Integrating bile acid metabolism into precision nutrition strategies for improved swine performance

Abstract

Maintaining optimal physiological conditions in pigs requires a precise nutrient supply, encompassing the digestion, absorption, metabolism, and excretion of carbohydrates, fats, dietary fiber, and proteins. Precision feeding aims to maximize economic and environmental benefits by delivering the appropriate feed composition and quantity to individual pigs or groups, aligned with their specific nutrient needs. Bile acid (BA) metabolism plays a crucial role in nutrient digestion, absorption, and metabolic regulation in pigs. This review explores the biochemical mechanisms of BA metabolism, its interactions with gut microbiota, and its influence on carbohydrate, lipid, protein, and fiber metabolism. The modulation of BA metabolism through precision nutrition strategies—such as dietary fat adjustments, BA supplementation, and the inclusion of prebiotics and probiotics – can enhance nutrient utilization, promote gut health, and improve feed efficiency. Furthermore, BA metabolism significantly impacts pig growth, reproductive performance, and gastrointestinal health, making it a key target for dietary interventions in both young pigs and breeding sows. By integrating precision nutrition strategies that regulate BA metabolism, swine production systems can achieve better feed conversion efficiency, reduce environmental waste, and enhance overall animal resilience. This review underscores the central role of BA metabolism in swine nutrition and its potential as a key target for precision feeding strategies. Leveraging BA metabolism to optimize nutrient absorption, modulate gut microbiota composition, and enhance overall pig performance provides valuable insights for advancing precision nutrition and feed development in swine production.

1. Introduction

Pigs require a balanced supply of nutrients, including carbohydrates, fats, dietary fiber, proteins, minerals, vitamins, and water, to support growth, reproduction, and lactation (Han et al., 2023; Lebret and Čandek-Potokar, 2022; Li et al., 2021a; Yan et al., 2023). The efficiency of nutrient utilization in pig diets is influenced by multiple factors, such as age, breed, feed composition, rearing stage, and production system; all of which are integral to precision nutrition (Andretta et al., 2016; Ellis et al., 2020; Remus et al., 2020b). In commercial pig production, nutrient requirements are traditionally estimated using empirical and factorial approaches that fail to account for inter- and intra-animal variability. Conventional group-based and stage-based feeding strategies necessitate formulating diets to meet the highest nutrient demands within a herd, ensuring all pigs can reach their growth potential. However, this often leads to excessive nutrient intake for most pigs, resulting in inefficiency and increased waste (Andretta et al., 2016; Remus et al., 2020b). Precision nutrition, by contrast, dynamically assesses the nutritional needs of individual pigs based on factors such as age, weight, growth stage, health status, and feed intake. Implementing individualized feeding strategies optimizes growth performance while simultaneously reducing feed waste and nutrient emissions, lowering production costs, and mitigating environmental impact (Andretta et al., 2016; Misiura et al., 2021; Remus et al., 2020a,b).

Bile acids (BAs) are primarily involved in the digestion, absorption, and metabolism of glucose, cholesterol, fat-soluble vitamins, and lipids (Jia et al., 2018). Beyond their digestive functions, BAs serve as essential signaling molecules that regulate triglyceride (TG) levels, cholesterol, glucose, and energy homeostasis (Cai et al., 2022; Jia et al., 2018). Disruption of any step in BA metabolism can result in inadequate nutrient utilization, impaired metabolic health, and suboptimal growth performance in pigs (Hanhineva et al., 2013; Hernandez et al., 2020). Therefore, targeted dietary interventions to support BA function are necessary, which emphasizes the importance of precision nutrition for optimizing BA metabolism. Precision nutrition in swine production allows for the customization of dietary formulations to meet the specific physiological needs of the animals. This approach ensures that nutrients are supplied in appropriate amounts and proportions, optimizing animal health and productivity. Regulating BA metabolism through dietary strategies is a powerful mean of improving carbohydrate and fat digestion, nutrient absorption and overall feed efficiency (Lefebvre et al., 2009). Further research on the relationship between BAs and specific feed components could refine dietary strategies across different stages of production (Singh et al., 2019). The practical application of precision nutrition in pig feed formulation includes: using dietary strategies to alter BA metabolism to improve nutrient absorption; directly adding BA supplements; and indirectly regulating BA metabolism by adding prebiotics, probiotics and other gut-modulating additives. Targeted regulation of BA metabolism through customized feed formulation can improve nutrient absorption. Optimizing gut health and ultimately improving overall performance has become a key focus of modern pig nutrition practices. A comprehensive understanding of the relationship between BA metabolism and precision nutrition in pigs requires acknowledging the pivotal role of BAs in nutrient digestion, absorption, and metabolism.

This review integrates the biochemical mechanisms of BA metabolism into precision nutrition strategies, revealing substantial opportunities to enhance pig productivity and health. It examines how BAs regulate the absorption and utilization of carbohydrates, fats, dietary fiber, and proteins, which are essential for effective precision feeding in pig production. Furthermore, the review outlines how dietary nutrition influences pig health, growth, and development through BA metabolism, providing valuable insights for the advancement of precision pig nutrition and feed development.

2. Bile acid metabolism and gut microbes

The processes of BA synthesis, transport, metabolism and regulation have been extensively reviewed. This section commences with an examination of the enterohepatic circulation of BAs, with a particular emphasis on their interactions with gut microbiota.

2.1. Bile acid synthesis, transport and metabolism

Bile acids are key components of bile and are exclusively synthesized in the liver (Fig. 1). They are produced from cholesterol in hepatocytes through cytochrome P450 (CYP)-mediated oxidation (Rizzolo et al., 2021). Bile acid synthesis occurs via two primary pathways: the classical (neutral) pathway and the alternative (acidic) pathway (Collins et al., 2023). The classical pathway of BA synthesis is initiated by cytochrome P450 7A1 (CYP7A1) and generates cholic acid (CA) and chenodeoxycholic acid (CDCA) through the action of two cholesterol hydroxylases, CYP7A1 and cytochrome P450 8B1 (CYP8B1) (Little et al., 2022). The alternative pathway synthesizes CDCA via hydroxylation of cholesterol side chains by cytochrome P450 27A1 (CYP27A1), followed by 7α-hydroxylation of 27-hydroxycholesterol and other oxysterols by CYP7B1 (Thomas et al., 2008). In the pig liver, CDCA is converted to hyocholic acid (HCA) via C-6α-hydroxylation of cytochrome P450 3A4 (CYP3A4) (Jia et al., 2018). In addition, several studies have reported that HCA may be formed in the intestine from α-methylcholic acid (α-MCA) (Jia et al., 2018). Cytochrome P450 8B1 controls the levels and ratio of CA and CDCA (Umemura et al., 2024). In hepatocytes, CA and CDCA are converted into conjugated bile acids—glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), taurocholic acid (TCA), and taurochenodeoxycholic acid (TCDCA)—through conjugation with glycine or taurine. This process is catalyzed sequentially by bile acid–CoA synthetase (BACS) and bile acid–CoA:amino acid N-acyltransferase (BAAT) (Alrehaili et al., 2022; Collins et al., 2023; Setchell et al., 2013). Glycocholic acid, GCDCA, TCA and TCDCA are then secreted from the liver into the bile via the bile salt export pump (BSEP) (Li et al., 2022). Meanwhile, sulfated or glucuronidated BAs are secreted from the liver into the bile via multidrug resistance-associated protein 2 (MRP2) (Koide et al., 2025). In the case of cholestasis, excess BAs and bilirubin can be excreted into the circulation via the basolateral outlet transport system mediated by multidrug resistance–associated proteins 3 and 4 (MRP3 and MRP4), organic anion transporting polypeptide 2 (OATP2), and organic solute transporter α/β (OSTα/β) (Jetter and Kullak-Ublick, 2020; Nerild et al., 2025; Qin et al., 2023; Tátrai et al., 2022). After a meal, the gallbladder contracts, releasing BAs into the intestine, where they aid in the emulsification and absorption of lipids and fat-soluble vitamins in the small intestine. In the gut, enzymes produced by gut microbes metabolize primary bile acids (PBAs) to form secondary bile acids (SBAs) (Collins et al., 2023; Lee et al., 2024).

Fig. 1.

Bile acids (BAs) are synthesized in the liver from cholesterol via classical and alternative pathways, both catalyzed by cytochrome P450 (CYP) enzymes. Once synthesized, BAs are conjugated to glycine or taurine by bile acid–CoA synthetase (BACS) and bile acid–CoA:amino acid N-acyltransferase (BAAT) before being secreted into the gut. Around 90% to 95% of BAs are reabsorbed through the portal circulation and returned to the liver. In the gut, microbiota convert primary BAs into secondary BAs and deconjugate them into unconjugated BAs. CA = cholic acid; CDCA = chenodeoxycholic acid; HCA = hyocholic acid; TCA = taurocholic acid; TCDCA = taurochenodeoxycholic acid; GCA = glycocholic acid; GCDCA = glycochenodeoxycholic acid; DCA = deoxycholic acid; LCA = lithocholic acid; HDCA = hyodeoxycholic acid; UDCA = ursodeoxycholic acid; BSH = bile salt hydrolase; OSTα/β = organic solute transporter α/β; MRP = multidrug resistance-associated protein; NTCP = Na⁺-taurocholate co-transporting polypeptide; OATP1 = organic anion transporting polypeptide 1; BSEP = bile salt export pump; ASBT = apical sodium-dependent bile acid transporter.

Following lipid absorption, approximately 95% of unconjugated BAs—including CA, CDCA, deoxycholic acid (DCA), ursodeoxycholic acid (UDCA), and hyodeoxycholic acid (HDCA)—are reabsorbed in the terminal ileum via the apical sodium-dependent bile acid transporter (ASBT) located on the brush border of intestinal epithelial cells (Collins et al., 2023; Lee et al., 2024). These BAs then bind to the ileal bile acid binding protein (IBABP) and are transported back to the liver with the blood after entering the portal vein via the basolateral BA transporter proteins OSTα, OSTβ, MRP2, and MRP3 (Deng and Bae, 2020; Takayama et al., 2021). Bile acids are then taken up into hepatocytes via Na⁺-taurocholate co-transporting polypeptide (NTCP), as well as organ anion transporting polypeptide 4 (OATP4) and organ anion transporting polypeptide 1 (OATP1) transporters (Goutam et al., 2022; Meier and Stieger, 2002). The above process of BA biosynthesis, transport and metabolism is known as the enterohepatic cycle of BAs (Fig. 1). In the process, BAs can enter the somatic circulation and send signals to virtually all organs by binding and activating specialized BA receptors.

2.2. Bile acid-specific receptors and signaling pathways

In the liver and intestine, BAs serve as both detergents and potent signaling molecules (Ringseis et al., 2020). Bile acid receptors are classified into two major groups: nuclear receptors (NR), such as the farnesoid X receptor (FXR), vitamin D receptor (VDR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), and membrane receptors, primarily the G protein-coupled receptor 5 (TGR5) (Ahmad and Haeusler, 2019). Upon receptor engagement, BAs modulate metabolic and signaling pathways both locally and systemically, influencing lipid and glucose homeostasis, energy metabolism, and immune function—processes that are tightly interconnected with microbial bile acid metabolism (Fig. 2). The capacity of BAs to activate their receptors varies based on the specific type of BA, and the BA pool composition in both the gut and circulation is strongly influenced by the gut microbiota (Ringseis et al., 2020). Therefore, alterations in the gut microbiota significantly affect the metabolism and health of the host by regulating BA metabolism. A thorough understanding of BA signaling is crucial for deciphering the microbial metabolism of BAs.

Fig. 2.

Bile acids (BAs) act as signaling molecules to influence body metabolism through BA receptors. CYP = cytochrome P450; OSTα/β = organic solute transporter α/β; MRP = multidrug resistance-associated protein; NTCP = Na⁺-taurocholate co-transporting polypeptide; OATP = organic anion transporting polypeptide; BSEP = bile salt export pump; ASBT = apical sodium-dependent bile acid transporter; LRH-1 = liver receptor homolog-1; HNF4α = hepatocyte nuclear factor 4α; JNK = c-Jun N-terminal kinases; ERK = extracellular signal-regulated kinases; FGFR4 = fibroblast growth factor receptor 4; FGF15/19 = fibroblast growth factor 15/19; FXR = farnesoid X receptor; TGR5 = G protein-coupled receptor 5; RXR = retinoid X receptor; SREBP1c = sterol regulatory element-binding protein 1c; FASN = fatty acid synthase; SCD-1 = stearoyl-CoA desaturase-1; G6PC = glucose 6-phosphatase; PEPCK = phosphoenolpyruvate carboxyl kinase; SHP = small heterodimer partner; IBABP = ileal bile acid binding protein; GLP-1 = glucagon-like peptide-1; WAT = white adipose tissue; BAT = brown adipose tissue; DIO2 = deiodinase 2; T3 = triiodothyronine; T4 = thyroxine; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; PKA = protein kinase A; CREB = cAMP response element-binding protein.

