Mengkuan Liu
Cuimei He1
Wanru Zheng
Jie Yin
Yixing Li- 1Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, College of Animal Science and Technology, Guangxi University, Nanning, China
- 2College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
Although advancements in the study of gut microbiota have clarified the close association between gut microbiota and the host's metabolism, the underlying mechanism remains unclear. Bile acids are important components of the host's metabolism and are deeply influenced by gut microbiota. In recent years, significant progress has been made in the study of how gut microbiota regulate their host's lipid metabolism through bile acids. This review summarizes the enterohepatic circulation of bile acids, the interaction between gut microbiota and bile acids, and the role of gut microbiota-bile acid signaling in the regulation of lipid metabolism. Finally, this review examines the effects of bile acid metabolism disorders on obesity. This review aims to provide a novel perspective for understanding the relationship between gut microbiota and the host's lipid metabolism.
1 Introduction
The gut microbiota is a complex, diverse, and constantly changing ecosystem comprising bacteria, fungi, viruses, archaea, and protozoa (Fang et al., 2021). Recently, increasing evidence has shown that gut microbiota played a crucial role in host metabolism, particularly in the regulation of lipid metabolism (Schoeler and Caesar, 2019). Studies have also shown that high-fat diet shift the gut microbiota toward a higher Firmicutes-to-Bacteroidetes ratio, thereby increasing energy acquisition and promoting obesity, while a low-fat diet reversed this phenomenon (Tong et al., 2021). This suggests that the gut microbiota was an important factor that regulated the host's lipid metabolism and deposition. The gut microbiota usually play a regulatory role through their metabolites, including short-chain fatty acids (SCFAs), amino acids, bile acids, polyamines, and lipopolysaccharide (LPS; Du et al., 2023). Importantly, bile acids were signaling molecules and metabolic integrators that can activate nuclear receptors, including farnesoid X receptor, pregnane X receptor, vitamin D receptor, and G protein-coupled bile acid receptor; therefore, they play important roles in regulating lipid metabolism and inflammation (Li and Chiang, 2014). Bile acids also participate in lipid metabolism through the enterohepatic circulation, and their metabolism is related to gut microbiota (Xu and Gui, 2024). Before reaching the ileum, bile acids undergo a series of biotransformation processes induced by intestinal microbiota, including dehydrogenation reactions, dissociation effects, oxidation of hydroxyl groups at C3, C7, and C12 positions, and desulfation reactions. These transformation processes were closely regulated by the intestinal microbiota (Jia et al., 2019). Additionally, gut microbiota modify bile acids, leading to changes in receptor signaling and microbial population, which may affect the host's metabolic status and regulate lipid metabolism (Agus et al., 2021). This review aims to examine the latest advances in studies on the underlying mechanisms through which intestinal microbiota regulate host lipid metabolism through bile acids and to provide insights for related research fields.
2 Bile acid enterohepatic circulation
Bile acid enterohepatic circulation ensures effective recovery and reuse of bile acids. Bile acids are organic acids synthesized by the liver and secreted into bile. These compounds play vital roles in the digestion, absorption, and metabolism of lipids (Figure 1). There are two pathways for bile acid synthesis: The primary pathway, accounting for over 75% of bile acid synthesis, is also known as the classical or neutral pathway. This process is mediated by CYP7A1 (cholesterol 7α-hydroxylase), its rate-limiting enzyme, which catalyzes cholesterol 7α-hydroxylation (Yu and Kiat, 2024). Subsequently, CYP8B1 (Sterol 12α-hydroxylase) participates in catalyzing the oxidative cleavage of the cholesterol side chain. The oxidized cholesterol products undergo further hydroxylation catalyzed by CYP7B1 (Oxysterol 7α-hydroxylase), ultimately producing primary bile acids, specifically cholic acid (CA; Chang, 2025). The alternative pathway, also known as the acidic pathway, is initiated by mitochondrial cytochrome P450 enzyme 27-hydroxylase (Cholesterol 27α-hydroxylase, CYP27A1; Chiang, 2013). This enzyme catalyzes the oxidation of sterol side chains, followed by the cleavage of three-carbon units in the lipoxygenase complex. This process leads to the formation of C-24 bile acids, which are ultimately transported to the liver, where oxidative metabolites were converted into chenodeoxycholic acid (CDCA; Gao, 2023). In this process, hydroxylation at the C-12 position is essential for bile acid formation. The classical pathway, involving CYP8B1 (12α-hydroxylase), produces both 12-hydroxylated and non-12-hydroxylated bile acids. In contrast, the alternative pathway lacks CYP8B1 (12α-hydroxylase) and exclusively generates non-12-hydroxylated bile acids (Wang Y. et al., 2024). Bile acids are then secreted into the intestine through the bile ducts to participate in the digestion and absorption of lipids.
Figure 1. Enteric-hepatic circulation of bile acids.
Primary bile acids are converted into secondary bile acids by gut microbiota in the intestines (Liu et al., 2023). Several secondary bile acids are amphiphilic bile acids, which are more suitable for the dissolution and excretion of cholesterol and fat in the body. First, enzymes from gut bacteria induce a deconjugation reaction in which bile acid molecules were separated from the glycine or taurine molecules to which they are bound. This step facilitates the subsequent transformation process, leading to further modifications (Pushpass et al., 2022). Subsequently, under the catalysis of bacterial enzymes, bile acid molecules begin to undergo the dehydroxylation reaction, leading to the synthesis of a series of secondary bile acids with different chemical structures and properties, including deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, that play important roles in metabolic processes in the human body (Wang and Zhao, 2024). Finally, secondary bile acids are reabsorbed in the intestines and return to the liver through the portal vein, allowing them to repeatedly participated in the synthesis and secretion of bile (Kumar Singh et al., 2019).
This figure shows the metabolic cycle of bile acids in the body, covering the complete process from cholesterol synthesis of primary bile acids to intestinal transformation, reabsorption, and enterohepatic circulation.
3 Relationship between gut microbiota and bile acid metabolism
3.1 Gut microbes are involved in bile acid metabolism
As an important metabolite in the host, the formation and metabolism of bile acids are significantly affected by the gut microbiota. While changes in the gut microbiota directly affect the metabolism of bile acids, Bifidobacterium and Lactobacillus (e.g., Lactobacillus rhamnosus, Lactobacillus acidophilus, and Lactobacillus reuteri) can produce bile salt hydrolytic enzyme (BSH), which participates in the deconjugation of bile acids, converting conjugated primary bile acids into free bile acids. The increase in the ratio of Bacteroides, Proteus, Firmicutes, Bacteroides, and Actinomycetes can increase secondary bile acids, among which Actinomycetes can promote the excretion and synthesis of bile acids (Table 1). The gut microbiota affects the metabolic transformation of bile acids through a variety of enzymatic reactions and signal regulation mechanisms. BSH and 7α-dehydroxylase produced by the gut microbiota are key enzymes in the uncoupling reaction of bile acid metabolism. After BSH and dehydrogenation, primary bile acids are converted into secondary bile acids, such as LCA, DCA, UDCA, and ωMCA (Foley et al., 2021; Ridlon et al., 2016). BSH is mainly produced by intestinal flora, such as lactic acid bacteria and Bifidobacterium, and is highly conservatively expressed in these organisms (Collins et al., 2023). Bile salts produced by the gut microbiota are mainly involved in the process of dissociating conjugated bile acids into free bile acids in the host. Subsequently, gut microbes convert CA and CDCA into DCA and LCA through 7α-dehydroxylase and convert UDCA to LCA through 7β-dehydroxylase (Foley et al., 2021). Moreover, studies have found that gut microbes can further convert α-MCA and β-MCA into murine deoxycholic acid (ωMCA) in mice (Ridlon et al., 2016). The increase of BSH activity enhanced the content of free bile acids, triggering the FXR-FGF15/19 negative feedback regulatory system for bile acids, reducing bile acid synthesis, and causing cholesterol to become supersaturated when gut microbiota is imbalanced (Fan et al., 2024). If bile acids cannot be effectively dissolved, they may precipitate to form stones. Importantly, gut bacteria, especially Lactobacillus and Bifidobacterium, can eliminate cholesterol by ingesting cholesterol or forming co-precipitates through assimilation (Horáoková et al., 2018). Furthermore, some bacteria convert cholesterol into insoluble prostaglandins, allowing them to be excreted through feces. The FXR-FGF15-CYP7A1 pathway also plays an important role in regulating the synthesis of primary bile acids by gut microbiota (Sayin et al., 2013).
