Modulating Host Lipid Metabolism via Gut Microbiota: Therapeutic Potential of Plant‐Derived Compounds

ABSTRACT

Lipid metabolic imbalance is a major contributor to metabolic disorders in humans and livestock, creating an urgent need for safe and effective regulatory approaches. Plant‐derived compounds, characterized by favorable bioavailability and low toxicity, serve as promising candidates that regulate host lipid metabolism through dynamic crosstalk with the gut microbiota. This review systematically investigates the bidirectional crosstalk between plant bioactive compounds (e.g., polysaccharides, flavonoids, saponins and polyphenols) and the gut microbiota. We detail how gut microbes metabolize these compounds to enhance their bioactivity and bioavailability, while plant extracts reshape microbial community structure to enrich beneficial taxa. Furthermore, we elucidate the mechanisms underlying lipid metabolism regulation, focusing on three critical signaling pathways: (1) SCFAs‐GPR43/41 signaling, (2) TLR4/NF‐κB inflammation suppression, and (3) bile acid‐FXR axis modulation. Collectively, this review synthesizes emerging evidence on plant‐microbiota interactions as a novel therapeutic strategy to restore lipid homeostasis in animal models, offering foundational insights for agricultural and biomedical applications.

Plant‐derived compounds modulate lipid metabolism via gut microbiota to combat metabolic disorders.

Abbreviations

2‐OG

2‐oleoylglycerol

cAMP

cyclic adenosine 3′,5′‐monophosphate

CAZymes

carbohydrate‐active enzymes

CUR

curcumin

DCM

diabetic cardiomyopathy

E. coli

Escherichia coli

F. prausnitzii

Faecalibacterium prausnitzii

FGF15/19

fibroblast growth factor 15/19

FXR

farnesoid X receptor

GPR43

G protein‐coupled receptor 43

GTA

gallnut tannic acid

HCN

hydrocyanic acid

HFS

high‐fat sucrose

HYP

Changshan pomelo residue pectin

LDL‐C

low‐density lipoprotein cholesterol

LPS

lipopolysaccharide

MASLD

metabolic dysfunction‐associated steatotic liver disease

MyD88

myeloid differentiation primary response gene 88

NF‐κB

nuclear factor kappa‐B

Nor‐DCA

nordeoxycholic acid

PEP

Phyllanthus emblica L. polysaccharides

PGN

pseudo‐germ‐free

PNS

Panax notoginseng saponins

PPARα

peroxisome proliferator‐activated receptor α

ROS

reactive oxygen species

SCFAs

short‐chain fatty acids

SCN

thiocyanate

SFP

sulforaphane

SPE

sweet potato extract

SREBP‐1c

sterol regulatory element‐binding protein‐1c

T2D

type 2 diabetes mellitus

TC

total cholesterol

TCM

traditional Chinese medicine

TG

triglyceride

TLCA

taurocholic acid

TLR4

Toll like receptor 4

TNF‐α

tumor necrosis factor‐alpha

TRIF

TIR‐domain‐containing adapter‐inducing interferon‐β

VLDL

very‐low‐density lipoprotein

β‐UDCA

β‐ursodeoxycholic acid

1. Introduction

Under physiological conditions, lipid metabolism maintains a dynamic balance among lipid uptake, de novo lipogenesis, fatty acid oxidation, and lipid export or storage (Xiaoxi et al. 2024; Mansoori et al. 2025; Wang, Yin, Liu, et al. 2024). Disruption of any of these interconnected processes, such as excessive lipid uptake or synthesis (Kaiqi et al. 2024), impaired oxidation (Bergman et al. 2024), or reduced lipid export (Saxton et al. 2019), can break this balance and ultimately lead to lipid metabolic disorders (Jia et al. 2024; Lewen et al. 2024). Consequently, identifying safe, effective, and economical approaches to sustain lipid metabolism homeostasis is crucial for maintaining organismal health (Xu et al. 2025). The gut microbiota forms a complex microecosystem within the host and influences diverse physiological processes through dynamic interactions (Yu et al. 2024). Recent studies have revealed a close association between animal gut microbiota and lipid metabolism‐related diseases (Chen, Kunda, et al. 2025; Yue et al. 2024; Gao et al. 2024; Zheng et al. 2024). Researchers have identified gut microbial metabolites as key regulators of metabolic disorders, particularly bile acids, short‐chain fatty acids (SCFAs) (Ding et al. 2025; Koutoukidis Dimitrios et al. 2024), trimethylamine N‐oxide (Li, Wang, et al. 2024), tryptophan, and indole derivatives (Allison et al. 2020). For instance, bile acids enhance brown fat consumption, promote hepatic glycogen synthesis, and boost insulin secretion and sensitivity by activating fibroblast growth factor 15/19 (FGF15/19) pathways (Maja et al. 2018). Administration of SCFAs to obese rodents has been shown to elevate energy expenditure and improve glucose tolerance, thereby helping to restore systemic lipid metabolism balance (Makki et al. 2018). Numerous studies have investigated the effects of gut‐derived probiotics on obesity, consistently demonstrating beneficial impacts on weight reduction and metabolic health (Jeanne et al. 2021; Alice et al. 2023; Ma et al. 2022).

A wide range of natural plants, including traditional Chinese medicine (TCM) and edible‐medicinal homologous plants, are widely used in the treatment of various diseases, and their therapeutic effects have been gradually validated and recognized (Man et al. 2024; Oh et al. 2024; Wang, Cao, Ma, et al. 2024). This efficacy largely stems from the bioactive compounds produced by these plants. In recent years, the effects of natural plants and their active components on host lipid metabolism have attracted extensive research attention (Bashiri et al. 2025; Zhu et al. 2025). However, the intricate mechanisms, especially those involving the crosstalk between gut microbiota and these compounds across different plant species and animal models, remain insufficiently understood and warrant further investigation. In this review, we focus on natural plants and their active constituents studied in various animal disease models, exploring their interactions with gut microbiota. This paper aims to uncover the application potential of natural plants and their bioactive components in modulating lipid metabolism balance, and to provide insights for future therapeutic strategies.

2. Impacts of Gut Microbiota on the Host Organism

As illustrated in Figure 1, the gut microbiota is increasingly recognized as a central regulator of host physiology, exerting broad effects beyond the gastrointestinal tract (Mi et al. 2024; Niccolai et al. 2024). Microbial colonization and community stability are essential for maintaining normal host functions, whereas dysbiosis‐often characterized by altered diversity and imbalanced taxa, has been linked to multiple diseases across organ systems (Qiurong et al. 2024; Hongming et al. 2024). We summarize their effects on four major functional domains of the host, including metabolism, digestion, reproduction, and respiration/circulation.

FIGURE 1.

Effects of gut microbiota on animal hosts.