2.2.1. Farnesoid X receptor and TGR5

Farnesoid X receptor (also known as NR1H4) is an NR for which BA is a proven natural ligand. In hepatocytes and enterocytes, FXR modulates genes related to BAs enterohepatic cycle to maintain BA homeostasis (Fig. 2). In the liver, FXR activity controls BA levels within the biliary tree and intestine, preventing their accumulation in hepatocytes (Gadaleta et al., 2010). In the intestine, FXR modulates BA efflux into the portal vein and reuptake into enterocytes, maintaining intracellular concentrations (Shin and Wang, 2019). Beyond BA regulation, FXR also influences lipid metabolism, glucose homeostasis, plasma lipoproteins, bacterial growth, and liver regeneration (Jiao et al., 2022; Radun and Trauner, 2021; Wang et al., 2008). Several studies suggest that unconjugated BAs have a greater capacity to activate FXR compared to conjugated forms (Xiang et al., 2021). The potency ranking of BAs for FXR activation is CDCA > DCA > lithocholic acid (LCA) > CA (He et al., 2022). In the liver, FXR activation induces small heterodimer partner (SHP) expression, which binds to liver receptor homolog-1 (LRH-1) and suppresses CYP7A1 (Thomas et al., 2008). Studies with tissue-specific FXR-deficient mice show that ileal FXR activation has a stronger inhibitory effect on CYP7A1-mediated BA synthesis compared to hepatic FXR activation (Massafra and van Mil, 2018). In the distal ileum, BAs activate FXR, inducing fibroblast growth factor 15/19 (FGF15/19) expression. Fibroblast growth factor 15/19 travels to the liver via the portal circulation, binds to the fibroblast growth factor receptor 4 (FGFR4)/β-klotho complex, and activates the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) pathways, further suppressing CYP7A1 (Wahlström et al., 2016).

G protein-coupled receptor 5, also known as G protein-coupled BA receptor 1 (GPBAR1), is encoded by a single exon gene that generates a protein comprising seven transmembrane domains of structure, three extracellular loops, and three intracellular loops (Perino et al., 2021). G protein-coupled receptor 5 can activate various intracellular signal pathways after binding to BA (Fig. 2) (Jia et al., 2018). It is primarily activated by the LCA and DCA, positioning TGR5 as a crucial mediator in microbiota-BA interactions (Jia et al., 2018). G protein-coupled receptor 5 mRNA is ubiquitously expressed, with the highest levels observed in the gallbladder, followed by brown adipose tissue, liver, and intestine (Burrin et al., 2013). The relatively high expression of TGR5 in biliary, gallbladder, and gastrointestinal tissues underscores its role in BA signaling and intestinal function.

Beyond the liver and intestines, FXR and TGR5 are also expressed in pancreatic β cells, while TGR5 is additionally expressed in pancreatic α cells, playing a crucial role in maintaining insulin secretion and glucose homeostasis (Fig. 2) (Fiorucci et al., 2021). Farnesoid X receptor activation enhances glucose-stimulated insulin secretion (GSIS) in β-cell lines, and GSIS is impaired in FXR-deficient mice (Dehondt et al., 2023). The FXR-regulated downstream target FGF15/19 is essential for glucose and insulin homeostasis (Kir et al., 2011). Fibroblast growth factor 15/19 promotes glycogen synthesis, lowers plasma glucose levels, and suppresses hepatic gluconeogenic gene expression by inhibiting the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-PGC-1α pathway (Potthoff et al., 2011). Additionally, FXR activation inhibits glucose-induced carbohydrate response element-binding protein (ChREBP), a key regulator of hepatic glycolytic genes, while reducing phosphoenolpyruvate carboxyl kinase (PEPCK) mRNA expression, thereby enhancing glycogen synthesis (Caron et al., 2013; Stayrook et al., 2005). The FXR-mediated regulation of PEPCK is dependent on SHP, which suppresses hepatocyte nuclear factor 4α (HNF4α)-mediated transcription and prevents forkhead box O1 (FOXO1) recruitment to the PEPCK promoter (Ploton et al., 2018). Small heterodimer partner activation reduces serum glucose levels in wild-type mice and inhibits growth hormone-mediated gluconeogenesis by blocking signal transducer and activator of transcription 5 (STAT5) signaling (Fiorucci et al., 2021; Kim et al., 2012). Furthermore, FXR activation in the intestine induces TGR5 expression, stimulating glucagon-like peptide-1 (GLP-1) secretion, which enhances insulin sensitivity and improves liver metabolism (Pathak et al., 2018). G protein-coupled receptor 5 activation influences insulin secretion both directly via β-cells and indirectly through the paracrine effect of α-cell-derived GLP-1 on β-cells (Lun et al., 2024). In skeletal muscle, TGR5 activation promotes muscle hypertrophy and enhances glucose utilization by stimulating glycolytic flux, thereby improving glucose metabolism dysfunction associated with diet-induced obesity and aging (Sasaki et al., 2021).

Bile acids also regulate gut homeostasis by affecting the function of intestinal stem cells (ISCs) through the activation of FXR and TGR5 (Lund et al., 2020; Sorrentino et al., 2020). Intestinal stem cells, located at the base of intestinal crypts, are essential for maintaining epithelial integrity through continuous self-renewal and differentiation into intestinal epithelial cells (IECs) and enteroendocrine cells (EECs) (Ma et al., 2022). The crypts form specialized niches that balance ISC self-renewal and differentiation. Farnesoid X receptor directly modulates ISC function by regulating stem cell proliferation and interacting with key signaling pathways. Interactions between BAs and FXR exert dual effects on ISC dynamics. Farnesoid X receptor -antagonistic BAs, including tauro-β-muricholic acid (T-βMCA) and DCA, stimulate Lgr5⁺ ISC proliferation and promote DNA damage, whereas selective FXR activation constrains aberrant Lgr5⁺ stem cell expansion (Fu et al., 2019). Additionally, FXR inhibits the Wnt/β-catenin signaling pathway, a key regulator of ISC proliferation, thereby preventing excessive stem cell growth and maintaining controlled epithelial cell turnover (Yu et al., 2020; Zhang et al., 2024c). G protein-coupled receptor 5 activation similarly influences ISC dynamics. Bile acids acting as TGR5 agonists promote ISC renewal and proliferation, with the BA-TGR5 axis playing a pivotal role in maintaining ISC populations, facilitating injury-induced epithelial regeneration, and directing ISC differentiation into enteroendocrine L cells and goblet cells (Sorrentino et al., 2020). Mechanistically, TGR5 activation stimulates the steroid receptor coactivator (SRC)–YAP signaling axis, enhancing enterocyte proliferation and ISC reorganization, thereby accelerating epithelial repair (Sorrentino et al., 2020).

2.2.2. Other receptors involved in BA signaling

Other NR, including the PXR (NR1I2), CAR (NR1I3), and VDR (NR1I1), also respond to BAs (Perino et al., 2021). Retinoid X receptor is primarily expressed in the liver and intestine, whereas CAR is predominantly found in the liver. Lithocholic acid and 3-keto LCA are the most potent BA ligands for PXR. Notably, their activation requires relatively high BA concentrations, indicating that PXR signaling is particularly relevant under pathological conditions such as cholestasis. Pregnane X receptor activation induces the uptake, modification, metabolism, translocation, and excretion of xenobiotics via phase I-III enzymes. Additionally, PXR protects against LCA-induced toxicity and prevents cholesterol cholelithiasis by regulating the biosynthesis and transport of BA (Nguyen et al., 2018). Pregnane X receptor activation inhibits the synthesis of BAs by disrupting the interaction between HNF4α and PGC-1α and decreasing the CYP7A1 expression. Both direct ligand-binding and indirect mechanisms can activate CAR (Nguyen et al., 2018). Although it unclear whether BAs act as natural ligands for CAR, evidence suggests that CAR and PXR may work synergistically to maintain BA homeostasis by co-inducing enzymes such as CYP3A4 and sulfotransferase 2A1 (SULT2A1). Simultaneous deletion of both receptors in mice exacerbates LCA-induced liver injury, highlighting their protective roles. Vitamin D receptor functions as an intestinal BA sensor. When activated by LCA, it induces CYP3A4 and SULT2A1 expression to metabolize LCA, protecting the intestine from BA toxicity (Li and Chiang, 2013). In addition, activation of the VDR also stimulate the gut FGF19-FGFR4 axis, helping to normalize enterohepatic circulation (Di Ciaula et al., 2022; Simbrunner et al., 2021). Vitamin D receptor activation increases intestinal FGF19 expression, which reduces CYP7A1 activation in the liver and lowers BA synthesis, potentially serving as a key bypass pathway for FXR signaling (Chiang and Ferrell, 2022; Ticho et al., 2019).

2.3. Bile acid metabolism and gut microbiota

2.3.1. The gut microbiome shapes the BA pool

Upon entering the gastrointestinal tract, PBAs undergo microbial biotransformation into SBAs through a series of reactions, including deconjugation, dehydroxylation, oxidation, epimerization, reconjugation, hydroxylation, amidation, sulfation, and acylation (Chiang, 2009; Kanda et al., 1998). The key gut microbes involved in BA metabolism are summarized in Table 1. Variations in the composition of the gut microbiota can alter the BA-microbiome modification, thereby influencing the types and levels of SBAs produced (Fogelson et al., 2023; Guzior and Quinn, 2021). The initial microbial response to PBAs is typically deconjugation, a process mediated by bile salt hydrolases (BSHs), a widely distributed class of bacterial enzymes (Foley et al., 2021; Guzior and Quinn, 2021). Bile salt hydrolases catalyze the hydrolysis of the C-24 N-acyl bond, releasing free BAs (e.g., CA and CDCA) and their conjugated amino acids, taurine or glycine. This reaction is often the rate-limiting step in microbial BA metabolism (Ridlon et al., 2016). Bile salt hydrolases are highly conserved and prevalent among major bacterial phyla, including Bacteroidetes, Firmicutes, and Actinobacteria, as well as in certain archaeal species (Jones et al., 2008). Following deconjugation, BAs undergo further microbial transformations, generating a structurally diverse BA pool.

Table 1.

Chemical transformations of bile acids (BAs) by the gut microbiota.

Modification	Enzyme	Bacteria	BA transformation	References
Hydrolysis (Deconjugation)	Bile salt hydrolase	Bacteroides, Firmicutes and Actinobacteria	Unconjugated bile acids (from glycine/taurine conjugates)	Jones et al. (2008)
Dehydroxylation	Bile acid-inducible (Bai) operon	Clostridium scindens, Clostridium hylemonae and Clostridium hiranonis	CDCA→LCA CA→DCA	Funabashi et al. (2020); Streidl et al., 2021
Oxidation and epimerization	3α-HSDH	Eggerthella lenta, Ruminococcus gnavus and Clostridium perfringens	DCA→3-oxoDCA	Doden et al., 2021; Harris et al., 2018
	3β-HSDH	Eggerthella lenta and Ruminococcus gnavus	3-oxoDCA→isoDCA	Doden et al., 2021; Harris et al., 2018
	7α-HSDH	Eggerthella lenta, Clostridium scindens and Escherichia coli	CDCA→7-oxoLCA	Doden et al., 2021; Harris et al., 2018
	7β-HSDH	Ruminococcus gnavus	7-oxoLCA→UDCA	Doden et al., 2021
	12α-HSDH	Eggerthella lenta, Clostridium leptum, Clostridium hylemonae, Clostridium hiranonis, and Clostridium scindens	DCA→12-oxoLCA	Doden et al., 2021; Harris et al., 2018
	12β-HSDH	Clostridium paraputrificum	12-oxoLCA→epiDCA	Doden et al., 2021
Desulfation	Sulfatase	Clostridium, Peptococcus, Fusobacterium and Pseudomonas.	Bile acid sulfate ester→Unsulfated bile acid	Huijghebaert and Eyssen, 1982
Esterification	Unknown	Unknown	Unesterfied bile acid→Fatty acid ethyl esterified bile acid	Dawson and Karpen, 2015
Amidation (Conjugation)	Unknown	Bacteroides, Bifidobacterium and Enterocloster	Unconjugated bile acids→12 additional amino acid-conjugated bile acids	Lucas et al. (2021); Quinn et al. (2020)

3α-HSDH = 3α-hydroxysteroid dehydrogenase; 3β-HSDH = 3β-hydroxysteroid dehydrogenase; 7α-HSDH = 7α-hydroxysteroid dehydrogenase; 7β-HSDH = 7β-hydroxysteroid dehydrogenase; 12α-HSDH = 12α-hydroxysteroid dehydrogenase; 12β-HSDH = 12β-hydroxysteroid dehydrogenase; CDCA = chenodeoxycholic acid; LCA = lithocholic acid; CA = cholic acid; DCA = deoxycholic acid; 3-oxoDCA = 3-oxodeoxycholic acid; isoDCA = isodeoxycholic acid; 7-oxoLCA = 7-oxolithocholic acid; UDCA = ursodeoxycholic acid; 12-oxoLCA = 12-oxolithocholic acid; epiDCA = epideoxycholic acid.