Table 1. Gut microbiota altered composition of bile acid.
On the one hand, the BSH produced by Lactobacillus reduces the reabsorption of bile acids in the small intestine. This metabolic process increases the excretion of bile acids in feces, which in turn leads to more cholesterol being converted into bile acids, thereby reducing serum cholesterol levels (Wang and Xue, 2020). On the other hand, free bile acids produced during the BSH decoupling process are difficult to digest and absorb in the intestines, resulting in an increase in the amount of free bile acids eliminated in feces (Pereira et al., 2003). Consequently, more cholesterol in the liver is converted into bile acids through the bile acid-FXR feedback mechanism (Choi et al., 2015), thereby reducing the overall cholesterol content. Some traditional Chinese medicine extracts that significantly increase the number of Lactobacillus in the intestines of poultry and livestock have been found to promote the proliferation of other beneficial bacteria in the intestines of Gallus gallus domesticus and accelerate the excretion and absorption of bile acids (Jiang et al., 2017; Wang Z. et al., 2024). Since Lactobacillus secrete acidic substances, these substances reduced the pH of the intestines and the solubility of bile acids, thereby inhibiting the absorption of bile acids in the intestines (Vivekanandan et al., 2024; Hong et al., 2015) and increasing the concentration of fecal bile acids. Furthermore, a recent study showed that adding Lactobacillus plantarum increased the fecal bile acid excretion of patients with hyperlipidemia by 15% and reduced the serum levels of low-density lipoprotein cholesterol (LDL-C) by 10% (Meng, 2023). Moreover, studies have found that in mice, antioxidants (tempol) preferentially reduced the abundance of Lactobacillus and BSH activity and increased the content of intestinal taurine-β-mouse bile acid (T-β-MCA; Li et al., 2013; Gonzalez et al., 2016). Bifidobacteria also affected bile acid metabolism by producing BSH. For example, the hydrolase BSH produced by Bifidobacteria rapidly hydrolyzes T-β-MCA into β-MCA (Tanaka et al., 1999) and reduced the inhibitory effect on the FXR signaling pathway (Wang and Xue, 2020). The number of Bifidobacteria in the gut of mice was increased by resistant starch and natural extracts [such as Salvia miltiorrhiza and resveratrol), and then decompose primary bile acids (deoxycholic acid (DCA) and lithocholic acid (LCA)] into secondary bile acids [such as glycodeoxycholic acid (GDCA) and taurodeoxycholic acid (TDCA)] through BSH (Li et al., 2024, 2021; Liu et al., 2024). However, if the levels of beneficial bacteria such as Bifidobacteria was decreased, a large amount of conjugated bile acids will be reabsorbed by the liver, and the enzymatic reaction for bile acid synthesis will be inhibited, resulting in a decrease in bile acid secretion (Qiu et al., 2025).
Additionally, other bacterial genera are also involved in regulating bile acid metabolism. For example, some strains of the genus Clostridium (such as Clostridium) convert lithocholic acid (LCA) to 3-oxo-LCA, which had antibacterial activity, through the action of 3β-hydroxysteroid dehydrogenase, thereby inhibiting the proliferation of intestinal pathogens (Cai et al., 2022). Another study showed that providing mice with different types of mixed live bacteria combinations (such as Bifidobacterium breve, Bifidobacterium longum, Lactobacillus anaerobius, Lactobacillus plantarum, Lactobacillus helveticus, pasteurized milk yeast, and heat-sensitive Streptococcus formed after high-temperature fermentation) promoted the excretion of more free bile acids (Winston and Theriot, 2020). It was further found that the production of new bile acids was stimulated by the inhibition of the FXR-FGF15 pathway from the colon to the stomach (Pathak et al., 2018). The above studies indicate that gut microbes can regulate bile acid metabolism by producing BSH.
3.2 Effect of bile acids on intestinal microbial composition
The change of bile acid also has a great influence on the composition of the gut microbiota. Studies have shown that bile acids inhibit the growth of harmful bacteria, such as Escherichia coli, Streptococcus, and Salmonella, by destroying bacterial cell membranes or regulating intestinal pH, thereby maintaining the homeostasis of the gut microbiota (Ridlon et al., 2016). Secondary bile acids such as deoxycholic acid increased the proportion of Bacteroidetes and reduce the proportion of Firmicutes, Bacteroidetes, and Lactobacillus through FXR (Qian et al., 2018; Xu et al., 2021). Furthermore, chenodeoxycholic acid inhibited the proliferation of harmful bacteria in the gut, such as Clostridium, Toona, and Erysipelothrix (Islam et al., 2011), indicating that secondary bile acids reshaped the composition of the intestinal microflora and were closely related to intestinal inflammation and diseases. Interestingly, primary bile acids, such as taurocholic acid, increased the microbial diversity of neonatal mice and significantly reduce the abundance of Escherichia coli, while ursodeoxycholic acid did not cause this change (van Best et al., 2020). Further research also found that changed in the concentration and composition of bile acids affect the diversity of gut microorganisms; 7α-dehydroxyl bacteria can rapidly dissolve the cell membranes of bacteria and cause the outflow of bacterial contents; however, their growth was inhibited with the increase in BA concentration, thus preventing ecological imbalance and the release of inflammatory markers (Bustos et al., 2018). However, the decrease in BA concentration was conducive to the growth of Gram-negative bacteria, which induced the release of inflammatory markers and increased the inflammatory response of the liver (Wang Y. et al., 2023). Additionally, the increase in bile acid concentration led to a decrease in the proportion of some beneficial bacteria such as Lactobacillus and Bifidobacteria, while the proportions of some potentially harmful bacteria were increased (Li, 2023). However, there is no complete pathway defining how bile acids regulate gut microbiota.
4 Gut microbiota regulates host lipid metabolism through bile acid signaling
Bile acids participate in regulating substance metabolism and maintain the homeostasis of the host's internal environment by activating several types of receptors. Currently known bile acid receptors were divided into two categories: the first category comprises nuclear receptors, including FXR, PXR, VDR and CAR, while the other category comprises membrane receptors, mainly TGR5 and S1PR2 (Ticho et al., 2019). Bile acid signaling, as a key mode of communication between the gut microbiota and the host, has attracted much attention from researchers in recent years (Figure 2). However, how gut microbes regulate lipid metabolism through bile acid signaling requires further detailed study.
Figure 2. Function of bile acid signaling.
This figure shows the mechanism by which bile acids regulate lipid metabolism, intestinal function, and microbiota interaction through the liver-gut axis.
4.1 Bile acids and farnesoid X receptor (FXR)
The FXR receptor is a ligand-regulated nuclear receptor, with bile acids being one of its ligands. Additionally, CA, DCA, and LCA act as agonists of FXR, while UDCA, TαMCA, and Tβ-MCA serve as its natural antagonists (Wahlström et al., 2016). FXR is expressed in multiple tissues, including the liver, intestines, kidneys, and adrenal glands, with the highest expression being in the liver and intestines. The main receptor of FXR is bile acid, and its activation is important for the regulation of bile acid metabolism (Teodoro et al., 2011). Studies had shown that the activation of FXR can promote the diversity and stability of the gut microbiome, thereby improving the host's gut health. For instance, in FXR-deficient mice, the diversity of the gut microbiome is significantly reduced, accompanied by challenges such as intestinal inflammation (Gadaleta et al., 2020; Li et al., 2021). Early colon cell studies have revealed that FXR-deficient mice are more prone to developing severe intestinal inflammation compared to wild-type mice, suggesting that intestinal FXR can alleviate intestinal inflammation (Ma et al., 2025). When treated with FXR agonists, these problems can be significantly improved, enhancing the diversity and stability of the gut microbiome (Wang H. et al., 2024). The activation of FXR can influence the host's immune response by modulating the composition of the gut microbiome. Some studies have also shown that FXR suppresses the occurrence and development of intestinal inflammation (Paik et al., 2022), and this may be related to FXR's regulation of anti-inflammatory substances produced by the gut microbiome. Additionally, FXR can promote the integrity of the intestinal barrier, thereby preventing harmful substances from entering the bloodstream and protecting the host from pathogenic and toxic invasions (Zhuang et al., 2023). Furthermore, FXR also influenced the host's energy metabolism and insulin resistance by regulating the metabolism of the gut microbiome. For example, studies have shown that the activation of FXR promotes the production of short-chain fatty acids by the gut microbiome, which were then absorbed and utilized by the host as an energy source, leading to improvement in insulin resistance in the host (Han et al., 2021).