2.1. Metabolism

The gut microbiota substantially contributes to host metabolic homeostasis by converting dietary substrates into bioactive metabolites and nutrients. Microbial fermentation of indigestible carbohydrates generates SCFAs, which serve as an energy source for the host and are closely associated with systemic metabolic balance (Keshet and Segal 2024; Wu et al. 2024). In addition, symbiotic microbes support host nutrition by synthesizing vitamins and amino acids (Dicks 2024; Lin et al. 2025), especially under suboptimal dietary supply conditions (Cunningham et al. 2021). Consistent with these functions, mounting evidence links microbial dysbiosis to a spectrum of metabolic disorders, including metabolic dysfunction‐associated steatotic liver disease (MASLD), steatohepatitis, pancreatitis, and type 2 diabetes. Human cohort studies have identified distinct microbial signatures in type 2 diabetes, characterized by enrichment of opportunistic pathogens and reduced butyrate‐producing capacity, implying that impaired microbial metabolic output may contribute to heightened metabolic vulnerability (Julienne et al. 2023). Together, these findings highlight that the gut microbiota functions as a metabolic “organ”, orchestrating host energy harvest, lipid handling, and metabolic resilience, thereby modulating the risk and progression of metabolic diseases.

2.2. Digestion

Beyond metabolism, the gut microbiota plays a direct and indispensable role in digestion and intestinal function (Dou et al. 2017). Early‐life disruption of microbial ecosystems and reduced microbial diversity are associated with increased susceptibility to gastrointestinal disorders, which is particularly relevant for young animals during critical developmental windows (Dingming et al. 2024; Hedin et al. 2024). Functionally, gut microbes facilitate the breakdown of complex dietary components, promote intestinal maturation, and maintain epithelial integrity, collectively contributing to efficient nutrient utilization. Microbiota‐derived metabolites also regulate intestinal motility and the luminal environment (Flint et al. 2012). For example, SCFAs modulate enteroendocrine signaling and are implicated in the regulation of intestinal transit, which may influence stool consistency and digestive efficiency (Samuel et al. 2008). When microbial communities are disrupted, these homeostatic processes may be impaired, increasing the risk of digestive and inflammatory conditions such as diarrheal irritable bowel syndrome, post‐weaning diarrhea, ulcerative colitis, and colorectal cancer (Wang, Li, and Zhang 2024; Yang, Xin, et al. 2024). Therefore, maintaining a stable gut microbiota is fundamental not only for nutrient digestion but also for preserving gut barrier function and minimizing the risk of gastrointestinal diseases.

2.3. Procreation

Reproductive health is tightly coupled to systemic metabolic status and immune balance, both of which are influenced by the gut microbiota. Emerging evidence supports the concept of a gut‐reproductive axis, whereby microbial dysbiosis and altered microbial metabolite profiles may affect reproductive function through changes in host metabolism, inflammatory tone, and endocrine regulation (Li et al. 2025). From this perspective, microbial disturbances may contribute to reproductive disorders, including orchitis, chronic endometritis, and dystocia (Efthalia et al. 2025). In addition, the gut microbiota may modulate host susceptibility to hormone‐related conditions, providing a plausible link to breast tumor risk (Mora et al. 2025). While mechanistic pathways may vary across species and models, the core concept is that microbial community composition and function can shape systemic environments relevant to fertility, pregnancy outcomes, and reproductive tract health. This multi‐layered relationship underscores why microbiota‐targeted interventions may hold promise as supportive strategies in reproductive health management.

2.4. Respiration and Circulation

The influence of the gut microbiota extends to respiratory and circulatory systems through inter‐organ communication (i.e., the gut‐lung and gut‐vascular axes) (Tang et al. 2026). Microbiota‐derived metabolites and immunomodulatory signals can modulate airway inflammation and host defense, establishing a conceptual framework for the association between gut microbial status and respiratory phenotypes (Chen et al. 2026). For instance, evidence indicates that microbial metabolites acquired early in life may influence subsequent susceptibility to airway inflammatory disorders, consistent with the “respiration” component illustrated in Figure 1 (Takashi et al. 2023). Similarly, systemic dissemination of microbial products or dysbiosis‐related inflammatory mediators may contribute to circulatory and systemic diseases, including sepsis, hypercholesterolemia, increased cardiac burden, and hyperuricemia (Chen, Ma, et al. 2025; Huang et al. 2026). These associations support a framework in which the gut microbiota serves as a key determinant of systemic inflammatory tone and metabolic‐inflammatory crosstalk, thereby shaping cardiovascular disease risk and host resilience to infection or stress.

3. Crosstalk of Natural Plants and Their Active Components With Gut Microbiota

Natural plant‐derived products and the host gut microbiota exert a bidirectional interaction. Bioactive compounds derived from plants can favorably improve the health of host animals by elevating the proportion of beneficial bacteria and inhibiting harmful bacteria, so as to maintain the homeostasis of the gut microbiome, promote normal metabolism, and preserve intestinal mucosal integrity. For these reasons, they are regarded as promising alternatives to antibiotics (Zhang et al. 2020). By reshaping the composition and relative abundance of gut microbiota, such bioactive compounds modulate a variety of physiological and biological processes in animals, demonstrating remarkable application prospects in biomedicine, animal husbandry, and veterinary medicine (Chen et al. 2022). Certain gut microbes confer benefits to the host by transforming dietary nutrients into bioactive metabolites and cooperating with the indigenous microbiota to preserve gastrointestinal homeostasis (Diba et al. 2016; Kadowaki and Quintana 2020). The health‐promoting effects of probiotics are well documented, including supplying the host with essential vitamins and energy (Lee and Sarkis 2010), promoting the development of intestinal tissues and the immune system (Elinav et al. 2011), alleviating inflammatory responses in both local and distant organs, reducing carcinogenicity, and inhibiting the colonization of pathogenic microorganisms in the gut (Gou et al. 2023; Kandari et al. 2024). Bacteroidetes and Firmicutes have been identified as the predominant phyla within the intestinal mucosal bacterial communities (Xue et al. 2024).

3.1. Plant‐Derived Natural Products Influence the Composition of Host Gut Microbiota

This section synthesizes the recurrent microbiota patterns induced by representative plant‐derived compounds and explicitly links these shifts to functional outcomes relevant to lipid homeostasis. For each experimental model, we summarize three key aspects: (1) the reported changes in key microbial taxa, (2) the functional interpretation of these taxa (e.g., SCFA production, endotoxin production and inflammatory propensity, as well as bile acid transformation), and (3) the lipid‐related phenotypes measured in the same studies (e.g., serum lipid levels, hepatic steatosis severity, and insulin resistance status). This structure is designed to clarify the underlying rationale and preclude unsupported extrapolations from descriptive sequencing results to overarching conclusions (Table 1).

TABLE 1.

Effects of natural plants and their active components on the gut microbiota.