Furthermore, deconjugated PBAs are converted to SBAs by the dehydroxylation reaction catalyzed by the bacterial 7α-dehydroxylase (Ridlon et al., 2016). Unlike deconjugation, which is widely distributed among gut bacteria, 7α-dehydroxylation is mediated by a limited group of anaerobic bacteria, primarily belonging to the genus Clostridium (Ridlon et al., 2010). The C7 hydroxyl dehydroxylation of CA and CDCA is converted to DCA and LCA, respectively (Ridlon et al., 2006). The genes encoding enzymes involved in the BA 7α-dehydroxylation pathway, collectively termed the bai (bile acid–inducible) operon, have been identified in Clostridium scindens VPI 12708, Clostridium hylemonae and Clostridium scindens (Funabashi et al., 2020). The bai operon consists of eight genes: baiB, baiCD, baiE, baiA2, baiF, baiG, baiH and baiI (Funabashi et al., 2020). Funabashi et al. (2020) successfully isolated and characterized these enzymes, reconstituting the pathway in vitro. In Clostridium sporogenes ATCC 15,579, the cloning of six key enzymes enabled the full eight-step conversion of CA to DCA. This conversion begins with the uptake of CA via the H⁺-dependent active transporter baiG, followed by thioesterification to CoA through the action of the CoA ligase baiB. Cholyl-CoA is subsequently oxidized by HSDH (baiA2) to generate 3-oxo-cholyl-CoA, which is further oxidized by the flavoprotein baiCD to produce 3-oxo-4,5-dehydrocholyl-CoA. The critical 7α-dehydroxylation step is catalyzed by 7α-dehydratase (baiE), yielding 3-oxo-4,5 to 6,7-didehydro-deoxy-cholyl-CoA. Coenzyme A is then removed by CoA transferase (baiF), forming an intermediate that undergoes reduction via flavoenzyme (baiH and baiCD), and HSDH (baiA2) to produce DCA. The same pathway is used for the 7α-dehydroxylation of CDCA. 7β-Dehydroxylation occurs in a similar fashion, the key difference being that BaiH is used in the place of baiCD for C4 oxidation (Funabashi et al., 2020).

Another key bacterial transformation of BAs is the oxidation of the 3α-, 7α-, or 12α-hydroxyl groups, catalyzed by bacterial hydroxysteroid dehydrogenases (HSDHs) (Ridlon et al., 2016). This enzymatic activity generates ketonic (oxo-) BAs, which can subsequently undergo epimerization through stereospecific reduction of the oxo group, yielding β-hydroxyl BAs or iso-BAs (Ridlon et al., 2006). Oxidation and epimerization occur at all three hydroxyl positions of CA and both hydroxyl positions of CDCA, contributing significantly to the structural diversity of non-conjugated BAs. Cholic acid can be epimerized into derivatives such as 3α,7β,12α-trihydroxy-5β-cholan-24-oic acid (UCA), 3α,7α,12β-trihydroxy-5β-cholan-24-oic acid (12-ECA), or 3β,7α,12α-trihydroxy-5β-cholan-24-oic acid (iCA). Similarly, CDCA can be converted into UDCA or 3β,7α-dihydroxy-5β-cholan-24-oic acid (iCDCA) (Guzior and Quinn, 2021). In unmodified host-derived BAs, all hydroxyl groups are oriented toward the α-side of the steroid ring, resulting in a hydrophobic α-face and a hydrophilic β-face. The conversion of hydroxyl groups from an α to a β configuration increases hydrophilicity, yielding iso- (C-3), urso- (C-7), or epi- (C-12) BAs (Fuchs et al., 2025a,b). These transformations are facilitated by stereoselective microbial HSDHs, which generate stable oxo-BA intermediates and catalyze reactions in both directions. Several bacterial genera, including Bacteroides, Clostridium, Eubacterium, Peptostreptococcus, Ruminococcus, Bifidobacterium, Eggerthella, Enterobacter and Escherichia have either α-,β-, or both, HSDH enzyme activities (Doden et al., 2018; Gérard, 2013; Kisiela et al., 2012; Ridlon et al., 2006).

Other bacterial modifications of BAs include desulfation, esterification, and reconjugation. Sulfation increases solubility, reduces intestinal absorption, and promotes BA excretion via feces and urine. Compared with unsulfated BAs, BA sulfates are also less toxic, making sulfation a key detoxification pathway (Alnouti, 2009). Bile acid sulfatase activity has been found in Clostridium, Peptococcus, Fusobacterium, and Pseudomonas (Tazuke et al., 1998). The sulfatase activity requires a 3α/3β-sulfate group and a free C24 or C26 carboxyl group (Tazuke et al., 1998). Sulfate groups added by the host to facilitate excretion can be removed by bacteria expressing steroid 3-sulfatase, thereby reintroducing BA into the BA pool (Alnouti, 2009; Van Eldere et al., 1988). Additionally, bacteria esterify BAs with alcohols, short-chain fatty acids (SCFAs), and long-chain fatty acids. Bacteria in the genera Bacteroides, Eubacterium, Lactobacillus, Citrobacter, and Peptostreptococcus harbor esterases that convert BAs into their C-24 ethyl esters with ethanol addition (Edenharder and Schneider, 1985). Esterification serves as a detoxification mechanism by precipitating BA esters, thereby reducing the concentration of hydrophobic SBAs and toxic fatty acids and alcohols in fecal water (Schoeler and Caesar, 2019). Under the action of the gut microbiota, BAs are amide-bound with phenylalanine, tyrosine, and leucine, forming BA-amino acid conjugates (Quinn et al., 2020). Among 70 human intestinal bacterial species examined, 27 demonstrated the ability to conjugate CDCA, CA, and DCA with various amino acids, including phenylalanine and tyrosine (Lucas et al., 2021). The specific enzymes mediating these conjugation processes and the functional roles of these complexes remain unidentified. Notably, reattachment of amino acids to free BAs may serve as a protective mechanism to mitigate BA-induced toxicity.

In addition to PBA microbial metabolism, intestinal microbes also shape the BA pool in various ways. Gut microorganisms influence the host BA pool composition, as manifested in the BA pool size, composition and concentration (Guzior and Quinn, 2021; Lavelle and Sokol, 2020). Sayin et al. (2013) found that the BA pools of germ-free were less diverse in chemical composition; the ratio of conjugated PBAs to SBAs was increased; and there was some degree of variation in the size and concentration of the BA pools. Germ-free mice exhibit a significantly larger BA pool than normal mice, suggesting that the gut microbiota generates regulatory signals that suppress BA synthesis. This regulation is partially mediated by intestinal FXR. Notably, the two main PBAs (i.e., T-αMCA and T-βMCA) accumulate in the intestines of germ-free mice. Tauro-β-muricholic acid is an FXR antagonist that cannot be metabolized in the absence of intestinal bacteria. Its accumulation inhibits intestinal FXR signaling, leading to reduced FGF15 expression. Since FGF15 negatively regulates CYP7A1 in mice, its suppression results in increased hepatic BA synthesis (Goodwin et al., 2000). Similarly, Gly-MCA improves metabolic balance by specifically inhibiting FXR in the intestine. Altering gut microbiota composition in mice can regulate FXR/FGF15/FGFR4/CYP7A1-mediated BA synthesis (Jiang et al., 2015a; Li et al., 2013). Beyond modulating BA synthesis, gut microbiota also regulates BA uptake. Microbial deconjugation prevents active BA reabsorption in the small intestine via the ASBT, facilitating their escape from enterohepatic circulation (Wahlström et al., 2016).

2.3.2. The BA pool shapes the gut microbiome

Bile acid is an essential regulator of the abundance, diversity and metabolic activity of the gut microbiota (Ridlon and Gaskins, 2024; Wang et al., 2021b). The BA pool is the result of a dynamic, reciprocal relationship between host metabolism and the gut microbiota (Fiorucci et al., 2024; Wang et al., 2021b). Studies have demonstrated that bile flow obstruction can lead to microbial overgrowth and translocation into the circulatory system, a process reversible with BA supplementation (Galloway et al., 2019). Specifically, unconjugated BAs such as DCA and CDCA act as potent antimicrobial agents, disrupting bacterial cell membranes by altering their integrity and permeability (Aleksić Sabo et al., 2021; Palace et al., 2021). Beyond membrane disruption, BAs contribute to oxidative stress by promoting RNA secondary structure formation, inducing DNA damage, altering protein conformation (leading to misfolding or denaturation), and generating reactive oxygen species (Ghallab et al., 2022; Molendijk et al., 2022; Zhuang et al., 2024). Despite its toxicity, the support of the diversity of the gut microbiota by BAs has been extensively investigated and confirmed. Tauro-β-muricholic acid and TCA inhibit bacteria in the gut microbiota of newborns, thereby creating new habitats for incoming microbes and promoting the diversity of adult gut microbiota members. Supplementation of newborns with T-βMCA consistently reduced the number of Escherichia and increased the number of Lactobacillus, with the Lactobacillus/Escherichia closer to that of adults (van Best et al., 2020).

Recent studies indicate that BA supplementation significantly influences both the BA pool and gut microbiota composition. Islam et al. (2011) demonstrated that feeding rats varying concentrations of BAs for ten consecutive days altered the composition and abundance of cecal microbiota while reducing microbial diversity. Specifically, Firmicutes abundance increased, whereas Bacteroidetes abundance decreased. Additionally, bacteria from the classes Clostridia and Erysipelotrichi expanded in abundance, gut microbial diversity declined, and the 7α-dehydroxylation activity of gut microbes converted supplemented BAs into DCA, thereby modifying BA pools (Islam et al., 2011). In Apc ^min/+ mice, continuous supplementation with a 0.4% CA diet for 12 weeks increased the abundance of pathogenic intestinal bacteria such as Prevotella and Desulfovibrio while decreasing beneficial genera, including Ruminococcus, Lactobacillus, and Roseburia (Wang et al., 2019). Similarly, Jin et al. (2022) reported that 0.2% DCA supplementation for six months in 2–3-month-old INS-GAS mice elevated serum total BA levels (UCA, GCA, LCA, GDCA, CA, GUDCA, GHDCA, and DCA), while accelerating gastric intestinal metaplasia and dysplasia. Gastric intestinal metaplasia represents a key precancerous stage of intestinal-type gastric cancer (GC). Deoxycholic acid-induced changes in the gastric microenvironment were highly correlated with abnormal BA metabolism and microflora dysbiosis, with a rapid increase in the abundance of Gemmobacter and Lactobacillus (Jin et al., 2022). Zhang et al. (2024b) reached a similar conclusion, demonstrating that supplementation with 0.2% DCA in drinking water for five consecutive weeks modulated BA metabolism by increasing the abundance of Akkermansia muciniphila in the mouse colon. This was accompanied by an increased abundance of 3-epi-DCA, Apo-CA, and its isomers 12-KLCA, 7-KLCA, IHDCA, and DCA. These changes further inhibited the interleukin (IL)-17 and tumor necrosis factor (TNF) inflammatory signaling pathways, thereby reducing chronic systemic inflammation (Zhang et al., 2024b). Similarly, Nie et al. (2024) demonstrated that 3-succinylated cholic acid (3-sucCA), a SBA metabolized by gut microbiota, alleviated metabolic-associated steatohepatitis (MASH) by increasing the abundance of Akkermansia muciniphila. In addition, 3-sucCA suppressed Clostridium sporogenes and Enterococcus hirae in the colon (Nie et al., 2024). These findings suggest that BA supplementation modulates gut microbiota composition by altering the host BA pool. It is worth mentioning that BAs can inhibit the growth or virulence of intestinal pathogens. Primary BAs regulate the timing of virulence factor production in pathogens. For example, upon sensing CA and DCA, adherent-invasive Escherichia coli (E. coli) accelerates its penetration through the gastrointestinal mucosal layer (Gibold et al., 2016). Chenodeoxycholic acid exerts a protective effect by inhibiting the germination of Clostridium difficile spores, a process mediated by Clostridium scindens via 7α-dehydroxylation to produce SBAs (Sorg and Sonenshein, 2010). Similarly, LCA disrupts the division of vancomycin-resistant Enterococcus (VRE) diplococci, leading to the formation of long chains and increased biofilm formation, which enhances their susceptibility to daptomycin (McKenney et al., 2019). Additionally, several SBAs, including DCA, isoDCA, UDCA, LCA, and isoLCA, exhibit anti-colonization activity against pathogenic bacteria (Buffie et al., 2015; Sorg and Sonenshein, 2010; Thanissery et al., 2017). Chenodeoxycholic acid exhibits antimicrobial activity against Salmonella enterica serovar Typhimurium by targeting the virulence regulator histidine-responsive regulatory protein D (HilD), thus inhibiting its invasion of intestinal epithelial cells (Eade et al., 2016; Yang et al., 2023). The type VI secretion system (T6SS) of bacteria is a virulence factor that can attack both eukaryotic and prokaryotic target cells. Deoxycholic acid can inhibit the Vibrio cholerae T6SS expression (Bachmann et al., 2015). Collectively, BAs exert multifaceted effects on microbial pathogenicity and anti-colonization, which are highly dependent on BA type. Therefore, modulating the size and composition of the BA pool through BA supplementation represents a key host mechanism for regulating gut microbiota density, composition, and structure.