Further research on bile acids had led to the discovery of the important relationship between them and their receptor, FXR, and how they affect lipid metabolism. Experimental evidence has shown that knocking out the FXR gene in mice significantly increased the total triglyceride content in the blood (Moschetta et al., 2004). This also affected Sterol Regulatory Element-Binding Protein (SREBP), a molecular switch belonging to a group of proteins that integrated into cells and served as an important regulatory factor for fat synthesis (Debose-Boyd and Ye, 2018). This is because endogenous bile acid-activated FXR mediates the downregulation of SREBP-1c expression and decreases the expression of fatty acid synthase (FAS) in a SHP-dependent manner, thereby inhibiting liver fat production (Watanabe et al., 2004). Another important transcriptional factor, carbohydrate response element binding protein (ChREBP), had been shown to promote carbohydrate conversion to lipids and inhibit lipid synthesis through bile acid activation of FXR to downregulate ChREBP expression (Duran-Sandoval et al., 2005). Furthermore, peroxisome proliferator-activated receptor alpha (PPAR-α) plays a role in regulating lipid metabolism and fatty acid oxidation; its activation by FXR leads to increased fatty acid oxidation metabolism and reduced fat deposition (Li and Chiang, 2009).
Membrane receptor SRB1 was a protein responsible for removing high-density lipoprotein cholesterol (HDL-C) from the blood and was regulated by FXR. The activation of hepatic FXR leads to reduced phosphorylation of p-JNK, subsequently stimulating the expression of Hepatocyte Nuclear Factor 4 alpha (HNF4α) and SRB1, further enhancing the clearance capacity of HDL-C (Zhang et al., 2010). On the other hand, the absence of FXR demonstrated that elevated levels of high-density lipoprotein (HDL) cholesterol in plasma are regulated by SRB1 (Lambert et al., 2003). ApoCII was another target gene of FXR whose increased expression promoted the production of lipoprotein lipase (LPL), leading to an increase in triglyceride hydrolysis rate (Lambert et al., 2003). Additionally, FXR also promotes the expression of Phospholipid Transfer Protein (PLTP) to accelerate the removal of lipid substances in HDL (Kast et al., 2001). Overall, the bile acid receptor FXR controls the body's lipid balance by affecting multiple processes, including lipid generation, lipid oxidation metabolism, and lipid transport and uptake, thereby maintaining the body's lipid homeostasis.
4.2 Bile acids and G protein-coupled receptor 5 (TGR 5)
A novel bile acid membrane receptor called TGR5 was first discovered by Maruyama et al. in 2002 (Maruyama et al., 2002). TGR5 is a GPCR (a member of the superfamily), also known as GPBAR1 or membrane-type bile acid receptor (M-BAR), and is an important bile acid receptor (Castro et al., 2019). This significant and widely distributed substance is mainly present in various types of cells in different tissues, such as lipid cells, large mononuclear leukocytes, bile duct surface cells, smooth muscle cells within the microvasculature of hepatic sinusoids, and sites of stone formation, among others (Kawamata et al., 2003; Keitel et al., 2009; Reich et al., 2007). It has also been found in some specific organs, such as the insulin-secreting β cells, and its impact at these sites has been identified (Keitel, 2008). Evidence also suggests that this molecule appeared in certain specific brain regions and played specific roles, such as regulating the speed of gastric motility to maintain the normal operation of the digestive system (Poole et al., 2010).
Although all types of bile acids can activate the TGR5 receptor, it exhibits a stronger response to secondary bile acids than to primary bile acids, especially with a specificity for tauroursodeoxycholic acid (TLCA), lithocholic acid (LCA), and deoxycholic acid (DCA; Bunnett, 2014). TGR5 is involved in regulating intestinal motility changes caused by bile acids. The activation of TGR5 can stimulate intestinal contraction; however, excessive TGR5 expression may accelerate intestinal transit, and conversely, the absence of TGR5 may lead to constipation issues (Alemi, 2013). Since TGR5 was expressed in enteric neurons, it played a crucial role in regulating intestinal motility. In vivo experiments have shown that the absence of the TGR5 receptor can lead to disruption of tight junction structures in the intestinal epithelium, thereby affecting intestinal motility (Cipriani et al., 2011; Ichikawa et al., 2012). Furthermore, in terms of fat metabolism, studies have shown that the activation of TGR5 can promote adipocyte differentiation and lipid metabolism, thereby regulating fat accumulation within the body. Additionally, during lipolysis, activation of TGR5 transduces signals to the mammalian target of rapamycin complex I (mTORC1), which was primarily involved in metabolic activities and indirectly participates in fat breakdown, through protein kinase B (AKT; Wang H. et al., 2024). Subsequently, mTORC1 will perform secondary phosphorylation of 4E-binding protein 1 (4E-BP1), thereby regulating the degree of gene translation and ultimately driving the process of fat breakdown (Li et al., 2020). In summary, gut microbes regulate lipid metabolism by affecting adipocyte differentiation and lipid metabolism through bile acid receptor TGR5, thereby maintaining lipid homeostasis.
4.3 Bile acids and pregnane X receptor (PXR)
PXR has been identified since 1998 as a member of the superfamily of nuclear receptors (NR). Its presence has been demonstrated in hepatic cells and the intestine in all known mammalian species (Chen et al., 2024; Zollner et al., 2010; Mora et al., 2008). These tissues serve as primary organs responsible for the intake, distribution, metabolism, and clearance of external substances and internal elements. In recent years, with the in-depth study of the intestinal microbiome, researchers have discovered a close interplay between the PXR and the gut microbiota. PXR acted as a nuclear receptor for bile acids and is involved in the biosynthesis, transport, and regulation of bile acids. Additionally, the transcription of CYP7A1 was inhibited by PXR in the liver, which affects bile acid synthesis (Zhou et al., 2023). Further research has also indicated that PXR activation can promote the interactions between PXR and HNF4α and blocked the activation of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α by HNF4α, leading to the inhibition of CYP7A1 transcription (Thomas et al., 2022). Furthermore, PXR activation regulated the expression of organic anion transport peptide 2(OATP2), sulfotransferase, and mouse Cyp3A11/human CYP3A4, potentially facilitating bile acid metabolism and transport (Cipriani et al., 2011). This is because OATP2, which was located on the basolateral membrane of hepatic cells and involved in the cellular uptake of bile acids, was induced by PXR and may increase the uptake of bile acids from sinusoidal blood into hepatic cells, where detoxification pathways (such as hydroxylation and sulfation) may occur via Cyp3a11/CYP3A4 and sulfotransferase, respectively (Maglich et al., 2002).
In the intestinal tract, PXR interacted with the gut microbiota. However, the effect of this interaction was further influenced by the composition and function of the gut microbial community. Studies have shown that the activation and deficiency of PXR can affect the diversity and abundance of the gut microbial community (Liu T. et al., 2020). For example, PXR knockout mice had increased gut microbial richness leading to an increase in the pro-inflammatory bacterium Helicobacter pylori. PXR ligands, such as bile acids and pregnane X, regulate the metabolic pathways of the gut microbiota, thereby affecting their growth and reproduction (Little et al., 2022). However, when PXR is blocked by statins such as atorvastatin, the intestinal microbial composition of mice is significantly altered, leading to a reduction in the diversity of the host's intestinal microbiota (Benakis et al., 2016). The Firmicutes to Bacteroidetes (F/B) ratio is one of the markers of obesity. In male wild-type mice, a high-fat diet had been shown to upregulate the F/B ratio in a PXR-dependent manner; however, the F/B ratio remained unchanged in female PXR knockout mice after a high-fat diet (Kim et al., 2021). Therefore, PXR may partially promoted the occurrence of high-fat diet-induced obesity through the regulation of changes in the gut microbiome (Xie and Liu, 2021). The activation of PXR can also affect the homeostasis of intestinal microflora and maintain intestinal health (Pushpass et al., 2022). Furthermore, intestinal flora can activate PXR by metabolizing short-chain fatty acids, thereby regulating metabolic processes in the human body, such as cholesterol metabolism and glucose metabolism. However, excessive SCFAs may lead to an imbalance in energy regulation, thereby promoting obesity (Du et al., 2022). The interaction between PXR and the intestinal microbiota is a complex and important research field. In the future, with the in-depth study of the intestinal microbiota and the function of PXR, additional discoveries regarding the mechanisms of their interaction will provide novel ideas and approaches for the prevention and treatment of related diseases.