Disease model	Natural plants and active components	Regulation of gut bacteria	References
Obesity/HFD‐induced metabolic disorder models	CUR	Increase Akkermansia, Bacteroides, Parabacteroides and Alloprevotella	(Li et al. 2021; Shen et al. 2017)
	SPE	Decrease Kineothrix; increase Eubacterium_coprostanoligenes_group_unclassified	(Liu et al. 2025a)
MASLD and hepatic steatosis‐related models	Vegetable protein, chia oil, dehydrated nopal, CUR	Decrease Blautia producta ; increase Prevotella copri , Akkermansia muciniphila , Ruminococcus bromii , Faecalibacterium prausnitzii and Mucispirillum schaedleri	(Sánchez‐Tapia et al. 2024)
	Choline‐low high‐fat and high‐sugar diet, representing a typical western diet	Increase Blautia and Akkermansia; decrease Alistipes and Muribaculaceae	(Yang et al. 2023)
Hyperlipidemia/dyslipidemia models	EBE and ELE	Decrease Desulfovibrionaceae and Erysipelotrichaceae; increase Ruminococcaceae	(Wang et al. 2023)
	EBE and ELE	Decrease Erysipelothrichaceae and Ruminococcaceae	(Zhineg et al. 2023)
	Aqueous extract of fermented Eucommia ulmoides leaves	Decrease Firmicutes/Bacteroidetes ratio; increase Lactobacillus, Rombousia, Bacteroides, Roseburia, Clostridia_UCG‐014_Unclassified	(Duan et al. 2024)
T2D/insulin resistance‐related models (including DCM)	Myricetin	Increase Alistipes, Roseburia, Lactobacillu, and Lachnospiraceae	(Yang, Gao, et al. 2024)
	Myricetin	Increase SCFAs‐producing bacteria (Roseburia, Bifidobacterium, and Faecalibaculum)	(Liao et al. 2017; Zhu et al. 2024)
	HYP	Decrease norank_f_norank_o_Clostridia_UCG‐014, elicobacter and Desulfovibrio; increase Lactobacillus, norank_f_Muribaculaceae and Bacteroides	(Ding et al. 2025)

3.1.1. Obesity/HFD‐Induced Metabolic Disorder Models

Across HFD‐induced obesity models, plant‐derived compounds frequently remodel the gut microbiota toward a profile associated with reduced metabolic inflammation and improved lipid homeostasis (Sivaprakasam et al. 2016). For example, curcumin supplementation increases the abundance of Akkermansia and multiple SCFA‐associated genera (e.g., Bacteroides, Parabacteroides and related taxa), while reducing endotoxin‐associated bacteria such as Desulfovibrio and lowering the Firmicutes/Bacteroidetes ratio (Li et al. 2021; Shen et al. 2017). Notably, these compositional changes are accompanied by increased intestinal SCFA concentrations and reduced circulating LPS, along with improvements in obesity‐related phenotypes such as decreased fat mass and attenuated hepatic steatosis (Liu et al. 2025). Thus, in this context, the microbiota shift is interpreted as functionally meaningful because it co‐occurs with metabolite‐level readouts (SCFAs/LPS) and host metabolic outcomes, rather than being inferred solely from taxonomy.

3.1.2. MASLD and Hepatic Steatosis‐Related Models

In HFD‐induced MASLD/steatosis models, interventions containing plant‐derived ingredients are associated with taxonomic‐level microbiota remodeling that is plausibly linked to hepatic lipid metabolism via gut barrier‐inflammatory and microbial metabolite pathways. A dietary intervention comprising vegetable protein, chia oil, dehydrated nopal, and curcumin (CUR) reduced the abundance of Blautia producta while elevating levels of Prevotella copri , Akkermansia muciniphila , Faecalibacterium prausnitzii , and Mucispirillum schaedleri (Sánchez‐Tapia et al. 2024). Importantly, such mechanistic interpretation is not based solely on taxonomic data. The same study demonstrated improvements in MASLD‐relevant phenotypes (e.g., attenuated hepatic lipid accumulation and steatosis, as well as enhanced systemic metabolic indices), accompanied by microbiota‐associated functional readouts (e.g., changes in intestinal permeability/barrier markers and/or inflammatory indices) (Sánchez‐Tapia et al. 2024; Yang et al. 2023). Accordingly, we interpret this microbiota profile as indicative of a gut microenvironment characterized by enhanced barrier function and diminished inflammatory tone, which may indirectly alleviate hepatic lipid accumulation. Nonetheless, direct causal mediation by specific taxa requires microbiota‐targeted validation (e.g., antibiotic depletion or fecal microbiota transplantation).

3.1.3. Hyperlipidemia/Dyslipidemia Models

In hyperlipidemia/dyslipidemia models, Eucommia bark/leaf extracts (EBE/ELE) reduced the abundance of Desulfovibrionaceae and Erysipelotrichaceae while increasing the level of Ruminococcaceae (Wang et al. 2023; Duan et al. 2024). Importantly, this shift is not inferred solely from taxonomic information. In the same studies, EBE/ELE increased fecal SCFA concentrations and upregulated host SCFA‐sensing receptors (GPR41/GPR43), accompanied by improved lipid‐related outcomes (e.g., reduced circulating TG/TC levels and attenuated lipid accumulation) (Wang Zhineg et al. 2023; Wang et al. 2023; Duan et al. 2024). Therefore, the signature characterized by reduced Desulfovibrionaceae/Erysipelotrichaceae and enriched Ruminococcaceae is interpreted here as a mechanistically supported functional profile, reflecting enhanced microbial fermentation capacity and lowered proinflammatory potential, rather than merely a descriptive taxonomic observation (Nitzan et al. 2018).

3.1.4. T2D/Insulin Resistance‐Related Models (Including DCM)

In T2D and insulin resistance‐related models, plant‐derived compounds are consistently associated with enrichment of SCFA‐producing or SCFA‐associated bacteria (Yang, Gao, et al. 2024). This is functionally relevant because SCFAs signal through GPR41/43 to modulate energy expenditure, inflammation, and lipid metabolism. In a streptozotocin plus HFD‐induced DCM model, myricetin elevated the abundance of SCFA‐producing genera (e.g., Roseburia and Bifidobacterium‐related taxa), accompanied by remodeled microbial metabolite profiles and improved host cardiometabolic phenotypes (Liao et al. 2017; Zhu et al. 2024). Similarly, in streptozotocin‐induced T2D, pectin from Citrus aurantium residue modulated the microbiota by decreasing Helicobacter and increasing Lactobacillus/Muribaculaceae/Bacteroides, accompanied by elevated SCFA production and improved glycolipid profiles (Ding et al. 2025). These examples illustrate the approach used in this review to interpret microbiota shifts, taxa changes are discussed in conjunction with matched microbial metabolite and host phenotypic readouts, thereby establishing a more robust framework for connecting microbiota modulation to lipid‐related outcomes.

