkers, serum fibroblast growth factor 21, and adipose tissue gene expression in women with overweight or obesity: a double-blind randomized controlled pilot study. J Transl Med. 2020;18(1):122. doi: 10.1186/s12967-020-02288-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0230] 230.Zhou L, Lu G, Nie Y, Ren Y, Shi JS, Xue Y, Xu ZH, Geng Y. Restricted intake of sulfur-containing amino acids reversed the hepatic injury induced by excess Desulfovibrio through gut-liver axis. Gut Microbes. 2024;16(1):2370634. doi: 10.1080/19490976.2024.2370634. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0231] 231.Nichenametla SN, Mattocks DAL, Cooke D, Midya V, Malloy VL, Mansilla W, Øvrebø B, Turner C, Bastani NE, Sokolová J, et al. Cysteine restriction-specific effects of sulfur amino acid restriction on lipid metabolism. Aging cell. 2022;21(12):e13739. doi: 10.1111/acel.13739. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0232] 232.Varghese A, Gusarov I, Gamallo-Lana B, Dolgonos D, Mankan Y, Shamovsky I, Phan M, Jones R, Gomez-Jenkins M, White E, et al. Unravelling cysteine-deficiency-associated rapid weight loss. Natur. 2025;643:776–784. doi: 10.1038/s41586-025-08996-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0233] 233.Lobel L, Cao YG, Fenn K, Glickman JN, Garrett WS. Diet posttranslationally modifies the mouse gut microbial proteome to modulate renal function. Sci. 2020;369(6510):1518–1524. doi: 10.1126/science.abb3763. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0234] 234.Kouno T, Zeng S, Wang Y, Duan Y, Lang S, Gao B, Hartmann P, Cabré N, Llorente C, Galbert C, et al. Engineered bacteria producing aryl-hydrocarbon receptor agonists protect against ethanol-induced liver disease in mice. Alcohol Clin Exp Res (Hoboken). 2023;47(5):856–867. doi: 10.1111/acer.15048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0235] 235.Dimopoulou C, Guerra PR, Mortensen MS, Kristensen KA, Pedersen M, Bahl MI, Sommer MAO, Licht TR, Laursen MF. Potential of using an engineered indole lactic acid producing Escherichia coli Nissle 1917 in a murine model of colitis. Sci Rep. 2024;14(1):17542. doi: 10.1038/s41598-024-68412-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[cit0236] 236.Dimopoulou C, Bongers M, Pedersen M, Bahl MI, Sommer MOA, Laursen MF, Licht TR. An engineered Escherichia coli Nissle 1917 increase the production of indole lactic acid in the gut. FEMS Microbiol Lett. 2023;370. doi: 10.1093/femsle/fnad027. [DOI] [PubMed] [Google Scholar]

[cit0237] 237.Kurtz CB, Millet YA, Puurunen MK, Perreault M, Charbonneau MR, Isabella VM, Kotula JW, Antipov E, Dagon Y, Denney WS, et al. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci Transl Med. 2019;11(475). doi: 10.1126/scitranslmed.aau7975. [DOI] [PubMed] [Google Scholar]

PERMALINK

Gut microbial metabolites of amino acids in liver diseases

Mengyao Hu

Yi Xu

Hongwei Zhou

Xiaolong He

ABSTRACT

1. Introduction

2. Regulation of gut microbiota on amino acid metabolism

2.1. Aromatic amino acids

Figure 1.

2.2. Branched-chain amino acids

Figure 2.

2.3. Sulphur-containing amino acids

2.4. Basic amino acids

3. Microbial amino acid metabolites as signalling molecules in the gut-liver crosstalk

Table 1.

Table 2.

Figure 3.

3.1. Amines

3.2. Indoles

3.3. Aromatic derivatives

3.4. Branched-chain fatty acids

3.5. Sulphur-containing compounds

4. Translational implications of targeting amino acid metabolism

4.1. Biomarker potential of amino acid metabolism

4.2. Therapeutic strategies targeting amino acid metabolism

5. Conclusions and future perspectives

Funding Statement

Disclosure statement

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Gut microbial metabolites of amino acids in liver diseases

Mengyao Hu

Yi Xu

Hongwei Zhou

Xiaolong He

ABSTRACT

1. Introduction

2. Regulation of gut microbiota on amino acid metabolism

2.1. Aromatic amino acids

Figure 1.

2.2. Branched-chain amino acids

Figure 2.

2.3. Sulphur-containing amino acids

2.4. Basic amino acids

3. Microbial amino acid metabolites as signalling molecules in the gut-liver crosstalk

Table 1.

Table 2.

Figure 3.

3.1. Amines

3.2. Indoles

3.3. Aromatic derivatives

3.4. Branched-chain fatty acids

3.5. Sulphur-containing compounds

4. Translational implications of targeting amino acid metabolism

4.1. Biomarker potential of amino acid metabolism

4.2. Therapeutic strategies targeting amino acid metabolism

5. Conclusions and future perspectives

Funding Statement

Disclosure statement

References

ACTIONS

PERMALINK

RESOURCES

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