4.4 Bile acids and vitamin D receptor (VDR)
The vitamin D receptor (VDR) is a protein containing six functional domains. Its E domain is mainly used for interacting with molecular partners, and VDR can simultaneously recognize and bind to various ligands, including vitamin D (Zhang et al., 2020). Additionally, it can also exert its activity by recognizing secondary bile acids, especially cholic acid and its derivatives, including lithocholic acid, glycochenodeoxycholic acid, and 7-ketolithocholic acid. However, these secondary bile acids can significantly affect the expression of VDR (Han and Chiang, 2009). The enterohepatic circulation of bile acids may enhance the activity of VDR in the liver and intestines. The concentration of lithocholic acid in the liver and intestines increases, thereby stimulating VDR activity and converting it into more harmless metabolites when cholestasis occurs (Qin and Wang, 2019). Existing studies have confirmed that lithocholic acid can induce the expression of CYP3A4 in the liver through VDR, further promoting the oxidation of bile acids (Cheng et al., 2014), while intestinal VDR deficiency exacerbated liver damage caused by lithocholic acid. However, in transplanted intestine-specific VDR-deficient mice, abnormal overexpression of CYP3A4 led to attenuation of liver damage caused by lithocholic acid (Wang et al., 2022). This demonstrates the association between the expression level of VDR and liver damage in such an environment. Furthermore, some studies have found that in mice with VDR gene knockout, lithocholic acid can trigger VDR activation and increase calcium levels in the blood (Yao et al., 2019).
Some studies indicated that the gut microbiota and its derivatives also influence the function of VDR, such as short-chain fatty acids (propionic acid) and their derivatives (butyrate ester), which were metabolic products of specific microbial communities that enhance the expression of VDR in the gut while mitigating inflammatory responses (Nehring et al., 2007; Hays et al., 2024). On the other hand, the abundance of VDR may potentially influence changes in gut bacteria. A study reported that compared to the gut microbiota of mice with VDR gene deficiency, normal mice had a significant decrease in the population of acid-producing bacteria that were observed in the VDR-deficient mice and a noticeable increase in Clostridia and other bacilli (Jin et al., 2015). This further confirms the potential association between VDR and the gut microbiota environment.
5 Bile acid metabolism disorder and obesity
In the increasingly fast-paced modern society, obesity is becoming a major concern even in younger populations. As one of the important influencing factors of obesity, disorders in bile acid metabolism have been receiving increasing attention alongside obesity-related indicators, such as body weight, body fat percentage, serum lipid, and related gene expression (Table 2). Moreover, obese individuals often had abnormal bile acid metabolism, which may further promoted the occurrence and development of obesity (Wang and Xue, 2020).
Table 2. Effects of bile acid changes on obesity.
Bile acid is a major influencing factor in the digestion and absorption of fats (Weida et al., 2020). Bile acid metabolism disorders mainly manifests as reduced bile acid synthesis and obstructed excretion in obese populations (Xie et al., 2016). This may be the result of the combined effects of obesity-induced insulin resistance, lipid metabolism disorder, and impaired liver function, which led to increased fat accumulation, thereby triggering obesity (Buzzetti et al., 2016; Gonzalez et al., 2016). Watanabe et al. fed bile acid (CA) to obese mice induced by high-fat diet and observed that bile acid metabolism disorders affected the balance of gut microorganisms, further impacting the occurrence of obesity and metabolic diseases (Watanabe et al., 2006). Studies have also indicated that bile acids affect the composition of the gut microbiota through their partial antibacterial properties or involvement in the immune function of the intestinal mucosa, thereby influencing the occurrence of obesity (Cui and Gao, 2022). Therefore, investigating and understanding the link between bile acid metabolism imbalance and obesity plays an extremely important role in the prevention and treatment of obesity and related diseases. Future research should further explore disorders in bile acid metabolism and how to prevent and treat obesity and related diseases by regulating bile acid metabolism. Additionally, approaches for optimizing bile acid metabolism can be explored in obese populations to reduce the risk of obesity and related diseases while also maintaining healthy lifestyle habits such as a balanced diet and moderate exercise.
6 The bile acid pathway alleviates lipid metabolism disorders through gut microbiota
Bile acids are a class of substances synthesized by cholesterol in the liver and play a key role in fat digestion and absorption. In recent years, studies have shown that the bile acid pathway effectively alleviated lipid metabolism disorders under the influence of the gut microbiota. For example, inulin promoted the excretion of bile acids and reduced the reabsorption of bile acids by increasing the alpha diversity of gut microbiota (Wang et al., 2022). This led to a reduction in the serum triglyceride (TG) and low-density lipoprotein (LDL) levels, thereby improving lipid metabolism in animals (Zhang et al., 2025). Studies had shown that feeding tetrahydropalmatine altered the structure of intestinal flora, effectively regulated bile acid metabolism, and improved abnormal lipid metabolism in ApoE gene knockout mice (Gao, 2024). In-depth studies have also reported that peanut red proanthocyanidins significantly increased the level of Akkermansia muciniphila and Parabacteroides distasonis in the intestine of obese type II diabetic mice (Masumoto et al., 2016; Roopchand et al., 2015). It had also been shown that Akkermansia is negatively correlated with obesity and diabetes, as the consumption of Akkermansia significantly reduces body weight while improving lipid metabolism abnormalities and blood glucose levels (Everard et al., 2013). Additionally, a gavage of Parabacteroides distasonis increases the levels of LCA, UDCA, and succinic acid in the gut; LCA and UDCA reduce blood lipids by activating the FXR pathway and repair the intestinal barrier, while succinic acid reduces hyperglycemia in ob/ob mice by activating intestinal gluconeogenesis, thereby improving lipid metabolism disorders (Wang et al., 2019). Thus, some plant extracts and microecological preparations effectively improve lipid metabolism disorders through the intestinal microbiota-bile acid pathway.
7 Conclusion and outlook
Bile acids, as crucial messengers between the gut microbiota and the host, play an important role in lipid metabolism. This review mainly explores the synthesis, metabolism, and regulatory role of bile acids in lipid metabolism and further discusses the key roles of bile acid receptors in bile acid metabolism and lipid metabolism. FXR, PXR, VDR, and TGR5, as important bile acid receptors, participate in the synthesis, transportation, metabolism, and excretion of bile acids by regulating the expression of related genes, maintaining the balance of bile acids in the body, and stabilizing lipid metabolism. Additionally, bile acids interact with the gut microbiota and the host, influencing lipid metabolism and overall health. This study comprehensively explores the interactive relationship between intestinal bile acids and microorganisms from the perspective of nutrition science, as well as the regulatory mechanism of the interaction on lipid metabolism. Furthermore, we provided some nutritional strategies that alleviate lipid metabolism disorders through the intestinal microbiota-bile acid pathway.
Although some progress has been made in the study of bile acids regulating host lipid metabolism through intestinal flora, there are still many unresolved questions. First, it is necessary to deeply understand the interaction mechanism between intestinal microbiota and bile acid metabolism and clarify the specific contribution and regulatory mechanism of various microbiota to bile acid metabolism. Second, beneficial gut microbiota need to be identified, while also exploring improvements in the host's lipid metabolism through the regulation of the gut microbiota community structure. Furthermore, the mechanisms of interaction between the gut microbiota and the host require further research.