Collectively, the above studies indicate that plant‐derived compounds do not merely “alter microbiota composition”. Instead, they frequently shift the community toward functionally relevant states characterized by (1) increased microbial fermentation products (SCFAs), (2) reduced endotoxin/inflammation‐associated signatures, and/or (3) modified bile acid metabolism capable of regulating host FXR‐related pathways. In this review, we highlight such connections only when the original studies report metabolite‐level or host signaling readouts in conjunction with lipid‐related phenotypes.

3.2. Gut Microbiota Metabolize and Utilize Natural Plants and Their Active Compounds

Before being absorbed by the gastrointestinal tract, natural plants and their active ingredients are degraded and biotransformed by gut microbes, then absorbed and transported to various tissues. The gut microbiota plays a key role in the metabolism of these plant components (Nitzan et al. 2018). Importantly, this biotransformation is not merely a metabolic fate of phytochemicals. In many cases, microbiota‐derived metabolites exhibit improved intestinal absorption, higher systemic exposure, or enhanced target engagement compared with their parent compounds, which may translate into more pronounced lipid‐modulatory activities. As shown in Figure 2, certain bacteria can modulate the fermentation of these compounds, affecting the metabolic absorption of their active constituents (Rowland et al. 2017). Accordingly, in the following examples, we highlight not only the underlying metabolic pathways but also the functional benefits of representative metabolites relevant to lipid metabolism, as summarized in Table 2.

FIGURE 2.

The gut microbiota enhances the bioavailability of bioactive ingredients from natural plants.

TABLE 2.

Gut microbiota regulates metabolism and absorption of natural plants.

	Gut microbiota	Natural plants and active components	Regulation	References
Polysaccharide	Bacteroides thetaiotaomicron	L‐fucose	Increase synthesis of fucosylated glycans	(Hooper et al. 1999)
	Lactobacillus gasseri JM1	Hericium erinaceus polysaccharide	Reduce molecular weight and increase the branched chain structure	(Su et al. 2023)
	Lactobacillus acidophilus CCFM202 and Lactobacillus plantarum CCFM6392	Maitake polysaccharides	Produce SCFAs (acetic acid and butyric acid)	(Yiasmin et al. 2022)
Flavonoids	E. coli	Baicalin	Hydrolyze baicalin into baicalein and oroxylin A	(Trinh et al. 2010)
	Dorea longicatena strains LCR19 and Marseille‐P2116	Isoflavone C‐glucoside puerarin	Produce daidzein and glucose	(Nakamura et al. 2020)
	Catenibacillus species	C‐glucosides, vitexin, isovitextin and homoorientin	Degrade to hydroxyphenylpropionic acids	(Tobias and Annett 2024)
Saponin	Proteobacteria and Bacteroides	PNS	Improve the activity of glycated reductase and redox metabolic enzymes	(Guo et al. 2020; Jingcheng Xiao et al. 2016)
	Prevotella and Penicillium sclerotiorum	Ginsenosides Rb1	Produce compound K and GF1	(Wei et al. 2011; Zhang, Chen, et al. 2021)
Polyphenol	Bacteroides distasonis , Bacteroides uniformis , Bacteroides ovatus , Enterococcus casseliflavus , Eubacterium cellulosolvens , Lachnospiraceae CG19‐1 and Eubacterium ramulus	Proanthocyanidins and ellagitannins	Convert into absorbable glycoside ligands	(Braune et al. 2016)
	Gordonibacter urolithinfaciens	Ellagic acid	Increase urolithin bioavailability	(Yang, Lee, et al. 2024)
	E. coli strain K‐12, substrain DH10B	Polyphenol CUR	NADPH‐dependent CUR/dihydrocurcumin reductase	(Azam et al. 2011)
Other	Lactobacillus acidophilus NCFM	Salicylate	Facilitate the bioactivation process through deglycosylation and salicylate liberation	(Theilmann et al. 2017)
	E. coli	Amygdalin	SCN metabolic pathway against HCN toxicity	(Wen et al. 2022)

3.2.1. Polysaccharide

As vertebrates lack endogenous polysaccharide hydrolases, most orally administered polysaccharides cannot be directly digested or absorbed. Instead, the gut microbiota plays an indispensable role in their breakdown and utilization. The gut microbiota encodes a wide range of carbohydrate‐active enzymes (CAZymes), which are categorized into four major functional classes: glycoside hydrolases, polysaccharide lyases, carbohydrate esterases, and glycosyltransferases (Xu et al. 2017). Upon ingestion, polysaccharides reach the intestine, where they serve as a carbon source for the gut microbiota and promote the growth of beneficial bacteria. CAZymes then break down these polysaccharides into secondary metabolites or fermentation products, which are absorbed by the body and influence cellular proliferation, apoptosis, and immune regulation (Cockburn and Koropatkin 2016). The gut microbiota also ferments polysaccharides to generate SCFAs. L‐fucose, a component present in seaweed, is regarded as a valuable alternative dietary substrate, given that numerous epithelial glycoconjugates are fucosylated. Accumulating evidence suggests that Bacteroides thetaiotaomicron enhances the expression of genes involved in fucosaccharide metabolism, thereby promoting the synthesis of fucosylated glycans (Hooper et al. 1999). Following fermentation with Lactobacillus gasseri JM1, the molecular weight of Hericium erinaceus polysaccharide decreases from 7.5 × 10⁷ Da to 3.5 × 10⁴ Da, accompanied by the formation of a branched‐chain structure. Subsequent analysis verified that the fermented Hericium erectus polysaccharide exhibited enhanced antioxidant activity in vitro (Su et al. 2023). A study on Maitake polysaccharides further revealed that different Lactobacillus species yield distinct levels of SCFAs. Specifically, Lactobacillus acidophilus CCFM202 mainly produces acetic acid, whereas Lactobacillus plantarum CCFM6392 predominantly generates butyric acid owing to its specific response to β‐glucan, leading to divergent pH levels in the final fermentation product (Yiasmin et al. 2022).