2.3.3. Bile acids alter the microbiota in a diet-dependent manner

Changes in gut microbiota composition, proportion, or abundance – triggered by factors like drugs, exercise, diet, or malnutrition – can profoundly affect BA metabolism. The use of antibiotics, including streptomycin, cefoperazone, and vancomycin, has long been associated with reduced production of SBAs due to the inhibition of gut microbial activity (Antunes et al., 2011; Kuno et al., 2018; Theriot et al., 2014; Vrieze et al., 2014). In addition, it has been demonstrated that there are other drugs that also exhibit antibiotic properties that affect BA levels, such as paroxetine, which can also lead to an increase in the PBA pool and a decrease in SBA, while further exacerbating BA dysbiosis (Dethloff et al., 2020). Exercise has also been linked to changes in BA profiles (Molina–Molina et al., 2018). Prolonged and intense physical activity results in a reduction of total serum and fecal BAs (Meissner et al., 2011; Yiamouyiannis et al., 1993). Long-distance runners, in particular, exhibit lower levels of SBAs, likely due to exercise-induced modulation of FXR and GPBAR1 expression in the gut and liver (Wertheim et al., 2009).

Bile acid metabolism in precision nutrition will be highly focused on diet, so diet-mediated BA metabolism is highlighted here. Cholesterol intake raises BA levels by serving as a precursor for BA and enhancing the BA synthesis pathway (Wan et al., 2020). von Schwartzenberg et al. (2021) found that caloric restriction in mice reduced the total BA pool, including LCA and DCA, along with overall microbiota levels. Previous studies have also confirmed a positive correlation between high-fat diets and elevated fecal BA levels. High-fat, low-fiber diets stimulate hepatic BA synthesis, with a portion entering the colon and undergoing microbial biotransformation (Zeng et al., 2024). This shift in BA metabolism is characterized by elevated levels of secondary and unconjugated BAs and an expansion of intestinal bacteria expressing 7α-dehydrogenase and BSH (Wan et al., 2020).

The Mediterranean diet, recognized for its health benefits, is defined by a favorable fatty acid profile – low in saturated fat and cholesterol, but rich in monounsaturated and polyunsaturated fats – along with high intakes of complex carbohydrates, fiber, and polyphenols (Cani and Van Hul, 2020; De Filippis et al., 2016). Numerous studies have shown that adherence to this diet reduces systemic inflammatory markers, alleviates intestinal inflammation, and promotes intestinal mucosal healing, all of which contribute to BA homeostasis. This effect is largely attributed to the anti-inflammatory and antioxidant properties of dietary polyphenols and unsaturated fatty acids, which enhance gut microbial diversity, increase the beneficial bacteria abundance (e.g., Lactobacillus, Bifidobacterium, and E. faecalis), and reduce harmful bacteria (Cani and Van Hul, 2020). On the other hand, dietary fiber can also reduce the absorption efficiency of cholesterol and BA, and increase the excretion of BAs and cholesterol in the faeces (Ellegård and Andersson, 2007; Ellegård et al., 2000). Overall, different dietary habits may have different roles in microbiota regulation and/or BA synthesis.

3. Correlation between dietary nutrients and the regulation of BA metabolism

Dietary microbes (probiotics or food microbes) and prebiotics (dietary fiber, polysaccharides, and polyphenols, etc.) are known to influence the gut microbiome composition and quantity (Ma et al., 2023; Xiao et al., 2023; Zong et al., 2020). Dietary diversity is critical in BA metabolism, particularly in the production of SBAs by gut microbes. Developing precise dietary and nutritional strategies aimed at optimizing BA metabolism and gut microbiota could play a critical role in supporting overall health.

3.1. Dietary fats and lipid metabolism

Dietary fats are essential for cell membrane formation, organ protection, growth, development, and sustaining high levels of daily activity (Wilde and Chu, 2011). The digestion and absorption of dietary fats, as well as their physiological functions, depend on multiple factors, including fat quantity and type, concurrent intake of fiber and protein, and gut microbiota composition (Martinez-Guryn et al., 2018). Under normal physiological conditions, dietary fats are hydrolyzed into fatty acids and monoglycerides, which associate with BAs to form water-soluble micelles. These micelles facilitate the transport of lipid metabolites to the intestinal mucosa, where they are absorbed into the bloodstream via epithelial cells (Chen et al., 2021a; Durník et al., 2022). The conjugation of BAs with taurine or glycine renders them amphiphilic, reducing passive reabsorption, enhancing micelle formation, and increasing the susceptibility of dietary triglyceride (TG) to lipase action, thereby promoting fat absorption (Hofmann, 1999). Additionally, BAs regulate the activity of digestive enzymes, including trypsin, lipoprotein lipase, and pancreatic lipase, thereby maintaining fat metabolism homeostasis (Lin and Ma, 2023). Bile acids mainly regulate lipid metabolism by activating FXR and TGR5 through specific SBAs. High-fat diets are associated with elevated plasma TG and cholesterol levels, increasing the risk of metabolic disorders (Kratz et al., 2013; Schwingshackl and Hoffmann, 2013). In hepatocytes, activation of FXR reduces triacylglycerol and cholesterol synthesis and improves liver lipid metabolism. Farnesoid X receptor -deficient mice exhibit increased plasma TG and cholesterol, whereas treatment with the FXR agonist INT-747 significantly lowers these levels (Pathak et al., 2017; Wang et al., 2018). Mechanistic studies indicate that FXR inhibits hepatic lipogenesis, promotes fatty acid oxidation, and facilitates TG clearance from plasma (Clifford et al., 2021). Furthermore, FXR activation downregulates sterol regulatory element-binding protein 1c (SREBP1c) and ChREBP, key regulators of lipogenesis, thereby decreasing fatty acid synthesis and hepatic TG accumulation, which can contribute to hepatic steatosis (Ting et al., 2011). The downregulation of SREBP1c further suppresses multiple lipogenic genes, including fatty acid synthase, acetyl-CoA carboxylase (Acc) and stearoyl-CoA desaturase-1 (SCD). Additionally, FXR enhances fatty acid uptake and β-oxidation through peroxisome proliferator-activated receptor alpha (PPAR-α) activation and directly regulates lipoprotein lipases such as apolipoprotein A5 (ApoA5) and apolipoprotein CII (ApoCII) to facilitate plasma TG hydrolysis and clearance (Joyce and Gahan, 2016). Farnesoid X receptor also plays a critical role in regulating cholesterol homeostasis, including its biosynthesis and reverse transport. Farnesoid X receptor-deficient mice exhibit reduced secretion of free cholesterol into bile (Repa et al., 2002; Wong et al., 2009). Sterol regulatory element-binding protein-2 regulates de novo cholesterol biosynthesis through a pathway initiated by hydroxy-methylglutaryl CoA synthase (HMGCoAS) and hydroxy-methylglutaryl CoA reductase (HMGCoAR) (Horton et al., 1998). In mice, hepatic HMGCoAR levels can be downregulated by FXR agonists. ATP-binding cassette (ABC) transporters ABCG5/ABCG8 are key regulators of sterol excretion into bile (Lambert et al., 2003; Repa et al., 2002). Farnesoid X receptor -deficient mice have reduced ABCG5/ABCG8 expression in the liver, as well as decreased expression of cholesterol ester hydrolase (CEH) and sterol carrier protein (SCP) (Repa et al., 2002). Cholesterol ester hydrolase hydrolyzes intracellular cholesterol esters into free cholesterol, while SCP facilitates the transport of free cholesterol from hepatocytes to the canalicular membrane. Farnesoid X receptor in the liver may also regulate cholesterol reverse transport. Farnesoid X receptor -deficient mice display reduced expression of scavenger receptor class B type 1 (SRB1), hepatic lipase, CEH, and SCP, alongside increased expression of lecithin–cholesterol acyltransferase (LCAT). Additionally, FXR deficiency elevates the expression of apolipoproteins, including ApoA-IV, ApoE, and ApoC-III (Repa et al., 2002).

The intestinal farnesoid X receptor (iFXR) shares functional similarities with hepatic FXR and plays a crucial role in maintaining lipid metabolic balance. Intestinal farnesoid X receptor activation promotes FGF19/15 release, which then binds to the FGFR4/β-klotho complex to regulate lipid homeostasis and glucose homeostasis (Song et al., 2025). In FXR-deficient mice fed a high-fat diet, FGF19 treatment reduced the expression of acetyl-CoA carboxylase 2 (Acc2), stearoyl-CoA desaturase 1 (Scd1), SREBP1c and CYP7A1 in the liver, thereby promoting fatty acid oxidation and reducing triacylglycerol synthesis (Miyata et al., 2011). Similarly, FGF19 overexpression in transgenic mice significantly decreases SREBP1c expression (Calkin and Tontonoz, 2012). Additionally, iFXR regulates cholesterol absorption through SHP-dependent modulation of Niemann-Pick C1-Like 1 (NPC1L1) in the proximal small intestine. Small heterodimer partner-knockout mice exhibit increased NPC1L1 expression and enhanced cholesterol absorption (Bhatnagar et al., 2009). Likewise, FGF19/15 administration in wild-type mice suppresses NPC1L1 expression, reducing cholesterol absorption while increasing hydrophilic BA levels. Mechanistically, FGF19 signaling promotes SHP phosphorylation, which inhibits sterol regulatory element-binding transcription factor 2 (SREBF2) activity. Since SREBF2 induces NPC1L1 transcription in the upper small intestine, its inhibition reduces cholesterol uptake. Interestingly, iFXR inhibition – rather than activation – may be advantageous in metabolic disorders. Intestinal farnesoid X receptor-deficient mice fed a high-fat diet do not develop obesity (Jiang et al., 2015b), likely because FXR activation in the intestine induces ceramide synthesis, which contributes to insulin resistance via the mechanistic target of rapamycin complex 1 (mTORC1)-SREBP1c-mediated lipogenesis pathway (Chavez and Summers, 2012; Gonzalez et al., 2016; Kir et al., 2011).