Author contributions
ML: Writing – original draft, Writing – review & editing, Validation. WZ: Investigation, Writing – review & editing. CH: Writing – review & editing. XL: Investigation, Writing – review & editing. JY: Writing – review & editing. JM: Funding acquisition, Writing – review & editing. YL: Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This research was funded by the Guangxi Key Technologies R&D Program under the Department of Science and Technology of Guangxi Zhuang Autonomous Region (AB25069387); Guangxi Young Elite Scientist Sponsorship Program (GXYESS2025052); Guangxi Young Talent Project (ZX02080033424008); and Starting Research Fund for Advanced Talents of Guangxi University (A3340051033).
Acknowledgments
Thank Jie Ma teacher in the process of writing and revision of the guidance, as well as the help of teachers and sisters. Thanks for the support of the Guangxi Key Technologies R&D Program under the Department of Science and Technology of Guangxi Zhuang Autonomous Region (AB25069387); Guangxi Young Elite Scientist Sponsorship Program (GXYESS2025052); Guangxi Young Talent Project (ZX02080033424008); and Starting Research Fund for Advanced Talents of Guangxi University (A3340051033).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Gen AI was used in the creation of this manuscript.
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References
Agus, A., Clément, K., and Sokol, H. (2021). Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut 70, 1174–1182. doi: 10.1136/gutjnl-2020-323071
Alemi, F. (2013). The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 144, 145–154. doi: 10.1053/j.gastro.2012.09.055
Alves, A., Bassot, A., Bulteau, A. L., Pirola, L., and Morio, B. (2019). Glycine metabolism and its alterations in obesity and metabolic diseases. Nutrients 11:1356. doi: 10.3390/nu11061356
Benakis, C., Brea, D., Caballero, S., Faraco, G., Moore, J., Murphy, M., et al. (2016). Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nat. Med. 22, 516–523. doi: 10.1038/nm.4068
Bunnett, N. W. (2014). Neuro-humoral signalling by bile acids and the TGR5 receptor in the gastrointestinal tract. J. Physiol. 592, 2943–2950. doi: 10.1113/jphysiol.2014.271155
Bustos, A. Y., Font de Valdez, G., Fadda, S., and Taranto, M. P. (2018). New insights into bacterial bile resistance mechanisms: the role of bile salt hydrolase and its impact on human health. Food Res. Int. 112, 250–262. doi: 10.1016/j.foodres.2018.06.035
Buzzetti, E., Pinzani, M., and Tsochatzis, E. A. (2016). The multiple hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metab. Clin. Exp. 65, 1038–1048. doi: 10.1016/j.metabol.2015.12.012
Cai, J., Sun, L., and Gonzalez, F. J. (2022). Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 30, 289–300. doi: 10.1016/j.chom.2022.02.004
Castro, J., Harrington, A. M., Lieu, T., Garcia-Caraballo, S., Maddern, J., Schober, G., et al. (2019). Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivity. JCI Insight 4:e131712. doi: 10.1172/jci.insight.131712
Chang, Y. (2025). Effects ofTGR5 on LipidMetabolism, Cholesterol Metabolism, and Bile Acid Synthesis in the Livers of Fatty Liver Cows. Heilongjiang Bayi Agricultural Reclamation University. doi: 10.27122/d.cnki.ghlnu.2025.000320
Chen, G., Wang, Z., Qiu, S., You, T., Yue, T., et al. (2024). Fiora leaf extract affects the metabolism of serum gonadotropin in pregnant horses through PXR/CYP17A1 in the liver. J. Yunnan Agric. Univ. 39, 8894. doi: 10.12101/j.issn.1004-390X(n).202303028
Chen, X., Chen, Y., Stanton, C., Ross, R. P., Zhao, J., Chen, W., et al. (2023). Dose-response efficacy and mechanisms of orally administered Bifidobacterium breve CCFM683 on IMQ-induced psoriasis in mice. Nutrients 15:1952. doi: 10.3390/nu15081952
Cheng, J., Fang, Z. Z., Kim, J. H., Krausz, K. W., Tanaka, N., Chiang, J. Y., et al. (2014). Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice. J. Lipid Res. 55, 455–465. doi: 10.1194/jlr.M044420
Chiang, J. Y. (2013). Bile acid metabolism and signaling. Compr. Physiol. 3, 1191–1212. doi: 10.1002/j.2040-4603.2013.tb00517.x
Choi, S. B., Lew, L. C., Yeo, S. K., Nair Parvathy, S., and Liong, M. T. (2015). Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Crit. Rev. Biotechnol. 35, 392–401. doi: 10.3109/07388551.2014.889077
Cipriani, S., Mencarelli, A., Chini, M. G., Distrutti, E., Renga, B., Bifulco, G., et al. (2011). The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS ONE 6:e25637. doi: 10.1371/journal.pone.0025637
Collins, S. L., Stine, J. G., Bisanz, J. E., Okafor, C. D., and Patterson, A. D. (2023). Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat. Rev. Microbiol. 21, 236–247. doi: 10.1038/s41579-022-00805-x
Cui, X., and Gao, X. (2022). Progress on the gut-organ axis. Pharm. Res. 41, 531–536. doi: 10.13506/j.cnki.jpr.2022.08.009
Debose-Boyd, R. A., and Ye, J. (2018). SREBPs in lipid metabolism, insulin signaling, and beyond. Trends Biochem. Sci. 43, 358–368. doi: 10.1016/j.tibs.2018.01.005
Degirolamo, C., Rainaldi, S., Bovenga, F., Murzilli, S., and Moschetta, A. (2014). Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 10, 12–18. doi: 10.1016/j.celrep.2014.02.032
Du, X., Lv, Y., Wang, S., Wang, H., and Han, M. (2022). Mechanism of pregnane X receptor in cardiovascular diseases and regulation of traditional Chinese medicine. Cardiovasc. Dis. Prog. 43, 547–553. doi: 10.16806/j.cnki.issn.1004-3934.2022.06.017
Du, X., Tang, Z., Yan, L., and Fu, X. (2023). Progress in the relationship between gut flora metabolites and inflammatory bowel disease. Chin. J. Microecol. 35, 607–611. doi: 10.13381/j.cnki.cjm.202305020
Duran-Sandoval, D., Cariou, B., Percevault, F., Hennuyer, N., Grefhorst, A., van Dijk, T. H., et al. (2005). The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J. Biol. Chem. 280, 29971–29979. doi: 10.1074/jbc.M501931200
Everard, A., Belzer, C., Geurts, L., Ouwerkerk, J. P., Druart, C., Bindels, L. B., et al. (2013). Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A. 110, 9066–9071. doi: 10.1073/pnas.1219451110
Fan, M., Cui, M., Zhao, M., Jiang, Q., and Lu, Y. (2024). Research progress on the role of intestinal flora in cholelithiasis and its prevention and treatment. J. Gastroenterol. Hepatol. 33, 432–435. doi: 10.3969/j.issn.1006-5709.2024.04.013
Fang, Y., Yan, C., Zhao, Q., Xu, J., Liu, Z., Gao, J., et al. (2021). The roles of microbial products in the development of colorectal cancer: a review. Bioengineered 12, 720–735. doi: 10.1080/21655979.2021.1889109
Foley, M. H., O'Flaherty, S., Allen, G., Rivera, A. J., Stewart, A. K., Barrangou, R., et al. (2021). Lactobacillus bile salt hydrolase substrate specificity governs bacterial fitness and host colonization. Proc. Natl. Acad. Sci. U.S.A. 118:e2017709118. doi: 10.1073/pnas.2017709118
Gadaleta, R. M., Garcia-Irigoyen, O., Cariello, M., Scialpi, N., Peres, C., Vetrano, S., et al. (2020). Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor. EBioMedicine 54:102719. doi: 10.1016/j.ebiom.2020.102719
Gao, C. (2023). Research on FXR's Metabolic Regulation Mechanism in Fatty Liver of Dairy Cows. Heilongjiang Bayi Agricultural Reclamation University. doi: 10.27122/d.cnki.ghlnu.2023.000097
Gao, F. (2024). The Effects and Mechanisms of Tannic Extract and Tetrahydropteridine on Regulating Gut Microflora and Bile Acid Metabolism to Anti-Atherosclerosis. Beijing: China Academy of Chinese Medical Sciences.