3.2.2. Flavonoids

Flavonoids are widely recognized for their diverse pharmacological properties, including anti‐inflammatory, antibacterial, cardiovascular‐protective, and neuroprotective effects. However, flavonoid glycosides contain glucoside linkages that hinder intestinal absorption, leading to low bioavailability. Recent studies indicate that the gut microbiota plays a critical role in enhancing flavonoid bioavailability by converting these compounds into simpler phenolic acids via enzymatic hydrolysis, reduction, dehydroxylation, and other processes (Xue Gong et al. 2020). For instance, a preliminary study on astragali decoction revealed that Escherichia coli ( E. coli ) can hydrolyze baicalin into baicalein and oroxylin A. In contrast, baicalin itself is barely detectable in serum following oral administration, highlighting the essential function of the microbiota in its biotransformation and absorption (Trinh et al. 2010). Compared with the parent compound, the resulting metabolites typically exhibit enhanced bioavailability and/or chemical stability, thereby improving their ability to reach metabolically relevant tissues. Baicalein and oroxylin A are more biologically active than the parent compound and can alleviate pruritus via antihistamine effects (Zhang et al. 2023). PUE, a gut‐colonizing bacterium, shares 98% similarity with Dorea longicatena strains LCR19 and Marseille‐P2116 (Nakamura et al. 2011). PUE has been shown to metabolize the isoflavone C‐glucoside puerarin into daidzein and glucose (Nakamura et al. 2020), a process mediated by the catalytic oxidation of puerarin by recombinant DgpA, a Gfo/Idh/MocA family oxidoreductase. In the chicken gut microbiota, Catenibacillus species, including C. scindens , C. faecavium , and C. faecigallinarum , exert significant effects on the metabolism of flavonoid compounds (Tobias and Annett 2024). The flavone C‐glucosides, vitexin, isovitexin, and homoorientin are completely degraded into their corresponding hydroxyphenylpropionic acids within 6 h (Tobias and Annett 2024). Given that flavonoids are increasingly proposed as phytogenic feed additives in agricultural production (Biswas et al. 2024), Catenibacillus species play a crucial role in supporting growth performance and immune function in poultry.

3.2.3. Saponin

Saponins, abundant bioactive constituents in TCM, exhibit notable therapeutic potential yet display poor bioavailability owing to their high polarity, which impedes direct intestinal absorption (Wang, Xue, et al. 2024). Modern pharmacokinetic investigations have revealed that the gut microbiota plays a critical role in the biotransformation of these compounds. Microbial metabolism in the gut converts natural saponins into derivatives with lower polarity and higher lipid solubility, thereby promoting their absorption into the systemic circulation (Wenrui et al. 2022). Moreover, microbial metabolites have been documented to exert more direct lipid‐modulating effects, including alleviating hepatic lipid accumulation, improving serum lipid profiles, and enhancing fatty‐acid oxidation, whereas the parent compound typically exhibit limited absorption (Toney et al. 2019). Such biotransformation enables saponins to achieve effective plasma concentrations more efficiently, strengthening their bioactivity and therapeutic potential. The biotransformation of Panax notoginseng saponins (PNS) by the gut microbiota has been validated in both in vivo and in vitro studies (Xu et al. 2023). The major metabolic pathways involve hydrolysis and dehydration, which mainly lead to the production of compound K, an active metabolite associated with multiple pharmacological benefits (Guo et al. 2020). Proteobacteria shows a strong correlation with deglycosylation metabolites and glycosidase activities, thereby facilitating the degradation of PNS (Xiao et al. 2016). Meanwhile, Bacteroides has been observed to enhance the activities of redox metabolic enzymes to promote PNS metabolism, likely by elevating glycated reductase activity, thus playing a key role in the metabolic conversion process of these saponins (Xiao et al. 2016). Ginsenosides represent the principal bioactive components of ginseng. They undergo stepwise deglycosylation catalyzed by glycoside hydrolases secreted by the mammalian gut microbiota, including β‐glucosidase, α‐rhamnosidase, and xylosidase (Akao et al. 1998). In the rat gut, the microbiota mainly promotes the metabolism of four ginsenoside subtypes: PPD, PPT, OT, and OA (Mi et al. 2023). Prevotella has been shown to hydrolyze ginsenoside Rb1 into compound K (Zhang et al. 2021). Penicillium sclerotiorum has been identified as a potential microorganism capable of metabolizing Rg1 into GF1 (Wei et al. 2011).

3.2.4. Polyphenol

Polyphenols, including proanthocyanidins and ellagitannins, commonly exist as high‐molecular‐weight oligomers and polymers, which restrict their oral bioavailability (Rowland et al. 2017). In the colon, bacteria such as Bacteroides distasonis , Bacteroides uniformis , Bacteroides ovatus , Enterococcus casseliflavus , Eubacterium cellulosolvens , Lachnospiraceae CG19‐1, and Eubacterium ramulus mediate the hydrolytic breakdown of these polyphenols. Proanthocyanidins and ellagitannins can only be utilized by the host following their conversion into absorbable phenolic metabolites (Braune et al. 2016). Previous studies have reported that ellagic acid from pomegranate juice markedly inhibits the growth of C. perfringens , C. clostridioforme , and C. ramosum (Bialonska et al. 2009; Zhang et al. 2025). Ellagic acid and glycosyl‐ellagic acid present in pomegranate extract and juice are utilized by Bifidobacterium and Lactobacillus, thereby increasing the abundance of these genera while significantly suppressing the growth of the B. fragilis group, clostridia, and Enterobacteriaceae (Li et al. 2015). Although the oral bioavailability of ellagic acid is extremely low, its microbial catabolite urolithin exhibits substantially higher bioavailability, up to 25–80 times higher than ellagic acid itself (Cortés‐Martín et al. 2020). Oral supplementation with Gordonibacter urolithinfaciens has been shown to significantly increase urolithin bioavailability (Yang, Lee, et al. 2024). Another plant extract that relies on gut microbiota breakdown is the polyphenol CUR. E. coli H10407 strain, O55:H7 strain CB9615, and BW2952 strain, which can convert CUR, were found in feces. In addition, a NADPH‐dependent CUR/dihydrocurcumin reductase was found in E. coli strain K‐12, substrain DH10B (Azam et al. 2011).

3.2.5. Other

Salicylate is a natural glycoside compound and the pharmacologically inactive precursor of salicylic acid, an analgesic and anti‐rheumatic drug. Following oral administration of salicin‐rich willow bark extract, salicylic acid accounts for 86% of the serum metabolites and serves as the primary metabolite (Schmid et al. 2001). Lactobacillus acidophilus NCFM can facilitate the bioactivation process through deglycosylation and salicylate liberation (Theilmann et al. 2017). A correlation exists between its ability to metabolize salicin and the presence of the intact LBA0724‐LBA0726 gene cluster. Strains lacking one or more genes in this cluster, or those with fragmented LBA0725 transporter gene, are unable to utilize salicin for growth (Theilmann et al. 2017).

Notably, the metabolic action of the gut microbiota on natural products may exert negative effects on the host. Amygdalin, found in plant seeds such as almonds and peach kernels, has been shown to exhibit significant effects in cancer treatment (Meenatchi et al. 2024). However, the toxicity associated with its hydrocyanic acid (HCN) metabolic pathway, manifested by respiratory distress and systemic convulsions, still makes the role of amygdalin controversial (Blaheta et al. 2016). Recent studies have shown that the gut microbiota is involved in the bidirectional regulation of amygdalin toxicity and detoxification. Host mitochondrial detoxification enzymes interrupt cellular respiration, block electron transport and oxidative phosphorylation, and convert HCN to thiocyanate (SCN) (Downs et al. 2010). This SCN metabolic pathway is thought to act as a host barrier against HCN toxicity, as evidenced by the steady increase in SCN levels in the pseudo‐germ‐free (PGN) group within 2 h after oral administration of amygdalin, compared with the control group (Wen et al. 2022). In addition, this pre‐barrier effect of the gut microbiota is associated with the abundance of E. coli (Wen et al. 2022).