Additionally, BAs influence host lipid metabolism through TGR5 (Baars et al., 2015; Chiang and Ferrell, 2020). Watanabe et al. (2012) showed that TGR5-mediated BA signaling regulates weight gain and metabolic rate in mice. G protein-coupled receptor 5 is highly expressed in brown adipose tissue (BAT), where its activation increases energy expenditure by inducing type 2 deiodinase (D2), which catalyzes the conversion of thyroxine (T4) into its active form, triiodothyronine (T3) (Huang et al., 2019). Triiodothyronine promotes mitochondrial autophagy in BAT, enhancing mitochondrial turnover by increasing synthesis relative to clearance, thereby supporting mitochondrial biogenesis and preserving mitochondrial integrity during thermogenesis (Yau et al., 2019). Furthermore, T3 upregulates the expression of thermogenic genes (uncoupling protein 1 [UCP1], PR domain zinc finger protein 16 [PRDM16], and peroxisome proliferator-activated receptor γ coactivator 1α [PGC1α]), fatty acid oxidation genes (carnitine palmitoyltransferase 1B [CPT1B] and acyl-CoA synthetase long-chain family member 1 [ACSL1]), and lipolysis-related genes (patatin-like phospholipase domain-containing protein 2 [PNPLA2] and lipase E [LIPE]), collectively enhancing systemic metabolism (Bianco and McAninch, 2013; Yau et al., 2019; Zekri et al., 2022). This TGR5-mediated pathway functions not only in BAT but also in skeletal muscle, where it similarly promotes thermogenesis and energy expenditure via TGR5 and D2 activation (Köhrle and Frädrich, 2022). White adipose tissue (WAT) primarily stores excess energy, whereas BAT generates heat (Zhang et al., 2021). White adipose tissue can undergo “browning,” a process in which beige adipocytes with thermogenic properties emerge (Giralt and Villarroya, 2013). G protein-coupled receptor 5 signaling promotes the phosphorylation of ERK at serine 616, which activates dynamin-related protein 1 (DRP1), to regulate mitochondrial fission (Velazquez-Villegas et al., 2018). Additionally, TGR5 enhances the expression of mitochondrial fission factor (MFF), which recruits DRP1 to mitochondria. These two pathways (TGR5–MFF and TGR5–ERK–DRP1) enhance mitochondrial fission, increasing mitochondrial abundance and thermogenic capacity in WAT (Velazquez-Villegas et al., 2018). Moreover, TGR5 activation stimulates the cAMP–protein kinase A (PKA)–CREB pathway, upregulating PGC1α, a key regulator of UCP1, thereby improving mitochondrial function and thermogenesis (Qi et al., 2020; Song et al., 2020b). Beyond UCP1-mediated thermogenesis, TGR5 also upregulates mitochondrial creatine kinase 2 (CKMT2), which drives the futile creatine cycle (FCC) to generate heat (Bertholet et al., 2017; Kazak et al., 2015; Sun et al., 2021). Thermogenesis requires energy substrates, with fatty acids serving as key fuels for mitochondrial β-oxidation (Esteves et al., 2021). G protein-coupled receptor 5 activation stimulates the cAMP–PKA pathway, promoting lipolysis in inguinal WAT by phosphorylating hormone-sensitive lipase (HSL), leading to TG hydrolysis and fatty acid release for mitochondrial oxidation (Ding et al., 2021; Recazens et al., 2021; Turchi et al., 2020).

In swine nutrition, endogenous FXR agonists, including CDCA, DCA, and CA, exhibit increased levels in pigs following a high-fat diet (Zheng et al., 2021a). Chenodeoxycholic acid can activate FXR and promote hepatic fatty acid β-oxidation and inhibit lipid uptake by inducing peroxisome proliferator-activated receptor α (PPARα) and inhibiting CD36, which highly affects hepatic lipid metabolism (Xi and Li, 2020). In addition, Maj et al. (2023) reported that a high-fat diet decreases FGF19 expression in the distal ileum, significantly affecting lipid transport and TG metabolism. They also observed an upregulation of CYP8B1, the enzyme responsible for catalyzing CA synthesis, leading to increased CA levels and elevated CA-to-CDCA ratios in the liver, ileum, and blood, along with reduced FGF19 expression (Maj et al., 2023). Similarly, Bisschop et al. (2004) found that a high-fat, low-carbohydrate diet increased the blood molar ratio of CA and lowered CDCA levels compared to a low-fat, high-carbohydrate diet. This alteration reduces FXR activation because CA is a less potent FXR agonist than CDCA, consequently hindering the production and signaling of gut-derived FGF19 in the liver. It is worth mentioning that young Iberian pigs fed a high-calorie, low-fat diet—which resulted in excess calories being provided entirely by sugars—maintained BA levels within the normal range and exhibited a slight decrease in circulating FGF19 levels (Cluzel et al., 2022). However, a high-fat, high-fructose diet led to an increase in PBAs and a significant 10-fold drop in circulating FGF19, contributing to greater liver damage in young Iberian pigs (Maj et al., 2022).

3.2. Carbohydrate and glucose metabolism

Carbohydrates, including sugars, starches, and fibers, are essential macronutrients and the primary energy source for pigs during growth and development. Their digestion and metabolism vary based on chemical structure and solubility (Zong et al., 2024). However, excessive carbohydrate intake is linked to obesity, diabetes, and metabolic disorders (Goldenberg et al., 2021; Ludwig et al., 2021; Moszak et al., 2020). Soluble carbohydrates are broken down into monosaccharides by digestive enzymes, absorbed in the small intestine, and pass into the bloodstream as glucose; providing energy and raising postprandial blood glucose levels, which triggers insulin secretion (Dimitriadis et al., 2021). Dietary fiber, a form of carbohydrate resistant to digestive enzymes, is classified as soluble or insoluble, a topic further explored in 3.3 dietary fiber. Unlike lipids, BAs are not directly involved in carbohydrate digestion and absorption but play a crucial role in carbohydrate metabolism. Bile acids can promote insulin release and influence carbohydrate metabolism by activating FXR and TGR5, both of which are expressed in pancreatic cells (Fig. 3) (Higuchi, 2020; Lun et al., 2024). In pancreatic β-cells, BA-TGR5 and BA-FXR signaling increases intracellular calcium levels, enhancing GSIS (Higuchi, 2020). Farnesoid X receptor activation in β-cells induces GLUT2 relocalization at the membrane, promoting glucose uptake and insulin release (Zhao et al., 2020). G protein-coupled receptor 5 activation in pancreatic α-cells shifts their secretion from glucagon to GLP-1 by inducing prohormone convertase1/3 (PC1/3) expression, exerting a paracrine effect on β-cells (Saikia et al., 2021). Disruptions in enterohepatic BA synthesis and circulation can impact GSIS in the pancreas via hepatopancreatic BA signaling pathways (Liu et al., 2024; Schertzer and Lam, 2021; Tawulie et al., 2023; Yan et al., 2021).

Fig. 3.

The interaction between dietary nutrients, the bile acid–FXR/TGR5 signaling pathways, and glucagon-like peptide-1 (GLP-1) secretion plays a central role in metabolic regulation. FXR = farnesoid X receptor; TGR5 = G protein-coupled receptor 5; DCA = deoxycholic acid; UDCA = ursodeoxycholic acid; ATP = adenosine triphosphate; ADP = adenosine diphosphate; GLP-1 = glucagon-like peptide-1; BSH = bile salt hydrolase.

G protein-coupled receptor 5 is widely expressed in the intestine, with the highest levels found in enteroendocrine L cells (Sorrentino et al., 2020). Bile acids released into the intestine activate TGR5, stimulating GLP-1 secretion by enteroendocrine L cells (Tian et al., 2022). This activation enhances mitochondrial oxidative phosphorylation, promoting GLP-1 release and supporting glucose homeostasis (Fig. 3). G protein-coupled receptor 5-induced GLP-1 also improves insulin resistance in skeletal muscle by activating the cAMP/PKA pathway, upregulating Sirtuin1 (SIRT1), and promoting glucose transporter 4 (GLUT4) translocation, thereby enhancing glucose uptake (Sasaki et al., 2021; Wei et al., 2023). Additionally, GLP-1 enhances insulin signaling by increasing phosphorylated insulin receptor substrate 1 (IRS1) and phosphorylated AKT levels (Duan et al., 2012; Jeon et al., 2019). It also promotes glycogen synthesis by upregulating glycogen synthase 1/2 (GYS1/2) through AMPK phosphorylation and may affect GLUT4 translocation to the cell membrane (Andreozzi et al., 2016; Wu et al., 2022). Furthermore, GLP-1 analogs enhance autophagy via Sestrin2 (SESN2) regulation in skeletal muscle cells, promoting GLUT4 expression and effectively increasing glucose uptake (Tian et al., 2023b).

Farnesoid X receptor is also highly expressed in enteroendocrine L cells (Yun et al., 2024). Farnesoid X receptor-deficient mice display delayed glucose uptake, highlighting its role in glucose metabolism (Li et al., 2013; Trabelsi et al., 2015). Upon activation by BAs or specific FXR agonists, FXR regulates glucose homeostasis through multiple mechanisms, including the suppression of gluconeogenic genes (Adorini and Trauner, 2023; Du et al., 2024; Zhao et al., 2021). It is worth mentioning that FXR enhances glucose homeostasis by inducing the expression of FGF15/19 and regulating BA synthesis through hydroxylases CYP7A1 and CYP8B1 (Song et al., 2025; Xiao et al., 2025). Treatment with FGF19 or overexpression of FGF19 reduces mice body weight and improves glucose homeostasis (Drexler et al., 2023; Zangerolamo et al., 2025). Similarly, mice with FGF15 deficiency have impaired glucose homeostasis (Bozadjieva-Kramer et al., 2021). Farnesoid X receptor 15/19 promotes glycogen synthesis, lowers plasma glucose levels, and inhibits hepatic gluconeogenesis by suppressing the CREB-PGC1α pathway (Gonzalez et al., 2016). Farnesoid X receptor activation further influences glucose metabolism by inhibiting ChREBP, thereby downregulating glycolysis-related genes and reducing PEPCK mRNA expression, ultimately enhancing glycogen synthesis in hepatocytes (Péan et al., 2020; Wang et al., 2015). These effects are mediated by SHP, which inhibits HNF4α-driven transcription and forkhead box O1 (FOXO1) recruitment at the PEPCK promoter, contributing to lower serum glucose levels in wild-type mice (Wattanavanitchakorn et al., 2018; Yamagata et al., 2004). Additionally, SHP suppresses growth hormone-induced gluconeogenesis by inhibiting STAT5 signaling, further reinforcing FXR's role in glucose regulation (Péan et al., 2020). Recent studies have identified FXR-responsive elements within the TGR5 promoter, indicating a regulatory relationship between these receptors (Pathak et al., 2017). Mice deficient in either FXR or TGR5 exhibit impaired GLP-1 secretion. Notably, the dual FXR/TGR5 agonist INT-767 stimulates GLP-1 secretion in TGR5-deficient mice but not in FXR-deficient mice, indicating that FXR activation is critical for GLP-1 secretion, potentially through interactions with TGR5 signaling pathways (Pathak et al., 2017, 2018).

In swine nutrition, pigs exhibit a high resistance to diet-induced type 2 diabetes mellitus (T2DM) despite following a “diabetic” lifestyle (Chávez-Talavera et al., 2020). Studies have demonstrated that HCA regulates blood glucose by activating TGR5 while inhibiting FXR, which promotes GLP-1 secretion from enteroendocrine L cells through a distinct signaling mechanism (Zheng et al., 2021b). Chávez-Talavera et al. (2020) showed that total HCA and total HCA/total CDCA ratio were negatively correlated with body mass index and homeostasis model assessment of insulin resistance (HOMA-IR). Similarly, Kong et al. (2024) showed that an increase in total BA and CDCA levels led to FXR activation, increased FXR binding to the glucagon-like peptide-1 receptor (GLP-1R) promoter, and enhanced recruitment of the histone acetyltransferase SRC1. This process resulted in increased acetylation of histone H3 at the promoter, thereby enhancing the β-cell response to GLP-1. Hyodeoxycholic acid can activate TGR5 on enteroendocrine L cells and promote the secretion of incretin GLP-1, and several studies have demonstrated a correlation between HDCA levels and diabetes remission, suggesting HDCA's role in the resolution of diabetes (Wahlström et al., 2024). Furthermore, the transplantation of healthy upper small intestinal microbiota has been shown to lower levels of TCDCA and reduce blood glucose by activating BSH. This effect is mediated by modulating the upper small intestinal microbiota–ileum–liver–blood–dorsal vagus nerve complex axis, targeting TCDCA-FXR interactions, and ultimately regulating glucose metabolism (Li et al., 2021b; Waise et al., 2021). In summary, the mechanisms by which modulation of the FXR–GLP-1 and TGR5–GLP-1 axes through endogenous or exogenous BA signaling influences glucose tolerance are likely to be elucidated in the near future.