Gonzalez, F. J., Jiang, C., and Patterson, A. D. (2016). An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 151, 845–859. doi: 10.1053/j.gastro.2016.08.057
Han, S., and Chiang, J. Y. (2009). Mechanism of vitamin D receptor inhibition of cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. Drug Metab. Dispos. 37, 469–478. doi: 10.1124/dmd.108.025155
Han, S. Y., Song, H. K., Cha, J. J., Han, J. Y., Kang, Y. S., and Cha, D. R. (2021). Farnesoid X receptor (FXR) agonist ameliorates systemic insulin resistance, dysregulation of lipid metabolism, and alterations of various organs in a type 2 diabetic kidney animal model. Acta Diabetol. 58, 495–503. doi: 10.1007/s00592-020-01652-z
Hays, K. E., Pfaffinger, J. M., and Ryznar, R. (2024). The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease. Gut Microbes 16:2393270. doi: 10.1080/19490976.2024.2393270
Hong, E. E., Erickson, H., Lutz, R. J., Whiteman, K. R., Jones, G., Kovtun, Y., et al. (2015). Design of coltuximab ravtansine, a CD19-targeting antibody-drug conjugate (ADC) for the treatment of B-cell malignancies: structure-activity relationships and preclinical evaluation. Mol. Pharm. 12, 1703–1716. doi: 10.1021/acs.molpharmaceut.5b00175
Horáoková, Š., Plocková, M., and Demnerová, K. (2018). Importance of microbi al defence systems to bile salts and mechanisms of serum choles terol reduction. Biotechnol. Adv. 36, 682–690. doi: 10.1016/j.biotechadv.2017.12.005
Ichikawa, R., Takayama, T., Yoneno, K., Kamada, N., Kitazume, M. T., Higuchi, H., et al. (2012). Bile acids induce monocyte differentiation toward interleukin-12 hypo producing dendritic cells via a TGR5-dependent pathway. Immunology 136, 153–162. doi: 10.1111/j.1365-2567.2012.03554.x
Islam, K. B., Fukiya, S., Hagio, M., Fujii, N., Ishizuka, S., Ooka, T., et al. (2011). Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 141, 1773–1781. doi: 10.1053/j.gastro.2011.07.046
Jia, E. T., Liu, Z. Y., Pan, M., Lu, J. F., and Ge, Q. Y. (2019). Gut microbiota regulate signaling pathways associated with bile acid metabolism in diseases. J. Zhejiang Univ. Sci. B 20, 781–792. doi: 10.1631/jzus.B1900073
Jiang, L. S., Li, W., Zhuang, T. X., Yu, J. J., Sun, S., Ju, Z. C., et al. (2021). Ginsenoside Ro Ameliorates high-fat diet-induced obesity and insulin resistance in mice via activation of the G protein-coupled bile acid receptor 5 pathway. J. Pharmacol. Exp. Ther. 377, 441–451. doi: 10.1124/jpet.120.000435
Jiang, S. L., Liu, H. J., Liu, Z. C., Liu, N., Liu, R., Kang, Y. R., et al. (2017). Adjuvant effects of fermented red ginseng extract on advanced non-small cell lung cancer patients treated with chemotherapy. Chin. J. Integr. Med. 23, 331–337. doi: 10.1007/s11655-015-2146-x
Jin, D., Wu, S., Zhang, Y. G., Lu, R., Xia, Y., Dong, H., et al. (2015). Lack of vitamin d receptor causes dysbiosis and changes the functions of the murine intestinal microbiome. Clin. Ther. 37, 996–1009.e7. doi: 10.1016/j.clinthera.2015.04.004
Kars, M., Yang, L., Gregor, M. F., Mohammed, B. S., Pietka, T. A., Finck, B. N., et al. (2010). Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes 59, 1899–1905. doi: 10.2337/db10-0308
Kast, H. R., Nguyen, C. M., Sinal, C. J., Jones, S. A., Laffitte, B. A., Reue, K., et al. (2001). Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol. Endocrinol. 15, 1720–1728. doi: 10.1210/mend.15.10.0712
Kawamata, Y., Fujii, R., Hosoya, M., Harada, M., Yoshida, H., Miwa, M., et al. (2003). A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440. doi: 10.1074/jbc.M209706200
Keitel, V. (2008). Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem. Biophys. Res. Commun. 372, 78–84. doi: 10.1016/j.bbrc.2008.04.171
Keitel, V., Cupisti, K., Ullmer, C., Knoefel, W. T., Kubitz, R., and Häussinger, D. (2009). The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology 50, 861–870. doi: 10.1002/hep.23032
Kim, S., Choi, S., Dutta, M., Asubonteng, J. O., Polunas, M., Goedken, M., et al. (2021). Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature. Pregnane X receptor exacerbates nonalcoholic fatty liver disease accompanied by obesity- and inflammation-prone gut microbiome signature. Biochem. Pharmacol. 193:114698. doi: 10.1016/j.bcp.2021.114698
Kuang, J., Wang, J., Li, Y., Li, M., Zhao, M., Ge, K., et al. (2023). Hyodeoxycholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis. Cell Metab. 35, 1752–1766.e8. doi: 10.1016/j.cmet.2023.07.011
Kumar Singh, A., Cabral, C., Kumar, R., Ganguly, R., Kumar Rana, H., Gupta, A., et al. (2019). Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency. Nutrients 11:2216. doi: 10.3390/nu11092216
Lambert, G., Amar, M. J., Guo, G., Brewer, H. B., Gonzalez, F. J., and Sinal, C. J. (2003). The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J. Biol. Chem. 278, 2563–2570. doi: 10.1074/jbc.M209525200
Li, F., Jiang, C., Krausz, K. W., Li, Y., Albert, I., Hao, H., et al. (2013). Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat. Commun. 4:2384. doi: 10.1038/ncomms3384
Li, H., Zhang, L., Li, J., Wu, Q., Qian, L., He, J., et al. (2024). Resistant starch intake facilitates weight loss in humans by reshaping the gut microbiota. Nat. Metab. 6, 578–597. doi: 10.1038/s42255-024-00988-y
Li, J., Cheng, R., and Wan, H. (2020). Overexpression of TGR5 alleviates myocardial ischemia/reperfusion injury via AKT/GSK-3β mediated inflammation and mitochondrial pathway. Biosci. Rep. 40:BSR20193482. doi: 10.1042/BSR20193482
Li, J., Liu, Z., Shen, G., Zhu, F., and Zheng, J. (2021). Progress in bile acid-gut flora and diarrhea-type irritable bowel syndrome. J. PLA Med. 46, 1258–1262. doi: 10.11855/j.issn.0577-7402.2021.12.14
Li, R. (2023). Relationship between Diarrhea After Cholecystectomy and Bile Acid Secretion Rhythm and Intestinal Flora Imbalance. Chongqing Medical University. doi: 10.27674/d.cnki.gcyku.2023.000152
Li, R., Wang, H., Shi, Q., Wang, N., Zhang, Z., Xiong, C., et al. (2017). Effects of oral florfenicol and azithromycin on gut microbiota and adipogenesis in mice. PLoS ONE 12:e0181690. doi: 10.1371/journal.pone.0181690
Li, T., and Chiang, J. Y. (2014). Bile acid signaling in metabolic disease and drug therapy. Pharmacol. Rev. 66, 948–983. doi: 10.1124/pr.113.008201
Li, T. G., and Chiang, J. Y. L. (2009). Regulation of bile acid and cholesterol metabolism by PPARs. PPAR Res. 2009:501739. doi: 10.1155/2009/501739
Little, M., Dutta, M., Li, H., Matson, A., Shi, X., Mascarinas, G., et al. (2022). Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice. Acta Pharm. Sin. B 12, 801–820. doi: 10.1016/j.apsb.2021.07.022
Liu, J., Peng, F., Cheng, H., Zhang, D., Zhang, Y., Wang, L., et al. (2023). Chronic cold environment regulates rheumatoid arthritis through modulation of gut microbiota-derived bile acids. Sci. Total Environ. 903:166837. doi: 10.1016/j.scitotenv.2023.166837
Liu, T., Song, X., Khan, S., Li, Y., Guo, Z., et al. (2020). The gut microbiota at the intersection of bile acids and intestinal carcinogenesis: an old story, yet mesmerizing. Int. J. Cancer 146, 1780–1790. doi: 10.1002/ijc.32563
Liu, Y., Chen, K., Li, F., Gu, Z., Liu, Q., et al. (2020). Probiotic Lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice. Hepatology 71, 2050–2066. doi: 10.1002/hep.30975
Liu, Z., Qi, X., and Wang, Z. (2024). The impact of gut microbiota structure on chronic heart failure based on the theory of 'the heart and small intestine being interrelated. Hubei J. Tradit. Chin. Med. 46, 59–64. doi: 10.12174/j.issn.2096-9600.2022.10.26
Lu, H., Wu, Z., Wan, M., Xiong, S., Huang, X., Liu, T., et al. (2025). Taurochenodeoxycholic acid alleviates obesity-induced endothelial dysfunction. Eur. Heart J. ehaf766. doi: 10.1093/eurheartj/ehaf766. [Epub ahead of print].