These features suggest that microbiota‐mediated conversion can unlock lipid‐regulatory potential that may be underestimated when only the parent phytochemical is considered. Key microbial biotransformation pathways and representative metabolites are summarized in Table 2, while their downstream lipid‐related signaling links are depicted in Figure 3.

FIGURE 3.

Mechanism underlying the crosstalk between plant‐derived natural products and the gut microbiota in regulating host lipid metabolic homeostasis.

4. Crosstalk Between Plant Extracts Interact and Gut Microbiota in Regulating Host Lipid Metabolism

Accumulating evidence indicates that the lipid‐modulatory effects of plant‐derived compounds are frequently mediated by microbiota‐dependent signaling cascades rather than direct actions on host metabolic tissues alone (Tang et al. 2017). In mumerous animal and translational studies, plant extracts initially remodel the gut microbial ecosystem and its metabolic output, leading to measurable changes in key microbial products‐most consistently short‐chain fatty acids (SCFAs), bile acid profiles, and endotoxin‐related signals (Larsson et al. 2012). These microbial signals are subsequently recognized by host receptors and integrated into inflammatory and metabolic signaling pathways (Guo et al. 2022), which coordinately reprogram lipid synthesis, oxidation, transport, and storage in key metabolic organs including the liver and adipose tissue (Musso et al. 2011).

To enhance mechanistic clarity, we organize the available evidence within a sequential “microbiota‐metabolite/signal‐host pathway‐lipid phenotype” framework and summarize three recurring routes through which plant‐microbiota interactions modulate lipid homeostasis (Figure 3 and Table 3): (1) SCFAs‐GPR41/43 signaling, (2) attenuation of LPS‐driven TLR4/NF‐κB inflammatory signaling, and (3) microbiota‐dependent bile acid remodeling coupled with downstream FXR signaling.

TABLE 3.

Effects of plant‐derived components on gut microbiota and lipid metabolism via microbiota‐derived signals and host pathways.

Plant component/intervention	Model/population	Key gut microbiota changes	Microbiota‐derived metabolite/signal changes	Host pathway/receptor readouts	Lipid/metabolic phenotypes	References
Oat	Humans with mild hypercholesterolemia	NR	Plasma propionate ↑	NR (no GPR41/43 reported)	TC ↓; LDL‐C ↓	(Louis et al. 2010)
Inulin replacing glucose	Intestinal cell models (with F. prausnitzii )	F. prausnitzii growth and carbohydrate utilization ↑	Butyrate‐related output ↑	NR	NR	(Fagundes et al. 2021)
Eucommia bark/leaf extract	HFD‐fed mice	Ruminococcaceae ↓	SCFAs/butyrate proposed as intermediate	SCFAs‐GPR43 gut‐fat axis	Fat accumulation ↓	(Wang et al. 2023)
PEP	High‐fat diet mice	Taxa‐receptor correlation: Romboutsia associated with GPR41	Total SCFAs ↑	GPR41/43 mRNA ↑	Adipose tissue hypertrophy, hyperlipidemia, liver steatosis, oxidative stress, and inflammation were reversed	(Hsu et al. 2025)
Sulforaphane	NAFLD‐related study	Increased SCFA production “notably linked to” Bacteroides and Lactobacillus	SCFA production ↑	GPR41/43 activation; GLP‐1 secretion ↑	Insulin resistance ↑	(Wang, Yin, Liu, et al. 2024)
Atractylodes macrocephala extract crystallize	High sugar, high fat, and excessive alcohol consumption induced MAFLD rats	Lactobacillus and norank_f__Muribaculaceae ↑; unclassified_f__Lachnospiraceae and Blautia ↓	LPS ↓; TLR4, Myd88, and NF‐κB proteins ↓	TLR4/MyD88/NF‐κB components ↓	Pathophysiological damage to the gut‐liver axis was reversed	(Li, Jiang, et al. 2024)
Cryptotanshinone	NR	Enterorhabdus and Akkermansia ↑; Erysipelatoclostridium ↓	FXR natural agonists ↑, such as deoxycholic acid and lithocholic acid	Bile acid metabolites were improved	NR	(Li et al. 2023)
Red. superfine powder	High sugar and high fat compounds in an excessive alcohol diet induced metabolic hypertension rats	Streptococcus ↑; Desulfobacter and Desulfovibrio ↓	SCFA production ↑; LPS ↓	TLR4/MyD88/NF‐κB components ↓	Blood pressure and blood lipid metabolism were improved	(Su et al. 2022)
Capsaicin	TRPV1−/− mice fed a high‐fat diet	Helicobacter, Desulfovibrio, and Sutterella ↓	LPS burden inferred ↓	TLR4 over‐activation alleviated; inflammatory cascades dampened	Intestinal barrier function was repaired	(Yang, Li, and Wang 2024)
Curcumin	High‐fat diet‐fed obese mice	The ratio of Firmicutes/Bacteroidetes and endotoxin‐producing Desulfovibrio bacteria ↓; Akkermansia population and SCFA‐producing bacteria↑	Caecal and colonic SCFA concentrations ↑	NR	Hepatic steatosis and insulin resistance ↓	(Li et al. 2021)
Salvia polysaccharides	NR	Desulfovibrio ↓	LPS burden inferred ↓	TLR4 signaling alleviated; inflammatory cascades dampened	NR	(Yang, Li, and Wang 2024)
Coptisine	High‐fat/high‐cholesterol diet‐fed Syrian golden hamsters	Enterobacter cloacae inhibited	LPS ↓	TLR4 ↓ and CD14 ↓	Serum TC ↓; TG ↓	(Zong et al. 2015)
Laminaria japonica Polysaccharide	High‐sugar and high‐fat diet combined with streptozotocin induced diabetes mellitus rats	NR	Secondary bile acids ↑: Nor‐DCA, TLCA, β‐UDCA	NR	Lipid metabolism ↑	(Zhang et al. 2024)
Lufanol/resveratrol/silymarin	MASLD contexts	NR	Bile acid excretion ↑; reabsorption ↓	FXR and bile acid efflux/transport‐related pathways ↑	Bile acid deposition and hepatic lipid accumulation ↓	(Qin et al. 2024)

Abbreviation: NR, not reported in the provided text excerpt.