3.3. Dietary fiber

A high-fiber diet is often associated with a low-fat diet, influencing host metabolism through the regulation of gut microbiota (Sun et al., 2023). Dietary fiber is categorized as crude feed or microbial-available carbohydrate and is traditionally classified into soluble fiber, which has physiological activity, and insoluble fiber, which adds bulk to the diet. Foods rich in dietary fiber are known to improve cardiovascular and gastrointestinal health, lower cholesterol levels, and reduce postprandial blood sugar (Gill et al., 2021). Numerous studies have shown that dietary fibre intake promotes the growth of beneficial intestinal bacteria (Bifidobacterium, Lactobacillus, and Akkermansia) (Swanson et al., 2020). Different dietary fibres have specific preferences for probiotics. For instance, the consumption of insoluble dietary fiber extracted from soybeans increases the relative abundance of Lactobacillus and the Lachnospiraceae_NK4A136_group in obese mice while reducing the abundance of Lachnospiraceae and Bacteroides_acidifaciens (Wang et al., 2021a). Similarly, insoluble dietary fiber rich in lignin enhances the abundance of Clostridium leptum and Bacteroides species, which are negatively correlated with total plasma cholesterol levels (Wang et al., 2021a). Bile acids are not directly involved in the digestion, absorption, or metabolism of dietary fiber. However, dietary fiber influences BA homeostasis by promoting BA excretion and modifying the composition of the gut microbiota, thereby increasing the overall hydrophobicity and diversity of the BA pool. The BA spectrum in the gut is highly dependent on the type and quantity of dietary fiber. Notably, dietary fiber plays a pivotal role in the SBA metabolism, and its absence can disrupt BA metabolism, with direct consequences for gastrointestinal function (Ocvirk and O'Keefe, 2021). Clinical and animal studies highlight the significance of a high-fiber diet (Kastl et al., 2022). For instance, a clinical study demonstrated that wheat bran consumption reduced fecal levels of DCA and LCA (Singh et al., 2019). Additionally, whole grain diets have been shown to significantly elevate the concentrations of TCA, GCA, and chenodeoxycholic acid compared to refined grain diets, thereby activating FXR and TGR5, which contribute to blood glucose regulation (Ginos et al., 2018; Singh et al., 2019). Similarly, Liu et al. (2020) reported that a whole grain diet lowers serum and liver lipid levels, including total cholesterol and TG, by enhancing intestinal BA reabsorption and reducing BA excretion.

Animal studies have yielded similar findings. Since BA metabolism is mediated by gut microbiota, soluble dietary fiber can influence the composition of the BA pool by altering microbial abundance and structure. Well-studied soluble dietary fibers include inulin, arabinoxylan, resistant starch, β-glucan, and pectin. Fructose-rich inulin is a prebiotic and natural polysaccharide composed of multiple β2-1 linked D-fructose and reducing end glucose units (Man et al., 2021). It is resistant to digestion and absorption in the gastrointestinal tract and is instead metabolized by gut microbiota. Inulin is abundant in the tubers and roots of plants such as artichokes, chicory, and dahlia, and its health benefits have been extensively documented (Man et al., 2021). Shen et al. (2024) demonstrated that supplementing mice with alcohol-related liver disease with 20% inulin and oligofructose for ten consecutive days increased the gut abundance of Bacteroides acidifaciens, a bacterium that regulates the BA profile by expressing BSH to produce unconjugated BAs. Bile salt hydrolases further activates intestinal FXR and its downstream FGF15, exerting beneficial effects (Shen et al., 2024). Additionally, administering 10% oligofructose for one week increased the intestinal levels of 6α-hydroxylated BAs (ω-muricholic acid [ωMCA], HCA and HDCA), thereby improving glucose metabolism via TGR5 signaling and enhanced GLP-1R activity (Makki et al., 2023). Similarly, arabinoxylan supplementation increased the relative abundance of Prevotellaceae_UCG_001, Lachnospiraceae_NK4A136_group, Clostridia_UCG_014, Alistipes, Bacteroides, and Ruminococcus, which influence SBA production, particularly DCA and LCA, by promoting 7α-dehydroxylation activity (Lin et al., 2024). Oat β-glucan not only binds BAs and promotes their excretion but also modulates gut microbiota composition, thereby influencing BA metabolism. Huang et al. (2025) demonstrated that supplementing mice with 10% high-molecular-weight β-glucan for two consecutive months increased the abundance of 7-ketodeoxycholic acid in the gut, which was associated with a reduction in Faecalibaculum faecium and an increase in Lactobacillus and Bifidobacterium. In a corresponding cell experiment, 7-ketodeoxycholic acid, as an FXR antagonist, inactivated the FXR-FGF15 signaling pathway in the ileum, resulting in an enhanced ability to synthesize BAs via alternative pathways (Huang et al., 2025). Resistant starch as a soluble dietary fiber is widely found in natural plants such as potatoes, corn, and rice. Compared to other starches, resistant starch is more difficult to degrade, is digested at a slower rate, and enters the bloodstream more gradually. Studies suggest that resistant starch enhances gut microbiota resilience to adverse conditions, including acidic environments, BAs, pepsin, and trypsin. Reuter et al. (2024) reported that supplementing mice with 16.5% resistant starch for two months altered microbial-mediated SBA metabolism, leading to an increase in DCA. Long-term resistant starch also promotes the production of CA, CDCA, β-MCA, LCA and UDCA in hyperlipidemic rats, and reduced the levels of TCA, dehydro-LCA, isoLCA, LCA-3-S and THDCA, while inhibiting the abundance of Romboutsia, Bacillus, Blautia, norank_f_Muribaculaceae and norank_f_Eubacterium_coprostanoligenes_group in the intestine. Pectin, a prebiotic fiber, is abundant in various fruits and vegetables (Lei et al., 2023). Supplementation with 5% pectin for three weeks significantly altered the BA pool composition in piglets, increasing the concentrations of HCA, HDCA, and THDCA, while reducing the abundance of Enterococcus and increasing Lactobacillus, Streptococcus, and Clostridium sensu stricto 1 (Yin et al., 2024). Correlation analysis suggests that dietary pectin may exert beneficial effects by modulating interactions between gut microbiota and BA metabolism within the enterohepatic cycle (Yin et al., 2024). Similarly, Wang et al. (2024) demonstrated that continuous supplementation with 400 mg/kg pectin for 15 weeks enhanced BA excretion, facilitated BA transport, inhibited BA reabsorption, and promoted cholesterol excretion. Additionally, pectin significantly modified the BA composition in mouse feces, leading to substantial alterations in the types and concentrations of functionally bound BAs. These changes inhibited FXR/FGF15 signaling in the ileum and stimulated hepatic BA synthesis (Wang et al., 2024).

3.4. Amino acid metabolism

Activation of hepatic FXR signaling is closely linked to amino acid metabolism. Specifically, FXR activation enhances glutamate shunting to ammonia by upregulating glutamine synthetase (GLUL) and promotes urea cycle flux through the induction of carbamoyl phosphate synthetase 1 (CPS1), argininosuccinate synthetase 1 (ASS1), and argininosuccinate lyase (ASL) (Massafra et al., 2017). Additionally, activation of the FGFR4/βK-ERK axis stimulates RSK and mitogen-activated protein kinase–interacting serine/threonine protein kinase 1 (MKNK1), leading to the phosphorylation of eukaryotic translation initiation factors 4B (EIF4B) and 4E (EIF4E) (Kir et al., 2011). Phosphorylation of EIF4B and EIF4E is critical for initiating cap-dependent translation in eukaryotic cells (Gingras et al., 1999). Furthermore, RSK phosphorylates ribosomal protein S6 (rpS6), a key modulator of ribosomal translation that enhances cap-dependent translation efficiency (Kir et al., 2011). In addition, amino acids are essential for BA synthesis and metabolism, with some BAs associated with the plasma amino acid metabolic pathway (Alemán et al., 2018). For instance, seafood is rich in taurine and aromatic amino acids, which significantly affect gut microbiota and BA production (Guzior and Quinn, 2021). Casein and other milk proteins, containing branched-chain amino acids, enhance BA utilization and are particularly effective in preventing obesity (Guzior and Quinn, 2021). Similarly, Tang et al. (2024b) demonstrated that dietary supplementation with 2% hydroxyproline improved feed conversion efficiency and reduced diarrhea in early-weaned piglets. These effects were associated with elevated levels of glycine, glutathione, and glycine-conjugated BAs, as well as reduced plasma cortisol and methionine sulfoxide levels.

4. Pig nutrition affects pig health and development through BA metabolism

4.1. Bile acids maintain pig gastrointestinal health

Bile acids are not only essential for bile flow and the digestion and absorption of dietary lipids, but they also function as enteroendocrine hormones with critical roles in regulating hepatic metabolism and maintaining intestinal integrity. Bile acids also shape the intestinal environment by influencing the growth and stability of commensal microbiota, preserving barrier integrity, and modulating immune responses. The interplay between BA metabolism and gut microbes has been extensively discussed in sections 2.1, 2.2, 2.3. The intestinal barrier serves as a key defense mechanism, protecting the organism from bacteria, antigens, and toxic metabolites. The physical and biological functions of intestinal epithelial and endothelial cells are crucial for maintaining the intestinal barrier. Dysregulation of epithelial transit and barrier function has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD), chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Diet serves as a key regulator of the mammalian intestinal epithelial barrier. Emerging evidence indicates that the prevalence of common gastrointestinal diseases in pigs, such as IBD, irritable bowel syndrome (IBS), and colorectal cancer (CRC), is strongly correlated with diet type and composition. This section discusses the regulation of nutrient supply and integrative factors of intestinal homeostasis by BAs as well as the association of BAs with common gastrointestinal disorders (Fig. 4).

Fig. 4.

Interactions between gut microbiota, microbial bile acids and host immunity. DCA = deoxycholic acid; LCA = lithocholic acid; isoDCA = isodeoxycholic acid; isoLCA = isolithocholic acid; isoalloLCA = isoallolithocholic acid; 3-oxoLCA = 3-oxolithocholic acid; OCA = obeticholic acid; BSH = bile salt hydrolase; DC = dendritic cell; Treg = regulatory T cell; Th1 = T helper 1 cell; Th17 = T helper 17 cell; Teff = effector T cell; Foxp3 = forkhead box protein P3; FXR = farnesoid X receptor; TGR5 = G protein-coupled receptor 5; VDR = vitamin D receptor; PXR = pregnane X receptor; CAR = constitutive androstane receptor; ASBT = apical sodium-dependent bile acid transporter; TNF-α = tumor necrosis factor-alpha; IL-1β = interleukin-1 beta; IL-6 = interleukin-6; IL-10 = interleukin-10; IL-12 = interleukin-12; IL-17A = interleukin-17A; IL-22 = interleukin-22; IFN-γ = interferon-gamma; FGF19 = fibroblast growth factor 19; BSH = bile salt hydrolase. Green upward arrows denote an increase in cytokine expression, while red downward arrows indicate a reduction in inflammatory factor levels.

4.1.1. Bile acids as integrators of nutrient supply, hormone secretion, and gut motility

Intestinal BA levels fluctuate based on diet type and intake, with BA-responsive receptors in enterocytes detecting nutrient availability and eliciting appropriate physiological responses. Farnesoid X receptor and TGR5, in particular, regulate a series of events, including fluid transport, hormone release, transporter protein expression, intestinal motility, and secretory responses that allow nutrients, fluids, and ions to be absorbed and utilized along the gastrointestinal tract.

Bile acids serve as critical regulators of enteroendocrine hormones that influence appetite and metabolism. G protein-coupled receptor 5 mediates BA-induced GLP-1 release through a cAMP-dependent mechanism (Müller et al., 2019). The established nutrient triggers for GLP-1 secretion are glucose and free fatty acids. G protein-coupled receptor 5 exhibits functional synergy with G protein–coupled receptors (GPCRs) involved in fatty acid signaling, which corresponds with the heightened response to BAs seen in high-fat diets (Goldspink et al., 2018; Harach et al., 2012; Hauge et al., 2017; Thomas et al., 2009). Bile acids also play a crucial role in regulating colonic electrolyte and fluid homeostasis by stimulating or inhibiting electrolyte and fluid secretion, a process that is highly dependent on the type and concentration of BA (Hegyi et al., 2018). The FXR agonist GW4064 inhibits Ca²⁺ and cAMP-dependent secretory responses and restores the osmotic drive for colonic fluid absorption (Keating et al., 2009; Mroz et al., 2014). Research with colonic epithelial cells and crypts has revealed that supraphysiological concentrations of BAs elevate intracellular Ca²⁺ levels, promoting the secretion of Cl⁻ from epithelial cells, which can drive intestinal fluid secretion and lead to secretory diarrhea. Conversely, the application of natural and synthetic TGR5 agonists has been found to reduce Cl⁻ secretion in the rat colon (Keitel et al., 2009; Ward et al., 2013).