Lu, X. Y., Shi, X. J., Hu, A., Wang, J. Q., Ding, Y., Jiang, W., et al. (2020). Feeding induces cholesterol biosynthesis via the mTORC1-USP20-HMGCR axis. Nature 588, 479–484. doi: 10.1038/s41586-020-2928-y
Łukawska, A., and Mulak, A. (2022). Impact of primary and secondary bile acids on Clostridioides difficile infection. Pol. J. Microbiol. 71, 11–18. doi: 10.33073/pjm-2022-007
Ma, Y., Yang, H., Wang, X., Huang, Y., Li, Y., and Pan, G. (2025). Bile acids as signaling molecules in inflammatory bowel disease: implications for treatment strategies. J. Ethnopharmacol. 337(Pt 3):118968. doi: 10.1016/j.jep.2024.118968
Maglich, J. M., Stoltz, C. M., Goodwin, B., Hawkins-Brown, D., Moore, J. T., and Kliewer, S. A. (2002). Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol. Pharmacol. 62, 638–646. doi: 10.1124/mol.62.3.638
Maruyama, T., Miyamoto, Y., Nakamura, T., Tamai, Y., Okada, H., Sugiyama, E., et al. (2002). Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun. 298, 714–719. doi: 10.1016/S0006-291X(02)02550-0
Masumoto, S., Terao, A., Yamamoto, Y., Mukai, T., Miura, T., and Shoji, T. (2016). Non-absorbable apple procyanidins prevent obesity associated with gut microbial and metabolomic changes. Sci. Rep. 6:31208. doi: 10.1038/srep31208
Meng, X. (2023). Study on the Mechanism of Lactobacillus plantarum LP104 Improving Hyperlipidemia through Intestinal-Hepatic Axis. Jilin: Jilin Agricultural University.
Mora, J. R., Iwata, M., and Von Andrian, U. H. (2008). Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698. doi: 10.1038/nri2378
Moschetta, A., Bookout, A. L., and Mangelsdorf, D. J. (2004). Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat. Med. 10, 1352–1358. doi: 10.1038/nm1138
Nehring, J. A., Zierold, C., and DeLuca, H. F. (2007). Lithocholic acid can carry out in vivo functions of vitamin D. Proc. Natl. Acad. Sci. U.S.A. 104, 10006–10009. doi: 10.1073/pnas.0703512104
Paik, D., Yao, L., Zhang, Y., Bae, S., D'Agostino, G. D., Zhang, M., et al. (2022). Human gut bacteria produce ??17-modulating bile acid metabolites. Nature 603, 907–912. doi: 10.1038/s41586-022-04480-z
Pathak, P., Xie, C., Nichols, R. G., Ferrell, J. M., Boehme, S., Krausz, K. W., et al. (2018). Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 68, 1574–1588. doi: 10.1002/hep.29857
Pereira, D. I., McCartney, A. L., and Gibson, G. R. (2003). An in vitro study of the probiotic potential of a bile-salt-hydrolyzing Lactobacillus fermentum strain, and determination of its cholesterol-lowering properties. Appl. Environ. Microbiol. 69, 4743–4752. doi: 10.1128/AEM.69.8.4743-4752.2003
Poole, D. P., Godfrey, C., Cattaruzza, F., Cottrell, G. S., Kirkland, J. G., Pelayo, J. C., et al. (2010). Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system. Neurogastroenterol Motil. 22, 814–825, e227–8. doi: 10.1111/j.1365-2982.2010.01487.x
Pushpass, R. G., Alzoufairi, S., Jackson, K. G., and Lovegrove, J. A. (2022). Circulating bile acids as a link between the gut microbiota and cardiovascular health: impact of prebiotics, probiotics and polyphenol-rich foods. Nutr. Res. Rev. 35, 161–180. doi: 10.1017/S0954422421000081
Qi, X., Yun, C., Sun, L., Xia, J., Wu, Q., Wang, Y., et al. (2019). Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat. Med. 25, 1225–1233. doi: 10.1038/s41591-019-0509-0
Qian, G., Qi, L., and Fan, Z. (2018). Effect ofchenodeoxycholic acid on the intestinal flora structure and intestinal function in rats. J. Nucl. Agric. 32:7. doi: 10.11869/j.issn.100-8551.2018.11.2267
Qin, X., and Wang, X. (2019). Role of vitamin D receptor in the regulation of CYP3A gene expression. Acta Pharm. Sin. B 9, 1087–1098. doi: 10.1016/j.apsb.2019.03.005
Qiu, X., Bai, X., Zhang, Y., and Huang, T. (2025). Advances in the study of the relationship between gut microbiota and acute lung injury. Chin. J. Microecol. 37, 233–239. doi: 10.13381/j.cnki.cjm.202502015
Qu, Q., Chen, Y., Wang, Y., Wang, W., Long, S., Yang, H. Y., et al. (2025). Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature 643, 201–209. doi: 10.1038/s41586-024-08348-2
Reich, M., Klindt, C., Deutschmann, K., Spomer, L., Häussinger, D., and Keitel, V. (2007). The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology 45, 695–704. doi: 10.1002/hep.21458
Ridlon, J. M., Harris, S. C., Bhowmik, S., Kang, D. J., and Hylemon, P. B. (2016). Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes 7, 22–39. Erratum in: Gut Microbes. 2016 Jun 9;7:262. doi: 10.1080/19490976.2015.1127483
Roopchand, D. E., Carmody, R. N., Kuhn, P., Moskal, K., Rojas-Silva, P., Turnbaugh, P. J., et al. (2015). Dietary polyphenols promote growth of the gut bacterium Akkermansia muciniphila and attenuate high-fat diet-induced metabolic syndrome. Diabetes 64, 2847–2858. doi: 10.2337/db14-1916
Sayin, S. I., Wahlström, A., Felin, J., Jäntti, S., Marschall, H. U., Bamberg, K., et al. (2013). Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 17, 225–235. doi: 10.1016/j.cmet.2013.01.003
Schoeler, M., and Caesar, R. (2019). Dietary lipids, gut microbiota and lipid metabolism. Rev. Endocr. Metab. Disord. 20, 461–472. doi: 10.1007/s11154-019-09512-0
Tanaka, H., Doesburg, K., Iwasaki, T., and Mierau, I. (1999). Screening of lactic acid bacteria for bile salt hydrolase activity. J. Dairy Sci. 82, 2530–2535. doi: 10.3168/jds.S0022-0302(99)75506-2
Tawulie, D., Jin, L., Shang, X., Li, Y., Sun, L., Xie, H., et al. (2023). Jiang-Tang-San-Huang pill alleviates type 2 diabetes mellitus through modulating the gut microbiota and bile acids metabolism. Phytomedicine. 113, 154733. doi: 10.1016/j.phymed.2023.154733
Teodoro, J. S., Rolo, A. P., and Palmeira, C. M. (2011). Hepatic FXR: key regulator of whole-body energy metabolism. Trends Endocrinol. Metab. 22, 458–466. doi: 10.1016/j.tem.2011.07.002
Thomas, J. P., Modos, D., Rushbrook, S. M., Powell, N., and Korcsmaros, T. (2022). The emerging role of bile acids in the pathogenesis of inflammatory bowel disease. Front. Immunol. 13, 1340–1355. doi: 10.3389/fimmu.2022.829525
Ticho, A. L., Malhotra, P., Dudeja, P. K., Gill, R. K., and Alrefai, W. A. (2019). Bile acid receptors and gastrointestinal functions. Liver Res. 3, 31–39. doi: 10.1016/j.livres.2019.01.001
Tong, Y., Gao, H., Qi, Q., Liu, X., Li, J., Gao, J., et al. (2021). High fat diet, gut microbiome and gastrointestinal cancer. Theranostics 11, 5889–5910. doi: 10.7150/thno.56157