4.1. SCFAs‐GPR43/41 Signaling

SCFAs (primarily acetate, propionate, and butyrate) are major end‐products of microbial fermentation and serve as a functional bridge connecting dietary and plant‐derived substrates to host lipid‐regulatory programs (Sanchez Helia et al. 2020). Consistent with this notion, individuals with hyperlipidemia often exhibit reduced abundance of SCFA‐producing taxa and/or diminished butyrate‐producing capacity compared with healthy controls (Yu Duan et al. 2024). Human dietary intervention studies further support a consistent metabolite‐phenotype relationship; for example, long‐term oat consumption elevated plasma propionate levels and decreased TC and LDL‐C in individuals with mild hypercholesterolemia, suggesting that enhanced microbial propionate production may contribute to improved circulating lipid profiles (Louis et al. 2010). From a microbial biochemistry perspective, butyrate can be generated via the butyryl‐CoA: acetate CoA‐transferase pathway in key gut commensal species (Louis et al. 2010). The functional importance of substrate availability has been experimentally demonstrated: replacing glucose with inulin promotes the growth and carbohydrate utilization of Faecalibacterium prausnitzii and enhances butyrate production in intestinal cell models (Fagundes et al. 2021). Upon production, host sensing of SCFAs is primarily mediated by the G protein‐coupled receptors GPR41 and GPR43, which respond to acetate, propionate, and butyrate. These receptors have been implicated in energy expenditure, enteroendocrine signaling, and lipid metabolism in multiple experimental systems (Schoeler and Caesar 2019). Mechanistically supported examples from plant‐intervention studies typically show a coordinated pattern: (1) increased SCFA levels and/or enrichment of SCFA‐producing functional taxa, (2) upregulated GPR41/43 expression in intestinal and/or adipose tissues, and (3) improved lipid‐related phenotypes.

For instance, Eucommia ulmoides extract intervention in HFD‐fed mice increased the relative abundance of Ruminococcaceae and upregulated GPR41/43 expression in intestinal and epididymal tissues, accompanied by reduced fat accumulation (Wang et al. 2023). In this context, butyrate acts as a key intermediate that links microbial fermentation to receptor activation and subsequent improvements in lipid phenotypes. Similarly, Phyllanthus emblica L. polysaccharides (PEP) have been shown to increase total SCFA levels and upregulate GPR41/43 mRNA in epididymal tissue under obese conditions, and correlation analyses further indicated that specific taxa (e.g., Romboutsia) may be associated with GPR41 expression (Hsu et al. 2025). In a NAFLD‐related study, sulforaphane increased SCFA production (an effect notably associated with Bacteroides and Lactobacillus), with subsequent activation of GPR41/43 and enhanced GLP‐1 secretion, thereby alleviating insulin resistance (Tian et al. 2024). Together, these findings support a unified mechanistic framework wherein plant‐derived substrates boost microbial SCFA generation, SCFAs trigger GPR41/43 signaling, and downstream endocrine and metabolic programs are reprogrammed to promote improved lipid homeostasis.

4.2. TLR4/NF‐κB Inflammation Suppression

A second convergent pathway links plant‐microbiota interactions to lipid metabolism through the mitigation of gut microbiota‐derived endotoxemia and its downstream inflammatory signaling. Lipopolysaccharide (LPS), a major component of the cell walls of Gram‐negative bacteria, can translocate into the systemic circulation when the gut barrier is compromised, triggering “metabolic endotoxemia” and activating Toll‐like receptor 4 (TLR4)‐mediated signaling (Cani et al. 2007; Chen and Gautron 2025). TLR4 activation subsequently engages NF‐κB signaling, elevating pro‐inflammatory cytokine production and promoting chronic low‐grade inflammation, an upstream driver of insulin resistance and lipid metabolic dysregulation (Heida et al. 2021). Mechanistically, inflammation intersects with lipid metabolism via the direct modulation of key lipid‐regulatory nodes. NF‐κB signaling can interact with SREBP‐1c and PPARα, thereby biasing hepatic metabolic programs toward increased de novo lipogenesis and reduced fatty‐acid oxidation. This shift ultimately favors hepatic lipid accumulation and dyslipidemia (Yaru et al. 2020). In immune cells, bacterial stimulation and inflammatory cues also induce lipid metabolic reprogramming (Jha et al. 2015), including altered glycolysis, mitochondrial respiration, and lipid droplet dynamics. Lipid droplets have emerged as functional organelles supporting inflammatory responses, and lipid flux through mitochondria‐ER‐peroxisome‐lipid droplet networks may further influence inflammatory lipid signaling (Zimmermann Julia et al. 2024). Downstream of the TLR4‐, the MyD88‐ and TRIF‐dependent signaling pathways represent two key arms that coordinate inflammatory responses and lipid remodeling (Hsieh et al. 2020; Kawai and Akira 2006). Within this mechanistic framework, plant‐derived compounds can reduce inflammatory pressure through two non‐mutually exclusive mechanisms: (1) reducing the gut‐derived LPS burden (e.g., by decreasing LPS‐associated taxa and/or enhancing gut barrier integrity), and (2) inhibiting host TLR4/MyD88/NF‐κB signaling activation. Numerous plant‐based interventions have reported reduced LPS levels and downregulated expression of key TLR4 signaling pathway components (including TLR4, MyD88, NF‐κB). Representative plant‐derived bioactive compounds and extracts include punicic acid, salidroside, atractyloides extract crystals, and Red. superfine powder (Li, Jiang, et al. 2024; Chen et al. 2024; Su et al. 2022; Wang, Li, Li, et al. 2024). As representative examples of the “microbiota‐LPS‐TLR4” linkage, compounds such as capsaicin, curcumin, and cryptotanshinone have been reported to reduce the abundance of Desulfovibrio, a Gram‐negative genus frequently associated with endotoxin‐related signals, thereby alleviating over‐activation of TLR4 signaling and dampening inflammatory cascades (Li et al. 2023; Sun et al. 2024; Yang, Li, and Wang 2024).

Notably, Enterobacter cloacae , isolated from the intestines of obese individuals and implicated in promoting obesity and insulin resistance, provides a case where microbial suppression aligns with host signaling and lipid phenotypes (Fei and Zhao 2013). Coptisine inhibited Enterobacter cloacae in a dose‐dependent manner, reduced TLR4 and CD14 expression in visceral fat of high‐fat/high‐cholesterol diet‐fed Syrian golden hamsters, lowered LPS levels, and improved serum TC and TG (Zong et al. 2015). Together, these data support a mechanistic model in which plant‐induced microbial remodeling reduces LPS‐driven innate immune activation, thereby relieving inflammation‐mediated constraints on lipid oxidation and limiting inflammation‐promoted lipogenesis.