Bile acids are recognized as modulators of intestinal motility, eliciting different responses depending on the region of the gastrointestinal tract (Camilleri et al., 2020; Dike et al., 2024). They slow gastric emptying, reduce small intestine transit speed, and enhance colonic motility and transit (Li et al., 2021c; Soares et al., 2020). G protein-coupled receptor 5 is found in gastric smooth muscle, where its activation inhibits ras homolog gene family member A (RhoA), causing gastric muscle relaxation (Rajagopal et al., 2013). In the colon, SBA promote the release of serotonin from intestinal mucosal cells and calcitonin gene-related peptide (CGRP) from intrinsic primary afferent neurons, which stimulates peristalsis (Alemi et al., 2013). Physiologically, these mechanisms are compatible with the concept of BAs as a substitute for nutrient availability. After feeding, BAs slow peristalsis in the small intestine to facilitate nutrient absorption; subsequently, BAs in the distal intestine stimulate peristalsis and promote defecation (Bajor et al., 2010).

4.1.2. Correlation between BA metabolism and gastrointestinal immunity

Pigs encounter various external stimuli throughout their breeding, including bacterial and viral infections, vaccinations, weaning, pregnancy to farrowing, transportation stress, and heat stress. These factors stimulate the production of multiple biomarkers, such as reactive oxygen species, malondialdehyde, cortisol, and inflammatory cytokines. Under such conditions, immune function and intestinal permeability may be compromised, resulting in decreased feed intake, diarrhea, constipation, or severe metabolic disorders. Consequently, inflammatory diseases of the gastrointestinal tract are particularly susceptible to development during this period. The development of gastrointestinal inflammatory diseases is closely linked to gut dysbiosis, which triggers excessive immune responses to pro-inflammatory microorganisms, leading to chronic inflammation and tissue damage. This dysbiosis compromises the integrity of the intestinal mucosal barrier, resulting in reduced mucus layer thickness and increased intestinal permeability, ultimately impairing the intestinal immune system. Such diseases are characterized by decreased gut microbial diversity, marked by a reduction in beneficial bacteria and an increase in potentially pathogenic species (Di Vincenzo et al., 2022). In addition, the gut microbiota in gastrointestinal inflammatory diseases showed impaired depolymerization and biotransformation, with elevated levels of conjugated BAs, reduced levels of SBAs (e.g., DCA, LCA, and TLCA), and elevated levels of PBAs (Das et al., 2019; Heinken et al., 2019). This shift suggests a reduction in SBA-producing bacteria, including Firmicutes, Clostridium IV and XIVa, Butyricicoccus, Clostridium, Faecalibacterium, Ruminococcaceae, and Roseburia (Heinken et al., 2019). These bacteria contain BSH and HSDHs enzymes which are responsible for the unbinding and biotransformation of BAs (Lloyd-Price et al., 2019; Sinha et al., 2020; Yang et al., 2021). Changes in specific BA ratios can serve as biomarkers of gut microbiota alterations. For instance, the DCA/(DCA + CA) ratio, an indicator of 7α-dehydroxylation activity, is positively correlated with Clostridium subcluster XIVa (Sinha et al., 2020). Compared to healthy individuals, serum DCA/(DCA + CA) ratios are significantly lower during both remission and exacerbation phases of gastrointestinal inflammatory diseases (Murakami et al., 2018).

The gut microbiome plays a crucial role in modulating the host immune system by influencing the development and function of immune cells (Neurath, 2024). Inflammatory bowel diseases are characterized by chronic inflammation driven by a dysregulated intestinal immune response (Lee et al., 2024). Reduced SBA levels have been implicated in intestinal inflammation, highlighting the importance of BA metabolism in immune homeostasis (Lee et al., 2024). Bile acid metabolism has emerged as a key determinant of immune homeostasis due to its profound impact on various immune cells of both the innate and adaptive immune systems (Won et al., 2025). Secondary BAs have been shown to alleviate intestinal inflammation by acting on key immune cells, including dendritic cells, macrophages, and T cells. A balanced ratio of T helper 17 (Th17) cells and Treg cells is essential for maintaining intestinal barrier integrity, microbiome diversity, nutrient absorption, and overall gastrointestinal health (Silva et al., 2016). Disruptions in this balance contribute to intestinal inflammation, and its regulation is considered a potential therapeutic strategy (Yan et al., 2020). Th17 is a unique subset of CD⁴⁺ T cells, which is characterized mainly by the secretion of IL-17 (Cerboni et al., 2021). These cells express the transcription factor retinoic acid-related orphan receptor γt (RORγt), and produce IL-21, IL-22, IL-23, and other cytokines, which are critical in the pathogenesis of autoimmune and infectious diseases. Th17 cells and their associated cytokines are generally considered to exacerbate intestinal inflammation (Jiang et al., 2023). In contrast, Treg cells exert an immunoregulatory effect by suppressing immune responses and promoting immune tolerance (Atarashi et al., 2013). Treg cells are characterized by the expression of forkhead box protein P3 (Foxp3) and can produce TGF-β, IL-10, and IL-35 (Zhang et al., 2023a). They are recognized to suppress various immune responses and inflammation. Naïve CD⁴⁺ T cells can differentiate into Th17 cells or Treg cells.

The proliferation and differentiation of Th17 and Treg cells are interdependent, with the potential to transition into one another under certain conditions (Bettelli et al., 2006). Secondary BAs modulate the balance between Th17 and Treg cells. Hang et al. (2019) identified two SBAs, 3-oxoLCA and isoalloLCA, as key regulators of naïve CD⁴⁺ T cell differentiation in mice. Specifically, 3-oxoLCA can inhibit the differentiation of Th17 cells and reduce the expression of IL-17a, while isoalloLCA enhances Treg cell induction (Hang et al., 2019). Further studies have shown that 3-oxoLCA, isoLCA, and LCA-3-S directly interact with the transcription factor RORγt, thereby limiting Th17 differentiation (Hang et al., 2019; Paik et al., 2022; Xiao et al., 2022b). Additionally, SBAs promote Treg cell development indirectly by inducing tolerogenic antigen-presenting cells (Hang et al., 2019). Colonization of germ-free mice with isoDCA-producing bacteria significantly increased colonic Treg cell populations (Li et al., 2021d). In addition, isoDCA indirectly promoted Foxp3 expression in naïve CD⁴⁺ T cells by antagonizing FXR activity to form an anti-inflammatory phenotype in dendritic cells, thereby promoting Treg cell production (Campbell et al., 2020). The isoDCA-producing microbiota facilitated colonic Treg cell expansion in a CNS1-dependent manner (Campbell et al., 2020). IsoalloLCA enhanced Treg cell differentiation by producing mitochondrial ROS, which caused an increase in Foxp3 expression (Campbell et al., 2020; Li et al., 2021d). In addition, Song et al. (2020a) found that LCA and 3-oxoLCA also regulate the expression of RORγ⁺ Foxp3⁺ Treg cells through the nuclear receptor VDR. In mice, 3-oxoLCA and isoalloLCA synergistically reduced the ratio of Th17 to Treg cells in the colon, but neither of these two bioactive substances alone produced these effects (Campbell et al., 2020; Hang et al., 2019; Li et al., 2021d; Paik et al., 2022). Collectively, these findings highlight the role of SBAs in modulating intestinal inflammation by regulating the balance between pro-inflammatory Th17 cells and immunosuppressive Treg cells.

CD⁴⁺ T effector (Teff) cells upregulate the xenobiotic transporter multidrug resistance protein 1 (MDR1) (encoded by Abcb1a) in the intestinal lamina propria to mitigate BA toxicity and suppress intestinal inflammation (Cao et al., 2017; Chen et al., 2021b). The nuclear receptor CAR (encoded by Nr1i3), a regulator of MDR1 expression in T cells, prevents BA toxicity and intestinal inflammation in mice. In the mouse ileum, Teff cells upregulate MDR1, thereby reducing oxidative stress and maintaining homeostasis in Teff cells exposed to conjugated BAs (Cao et al., 2017; Chen et al., 2021b). Coordinated interactions between ileal mucosal Teff cells and conjugated BAs regulate intestinal immune homeostasis. Teff cells lacking MDR1 develop mucosal dysfunction and intestinal inflammation after transfer to Rag1^−/− mice (Cao et al., 2017). Blocking the reabsorption of conjugated BA in the ileum restores homeostasis in MDR1-deficient cells and suppresses ileal inflammation (Cao et al., 2017). Mechanistically, CAR acts as a regulatory factor of MDR1 expression and induces the expression of the key anti-inflammatory cytokine IL-10 (Chen et al., 2021b). In T cell-reconstituted Rag1^−/− or Rag2^−/− mice, T cell deficiency of CAR exacerbates BA-driven ileitis, while drug-activated CAR suppresses ileitis (Chen et al., 2021b).

G protein-coupled receptor 5 activation can regulate the M1/M2 phenotype of intestinal macrophages and inhibit the production of pro-inflammatory cytokines such as TNF-α, interferon-gamma (IFN-γ), IL-1β, IL-6 and chemokine (C–C motif) ligand 2 (CCL2), suggesting that BAs may exert an immunomodulatory effect through TGR5 (Keitel et al., 2008). Guo et al. (2016) show that BAs and TGR5 activation inhibit NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation via the TGR5-cAMP-PKA axis, which endogenously constrains NLRP3 inflammasome-associated inflammation. Furthermore, TGR5 activation in dendritic cells suppresses NF-κB binding to the promoters of pro-inflammatory cytokines. Activation of TGR5 in ISCs triggers the SRC–YAP signaling pathway, leading to ISC renewal and proliferation (Sorrentino et al., 2020). Supplementation with DCA or LCA enhances ISC stemness through TGR5 activation, inhibits NLRP3 inflammasome activity, reduces inflammatory cytokine expression, and alleviates intestinal inflammation (Sorrentino et al., 2020). In addition, activation of FXR inhibits the Toll-like receptor 9 (TLR9)-dependent pro-inflammatory response of intestinal macrophages (Wildenberg and van den Brink, 2011). Obeticholic acid-mediated FXR activation decreases the differentiation and activation of intestinal DCs and prevents CD¹⁴⁺ monocytes from maturing into DCs (Gadaleta et al., 2011). Farnesoid X receptor activation in murine natural killer T cells also suppresses the production of osteopontin, IL-1β, and IFN-γ (Mencarelli et al., 2009). Overall, these data suggest that specific SBAs exert differential effects on the proliferation and differentiation of macrophages, DCs and naïve CD⁴⁺ T cells, thereby influencing the inflammatory response in the gastrointestinal tract.

4.1.3. Gastrointestinal inflammatory diseases treatments targeting the gut microbiota-BA axis

High-fat, high-protein, low-fiber diets are linked to the development and exacerbation of gastrointestinal inflammatory diseases (Holscher, 2017; Hou et al., 2011). Diet is highly correlated with the gut microbiota and the composition of BAs (Lewis et al., 2017). Enteral nutrition therapies utilize direct anti-inflammatory actions to alter the gut microbiota composition, reduce intestinal barrier permeability, and regulate immune responses (Whelan, 2013; Whelan et al., 2005). Moreover, enteral nutrition has been shown to partially restore the BA composition, specifically by increasing levels of hydrophobic BAs, such as LCA, which activate TGR5 receptors and reduce inflammation (Diederen et al., 2020). Among the most common enteral nutrition therapies for pigs is the inclusion of dietary fiber, with the interplay between dietary fiber and BAs discussed in section 3.3. It is worth noting that gastrointestinal inflammatory diseases are often intolerant of fermentable fibre-rich foods (Kuang and Binion, 2022). Mice fed a low-fiber diet, compared to a naturally fiber-rich diet, showed increased susceptibility to severe dextran sodium sulfate (DSS)-induced colitis. This condition worsened when highly soluble fiber inulin was added to the low-fiber diet (Llewellyn et al., 2018). In contrast, adding the moderately soluble fiber psyllium to a low-fiber diet provided potent protection in a model of DSS-induced colitis and T-cell-transferring colitis, and psyllium fiber was anticolitis through activation of the FXR (Bretin et al., 2023). These findings indicate the effects of fiber are contingent upon fiber type and the surrounding environment.

Numerous studies have demonstrated that probiotics, including Bifidobacterium, Lactobacillus, and Streptococcus thermophilus, can serve as dietary supplements to modulate gut microbiota, alter intestinal BA metabolism, and strengthen intestinal barrier integrity (Gareau et al., 2010; Sanders et al., 2019; Zhao et al., 2023; Zhou et al., 2024; Zoumpopoulou et al., 2018). Bifidobacterium longum CECT 7894 has been shown to increase the abundance of SBAs such as LCA, CDCA, UDCA, and HCA, which positively correlate with elevated levels of BSH and 7α-dehydroxylases (Xiao et al., 2022a). This strain alleviates the severity of DSS-induced colitis by modulating the gut microbiota composition and BA metabolism (Xiao et al., 2022a). Moreover, evidence suggests that mixtures of multiple probiotic strains are often more effective than single-strain treatments. For example, the GUT-103 and GUT-108 strains act synergistically to enhance the intestinal abundance of beneficial bacteria and restore gut microbial composition and function (van der Lelie et al., 2021).

Prebiotics are typically carbohydrates with diverse molecular structures, including polyphenols and polyunsaturated fatty acids, that enhance the composition and abundance of beneficial bacteria in the gut microbiota. For instance, plant-derived polyphenols like grape seed proanthocyanidins (GSP) have been found to reduce chronic intestinal inflammation in dogs by enhancing inflammatory markers and decreasing intestinal permeability (Zhang et al., 2023b). Grape seed proanthocyanidins treatment also promotes the growth of bacteria with anti-inflammatory potential, such as Ruminococcaceae, Faecalibacterium, Ruminococcus_torques_group, and Lachnospiraceae_NK4A136_group, which are involved in BA metabolism. Additionally, the levels of DCA and its microbial conversion product, LCA, were increased in feces (Zhang et al., 2023b). Similarly, Zhang et al. (2024a) reported that carvacrol and thymol enhanced the production of SBAs, specifically HDCA and 12-ketodeoxycholic acid (12-KCAC), by increasing the abundance of Bifidobacterium pseudomallei in the colon. Hyodeoxycholic acid and 12-KCAC mitigate DSS-induced colonic injury by reducing transmembrane guanylate cyclase 1A expression in the colonic epithelium, which leads to increased intracellular Ca²⁺ and cGMP levels, activation of protein kinase G (PKG), and subsequent inhibition of the mTOR signaling pathway (Zhang et al., 2024a). Furthermore, Liu et al. (2021) showed that apple polyphenols (APE) and phloretin can mitigate DSS-induced colitis by suppressing the activation of inflammatory pathways, preserving the integrity of the intestinal mucosa, and correcting metabolic disorders related to BAs and intestinal dysbiosis. These findings highlight the promise of probiotics and prebiotics in the prevention and treatment of gastrointestinal inflammatory diseases through modulation of the gut microbiota-BA axis. However, the considerable heterogeneity and potential biases in practical applications necessitate further investigation. To establish the effectiveness of probiotic and prebiotic products, large-scale, rigorously designed trials are crucial before endorsing these supplements for long-term use.

4.2. Correlation of BAs with sow reproductive performance

In pig farming, fertility is a key variable because it plays a crucial role in production efficiency. During pregnancy, the metabolic processing of BAs in the maternal organism undergoes dynamic changes. Notably, as pregnancy advances, maternal serum BA levels gradually increase, the ratio of CA to CDCA rises, and conjugated BAs become the dominant component in the third trimester (Gagnon et al., 2021; Huang et al., 2024; Jurate et al., 2017). In the early stages of pregnancy, the proportion of unconjugated BAs is at its highest, followed by a sharp decline (Huang et al., 2024; Zhu et al., 2019). In a mouse model of pregnancy, maternal estrogen levels gradually increased, and the expression of hepatic BA transport proteins (including multidrug resistance-associated protein 3 [MRP3], BSEP, and NTCP) and CYP27A1 was significantly downregulated, while the expression of CYP7A1 and CYP8B1 was upregulated, indicating that maternal hepatic BA synthesis increases through the classical pathway during pregnancy, and BA transport is blocked (Aleksunes et al., 2012; Zhu et al., 2013). Notably, unlike non-pregnant sows, fetal BAs contribute to maternal BA levels. The fetal liver begins synthesizing BAs around 14 weeks of gestation, with a notable increase in the synthesis rate occurring after 17 weeks of gestation (Colombo et al., 1987; Lester, 1979). Unlike adults, BA synthesis in the fetal liver primarily occurs via alternative pathways that are independent of CYP7A1 enzyme activity, leading to a predominance of CDCA in fetal circulation (Memon et al., 2020). Moreover, more than 80% of BAs secreted into the fetal gallbladder are conjugated with taurine (Setchell et al., 1988). In the absence of gut microbiota, enterohepatic circulation does not occur in the fetus (Memon et al., 2020; Somm and Jornayvaz, 2018). Therefore, the placenta plays a crucial role in transporting BAs to the mother for metabolism and excretion, preventing the buildup of potentially harmful BAs (Patel et al., 2003). The placenta serves as a crucial organ for nutrient and waste exchange between the embryo and the mother, with various BA transport proteins facilitating the fetal-placental-maternal BA cycle. The fetus's limited metabolic capacity leads to elevated BA levels compared to the mother, making fetal BA metabolism more vulnerable to environmental factors during pregnancy (Geenes et al., 2014). Additionally, SBAs have been identified in the fetal BA pool, and abnormal fetal BAs, such as 1β-hydroxylated and keto acids, have been detected in maternal blood and urine (Seki et al., 2011). These observations point to a fetal-placental-maternal circulation, crucial for regulating fetal BA homeostasis during pregnancy. Chen et al. (2023) found that early pregnancy supplementation with CDCA can enhance embryo implantation, prevent early pregnancy loss, and improve reproductive performance in sows. Chenodeoxycholic acid supplementation significantly reduces inflammation, oxidative stress, and insulin resistance in sows. The regulation of SBA metabolism by intestinal microorganisms demonstrates substantial changes, exhibiting long-term beneficial metabolic effects. Chenodeoxycholic acid supplementation represents a potential treatment strategy for mitigating embryonic loss during pregnancy.

Normal pregnancy is typically associated with a gradual increase in serum BA levels. While most maternal serum BAs remain within the normal range, those with levels exceeding this range may develop hyperbilirubinemia or intrahepatic cholestasis of pregnancy (ICP) (Ovadia et al., 2021). Intrahepatic cholestasis of pregnancy arises from disturbances in BA homeostasis due to toxic BA accumulation, genetic defects, altered intestinal microflora, or surges in reproductive hormones (Beuers et al., 2023; Lee et al., 2021; Tang et al., 2024a). The condition is characterized by maternal itching and elevated serum BAs, though these symptoms generally subside after delivery (Walker et al., 2020). However, ICP increases the risk of fetal distress, stillbirth, and perinatal death. Previous studies indicate that elevated BA levels adversely affect embryonic heart muscle cells and lungs, reducing the fetus's ability to eliminate BAs through the placenta. Consequently, maintaining BA balance within both maternal and fetal systems is crucial for fetal survival (Lee et al., 2021; Vasavan et al., 2021; Yang et al., 2022). Dysregulated BA metabolism in pregnant sows has been linked to placental malfunctions (Wang et al., 2022a). Although UDCA, an effective treatment for ICP, does not reduce the production of primary metabolites (allopregnanolone sulphate [PM4S] and pregnanolone sulphate [PM5S]) or enhance their clearance, numerous studies have demonstrated that the mechanisms by which UDCA treats ICP include stimulating the synthesis and insertion of BA transporters into liver cell membranes to promote BA secretion; preventing the apoptotic effects of more hydrophobic BAs on mitochondria, and altering micelle formation to buffer BA toxicity and reduce bile hydrophobicity (Beuers, 2006; Chappell et al., 2012; Gurung et al., 2013; Kong et al., 2016).

4.3. Correlation between BAs and piglet health and survival

Bile acids are essential for fetal development, and dysregulated BA levels have been implicated in fetal hematopoietic dysfunction, preterm birth, and intrauterine fetal demise. Wang et al. (2022b) investigated various metabolites associated with BA biosynthesis and secretion, identifying hypotaurine, taurodeoxycholic acid, and taurocholic acid as key markers for stillbirth and mummification in piglets. Weaning stress, often resulting in malnutrition, is frequently accompanied by a decline in performance, evidenced by low feed intake, intestinal atrophy, weight loss, intestinal inflammation, and diarrhea. This represents a significant challenge for the pig industry. Increased production and circulation of SBAs in weaned piglets correlate with a reduced abundance of Lactobacillus spp. and an elevated number of Clostridium scindens gene copies (Lin et al., 2019). The pro-health effects of Lactobacillus spp. are well-established, and the 7α-dehydroxylation activity of Clostridium scindens is critical for the production of SBAs. Xing et al. (2024) found that Lactobacillus reuteri and Lactobacillus amylovorus in the gut microbiota provide resistance to porcine epidemic diarrhea virus (PEDV) infection in weaned piglets. The presence of these Lactobacillus species increased LCA levels, which influenced the distribution of intestinal T cells, particularly enhancing CD⁸⁺ cytotoxic T lymphocytes (CTLs) (Xing et al., 2024). Both in vivo and in vitro studies confirmed that LCA promotes the expression of SLA-I in porcine intestinal epithelial cells through FXR receptor activation, facilitating the recruitment of CD⁸⁺ CTLs for antiviral defense (Xing et al., 2024). Therefore, the dramatic changes produced in weaned piglets may also be mediated by gut microorganisms. Song et al. (2021) reported that the addition of CDCA to the basal diet significantly improved body weight and average daily gain in piglets while decreasing the feed-to-weight ratio and incidence of diarrhea. Furthermore, CDCA increased the ratio of villus height to villus depth, the number of villus cells, and the expression of tight junction proteins, indicating an enhancement of intestinal barrier function. As an emulsifier, CDCA also boosted jejunal lipase activity and the mRNA expression of pancreatic lipase, promoting lipid digestion. 16S rRNA sequencing revealed that CDCA supplementation in weaned piglets increased the relative abundance of beneficial intestinal bacteria such as Prevotella 9 and Prevotellaceae TCG-001, while reducing the abundance of the harmful bacterium Dorea (Song et al., 2021). Overall, CDCA improves the growth performance of weaned piglets by enhancing intestinal barrier function, optimizing gut microbiota composition, and promoting lipid digestion (Song et al., 2021).

The survival and health of piglets are closely linked to the reproductive performance of sows, lactation capacity, and the composition of milk nutrients, all of which directly influence piglet growth and development during lactation and post-weaning. Supplementing the diets of sows during late gestation or piglets during lactation and weaning with prebiotics or other health-promoting substances has been shown to enhance performance. Tian et al. (2023a) demonstrated that dietary supplementation with galacto-oligosaccharides (GOS) increased the abundance of BSH-producing bacteria and elevated CDCA levels in piglets. Chenodeoxycholic acid suppressed the production of lipopolysaccharide (LPS)-induced pro-inflammatory cytokines, including IFN-γ, TNF-α, IL-6, and IL-1β, while promoting the expression of TGR5 and its downstream signaling via cAMP in lamina propria CD^11b+ cells (Tian et al., 2023a). Galacto-oligosaccharides modulates BA-dependent TGR5-cAMP signaling, inhibits NF-κB activation, and reduces intestinal inflammation through alterations in gut microbiota composition (Tian et al., 2023a). Similarly, Xue et al. (2024) found that oleanolic acid supplementation stabilized the BA pool, significantly elevating UDCA and CDCA levels in the ileum and cecum. Oleanolic acid inhibited NF-κB mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway. Additionally, it enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating FXR expression, which promoted the production of endogenous defense molecules (Xue et al., 2024). Wang et al. (2023) demonstrated that dietary supplementation with garcinol significantly improved BA dysregulation in sows during late gestation, preventing excessive BA accumulation in fetal tissues. In conclusion, BA metabolism is vital for piglet survival and development, presenting a promising dietary approach for managing intestinal diseases associated with pathogenic bacterial infections in piglets.

5. Conclusions

This review highlights the critical role of BA metabolism in pig nutrition and how it affects nutrient absorption, metabolic processes and gut health. The complex biochemical processes involved in BA metabolism highlight the importance of optimizing these pathways through precision nutrition strategies. The efficacy of pig feed can be improved by integrating targeted dietary interventions such as BA supplementation, dietary ratio modification and the addition of probiotics and prebiotics to promote gut health. These approaches can improve pig performance, feed efficiency and health, particularly in young pigs and pregnant sows where gut function is critical for development. In addition, modulation of BA distribution by precision nutrition can contribute to a more balanced gut microbiota, ultimately enhancing resistance to disease and improving resilience to environmental stressors. Overall, a detailed understanding of BA metabolism provides a framework for optimizing nutritional strategies to align with the physiological needs of pigs, thereby improving productivity and welfare in modern production systems.

Credit Author Statement

Siying Li: Writing – review & editing, Writing – original draft, Investigation. Yanmin He: Writing – review & editing, Investigation. Weike Shaoyong: Writing – review & editing, Investigation. Yizhen Wang: Supervision. Mingliang Jin: Supervision.

Declaration of competing interest

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the content of this paper. Yizhen Wang is an Editorial Board Member for Animal Nutrition and was not involved in the editorial review or the decision to publish this article.