4.3. Bile Acid‐FXR Pathway Modulation

Bile acids represent a major mechanistic nexus linking the gut microbiota to host lipid and cholesterol metabolism (Cai et al. 2022; Sun et al. 2022). Primary bile acids are synthesized from cholesterol in the liver, secreted into the intestinal lumen, and subsequently undergo extensive microbiota‐mediated transformations. In the gut lumen, microbial enzymes most prominently bile salt hydrolases and 7α‐dehydroxylation‐related activities deconjugate and convert primary bile acids into secondary bile acids, thereby reshaping the bile acid pool and signaling potential (Larabi et al. 2023; Ridlon et al. 2016). These secondary bile acids act as ligands for host nuclear and membrane receptors, including intestinal and hepatic FXR as well as the membrane receptor TGR5, enabling bile acids to function as endocrine‐like metabolic regulators (He et al. 2025; Wei et al. 2020). Accordingly, targeting the microbiota‐bile acid‐receptor axis has emerged as a promising strategy for the intervention of metabolic disorders (Winston and Theriot 2019; Xuemei et al. 2024).

Mechanistically, plant‐based interventions that modulate this pathway typically exhibit three key features: (1) modified bile acid composition and/or increased fecal bile acid excretion, together with (2) altered FXR signaling in the intestine and/or liver, accompanied by changes in downstream metabolic gene expression, and (3) improved lipid‐related phenotypes, such as favorable serum lipid profiles and alleviated hepatic steatosis. For example, algal polysaccharides elevated multiple classes of intestinal bacteria and promoted the secretion of specific secondary bile acids (e.g., Nor‐DCA, TLCA, β‐UDCA), accompanied by improved lipid metabolism in mice fed a high‐sugar, high‐fat diet (Zhang et al. 2024). In parallel, other studies observing reduced levels of Bacteroidia and Verrucomicrobia in bile acid‐microbiota analyses support the notion that bile acid pool remodeling and shifts in microbiota composition are tightly coupled (Liu et al. 2024).

Several plant extracts (e.g., lufanol, resveratrol, silymarin) have been reported to enhance bile acid excretion and reduce reabsorption, while upregulating FXR and pathways related to bile acid efflux and transport, thereby alleviating bile acid deposition and hepatic lipid accumulation in metabolic dysfunction‐associated fatty liver contexts (Qin et al. 2024). Such effects are frequently accompanied by consistent shifts in microbiota composition, including increases in Bacteroides and Bifidobacterium, as well as decreases in Enterococcus or Clostridium_sensu_stricto (Pang et al. 2023; Yi et al. 2024), which supports microbiota‐dependent remodeling of bile acid signaling. At the mechanistic level, microbial BSH activity and host cytochrome P450 enzymes, such as CYP2C70, contribute to maintaining the balance between conjugated and deconjugated bile acids (Jia et al. 2018; Takahashi et al. 2016). Therefore, compositional and functional changes in the gut microbiota can alter bile acid signaling profiles, which in turn regulate intestinal lipid absorption, cholesterol homeostasis, and systemic energy metabolism.

Beyond bile acid homeostasis itself, changes in bile acid excretion and FXR signaling have direct implications for the handling of cholesterol and triglycerides. Increased fecal bile acid excretion can enhance hepatic conversion of cholesterol into newly synthesized bile acids, thereby promoting cholesterol clearance and reducing cholesterol levels in both the liver and systemic circulation (Chiang and Ferrell 2020; Root et al. 2002). In addition, FXR‐linked endocrine signaling, notably the intestinal FXR‐FGF15/19 axis, regulates hepatic lipogenesis and VLDL secretion, thereby influencing triglyceride homeostasis (Fleishman and Kumar 2024). Collectively, these mechanistic links explain why plant‐derived compounds that modulate bile acid pools and FXR activity often lead to parallel improvements in serum lipid profiles and attenuation of hepatic lipid accumulation (Chambers et al. 2019; Zhang, Kuipers, et al. 2021).

5. Conclusions and Perspectives

Lipid metabolism disorders not only affect human diseases including obesity, diabetes, and hypertension, but also present substantial challenges to livestock health (Liu et al. 2025). Maintaining lipid homeostasis in animals is crucial for enhancing economic efficiency and ensuring animal welfare. Thus, identifying safe and natural interventions that effectively regulate lipid metabolism is of great urgency. In this review, we explore the potential mechanisms by which natural plants and their bioactive compounds modulate host lipid metabolism by interacting with the gut microbiota. Based on a summary of recent relevant studies, we highlight that the gut microbiota composition varies across species. Moreover, interactions between the gut microbiota and natural plant‐derived compounds are consistently observed across diverse animal disease models and plant sources, and play a pivotal role in maintaining host lipid metabolic homeostasis. As discussed above, the mechanisms by which plant‐derived natural products regulate lipid metabolism by shaping the gut microbiota are intricate, mainly including promoting SCFA production, inhibiting inflammatory responses, and modulating bile acid metabolism.

Notably, alongside rapid advances in life science and technology, research on TCM and natural plant‐derived interventions has achieved remarkable progress, yet several key challenges remain. First, many existing studies are still descriptive in nature, relying primarily on gut microbiota sequencing while failing to elucidate the detailed crosstalk between plant compounds and the microbiota. It is essential to deepen this understanding through targeted experimental approaches, such as administering plant compounds via gavage to germ‐free mice, performing fecal microbiota transplantation, or isolating potential probiotic strains. Further exploration is needed to explore the mechanisms by which intestinal microbiota metabolites affect host lipid metabolism, thereby clarifying the regulatory role of the natural plant‐intestinal microbiota‐metabolite axis in the host. For livestock production, functional assessments of natural plants and their active ingredients should extend beyond the rodent models (mice and rats) to mitigate species‐specific limitations and enhance the translational relevance of research findings. Different animal species exhibit distinct bioavailability and metabolic capacities. Therefore, significant scope remains for advancing the verification of the effects and mechanisms of natural plants on lipid metabolism in target animal species. In addition, challenges persist in the translational application of these findings, including issues related to dose standardization, individual differences, and bioavailability.

In conclusion, the interaction between natural plants, their active components, and the gut microbiota holds substantial promise for regulating host lipid metabolism. Future research should further investigate the regulatory mechanisms underlying this crosstalk and focus on validating effects in target species. These efforts will provide a more solid foundation for integrating natural plants and their bioactive compounds into human health maintenance and livestock production practices.

Author Contributions

Ji Cheng: visualization. Lijun Wang: writing – original draft, writing – review and editing. Yiqian Chen: methodology. Shifeng Pan: funding acquisition, project administration. Weilong Peng: conceptualization. Yao Lu: resources, funding acquisition.

Funding

The study was supported by the National Natural Science Foundation of China (no. 32072809, 32502991), the Natural Science Foundation of Jiangsu Province (BK20211119), the National Foreign Experts Project (High‐End Foreign Experts Introduction Programs of Ministry of Science and Technology, G2023014067L), the Open Fund of Meat Processing Key Laboratory of Sichuan Province (no. 22‐R‐17), the Research and Practice Innovation Plan for Postgraduates in Jiangsu Province (SJCX24_2305), the Special Project of Cross‐Cooperation of Northern Jiangsu People's Hospital (SBJC23007), Jiangsu Province Outstanding Postdoctoral Research Project (2025ZB572), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.