Tuerhongjiang, G., Li, Y., Meng, Z., Gao, X., Wei, Y., Muhetaer, G., et al. (2025). Deoxycholic acid ameliorates obesity and insulin resistance by enhancing lipolysis and thermogenesis. Lipids Health Dis. 24:70. doi: 10.1186/s12944-025-02485-x
van Best, N., Rolle-Kampczyk, U., Schaap, F. G., Basic, M., Olde Damink, S. W. M., Bleich, A., et al. (2020). Bile acids drive the newborn's gut microbiota maturation. Nat. Commun. 11:3692. doi: 10.1038/s41467-020-17183-8
Vivekanandan, K. E., Kasimani, R., Kumar, P. V., Meenatchisundaram, S., and Sundar, W. A. (2024). Overview of cloning in lactic acid bacteria: expression and its application of probiotic potential in inflammatory bowel diseases. Biotechnol. Appl. Biochem. 71, 881–895. doi: 10.1002/bab.2584
Wahlström, A., Sayin, S. I., Marschall, H. U., and Bäckhed, F. (2016). Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24, 41–50. doi: 10.1016/j.cmet.2016.05.005
Wang, B., Wang, S., Ding, M., Lu, H., Wu, H., and Li, Y. (2022). Quercetin regulates calcium and phosphorus metabolism through the wnt signaling pathway in broilers. Front. Vet. Sci. 8:786519. doi: 10.3389/fvets.2021.786519
Wang, H., Wang, J., Cui, H., Fan, C., Xue, Y., et al. (2024). Inhibition of fatty acid uptake by TGR5 prevents diabetic cardiomyopathy. Nat. Metab. 6, 1161–1177. doi: 10.1038/s42255-024-01036-5
Wang, H., Zheng, S., Shi, F., Zhao, M., and Zheng, L. (2023). Regulation of the bile acid-microecological axis in the progression of liver cirrhosis. Liver 28, 1119–1123. doi: 10.14000/j.cnki.issn.1008-1704.2023.09.027
Wang, K., Liao, M., Zhou, N., Bao, L., Ma, K., Zheng, Z., et al. (2019). Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids. Cell Rep. 26, 222–235.e5. doi: 10.1016/j.celrep.2018.12.028
Wang, Q., and Xue, D. (2020). The intestinal microbiota participates in gallbladder cholesterol stone formation by affecting bile acid metabolism. J. Hepatobiliary Pancreatic Surg. 32, 6–25.
Wang, Q., and Xue, D. (2020). The intestinal microbiota participates in gallbladder cholesterol stone formation by affecting bile acid metabolism. J. Hepato. Pancreat. Surg. 32, 6–25. doi: 10.11952/j.issn.1007-1954.2020.01.002
Wang, Y., Liu, J., and Liu, J. (2023). Progress in investigating the role of the enterohepatic immune axis in non-alcoholic fatty liver disease. J. Shanxi Med. Univ. 54, 554–560. doi: 10.13753/j.issn.1007-6611.2023.04.021
Wang, Y., Wang, Y., Hu, Y., Wu, Q., Gui, L., et al. (2024). CYP8B1 catalyzes 12alpha-hydroxylation of C27 bile acid: in vitro conversion of dihydroxycoprostanic acid into trihydroxycoprostanic acid. Drug Metab. Dispos. 52, 1234–1243. doi: 10.1124/dmd.124.001694
Wang, Y., and Zhao, C. (2024). Effects of intestinal microbiota on iron metabolism in non-alcoholic fatty liver disease. Chin. J. Gerontol. 44, 2044–2047. doi: 10.3969/j.issn.1005-9202.2024.08.062
Wang, Z., Sun, X., Li, A., Sang, M., and Su, D. (2024). Effect of starter starter on growth performance and intestinal environment of broiler chickens. Feed Stud. 47, 47–51. (in Chinese). doi: 10.13557/j.cnki.issn1002-2813.2024.04.009
Wang, Z., Sun, Y., Han, Y., Chen, X., Gong, P., Zhai, P., et al. (2023). Eucommia bark/leaf extract improves HFD-induced lipid metabolism disorders via targeting gut microbiota to activate the Fiaf-LPL gut-liver axis and SCFAs-GPR43 gut-fat axis. Phytomedicine 110:154652. doi: 10.1016/j.phymed.2023.154652
Watanabe, M., Houten, S. M., Mataki, C., Christoffolete, M. A., Kim, B. W., Sato, H., et al. (2006). Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484–489. doi: 10.1038/nature04330
Watanabe, M., Houten, S. M., Wang, L., Moschetta, A., Mangelsdorf, D. J., Heyman, R. A., et al. (2004). Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP 1c. J. Clin. Invest. 113, 1408–1418. doi: 10.1172/JCI21025
Weida, W., Chang, Y., and Hongfu, Z. (2020). The mechanism of bile acid on the metabolism of sugar and lipid in the body. J. Anim. Nutr. 32, 4565–4576. doi: 10.3969/j.issn.1006-267x.2020.10.010
Winston, J. A., and Theriot, C. M. (2020). Diversification of host bile acids by members of the gut microbiota. Gut Microbes 11, 158–171. doi: 10.1080/19490976.2019.1674124
Wu, L., Zhou, J., Zhou, A., Lei, Y., Tang, L., Hu, S., et al. (2024). Lactobacillus acidophilus ameliorates cholestatic liver injury through inhibiting bile acid synthesis and promoting bile acid excretion. Gut Microbes 16:2390176. doi: 10.1080/19490976.2024.2390176
Xie, G., Wang, X., Huang, F., Zhao, A., Chen, W., Yan, J., et al. (2016). Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int. J. Cancer 139, 1764–1775. doi: 10.1002/ijc.30219
Xie, J., and Liu, Q. (2021). Progress of pregnane X receptor in some glycolipid metabolic diseases. Chin. Med. 16, 1914–1916. doi: 10.3760/j.issn.1673-4777.2021.12.037
Xu, J., Xie, S., Chi, S., Zhang, S., Cao, J., and Tan, B. (2022). Protective effects of taurocholic acid on excessive hepatic lipid accumulation via regulation of bile acid metabolism in grouper. Food Funct. 13, 3050–3062. doi: 10.1039/D1FO04085E
Xu, M., Cen, M., Shen, Y., Zhu, Y., Cheng, F., Tang, L., et al. (2021). Deoxycholic acid-induced gut dysbiosis disrupts bile acid enterohepatic circulation and pro motes intestinal inflammation. Diges. Dis. Sci. 66, 568–576. doi: 10.1007/s10620-020-06208-3
Xu, Y., and Gui, Y. (2024). Impact and clinical significance of abnormal lipid metabolism on the course of Parkinson's diseaseImpact and clinical significance of abnormal lipid metabolism on the course of Parkinson's disease. Chin. J. Modern Neurol. Dis. 24, 131–138. doi: 10.3969/j.issn.1672-6731.2024.03.004
Yang, B., Huang, S., Zhao, G., and Ma, Q. (2022). Dietary supplementation of porcine bile acids improves laying performance, serum lipid metabolism and cecal microbiota in late-phase laying hens. Anim Nutr. 11, 283–292. doi: 10.1016/j.aninu.2022.08.003
Yang, N., Sun, R., Zhang, X., Wang, J., Wang, L., Zhu, H., et al. (2023). Alternative pathway of bile acid biosynthesis contributes to ameliorate NASH after induction of NAMPT/NAD+/SIRT1 axis. Biomed. Pharmacother. 164:114987. doi: 10.1016/j.biopha.2023.114987
Yao, B., He, J., Yin, X., Shi, Y., Wan, J., and Tian, Z. (2019). The protective effect of lithocholic acid on the intestinal epithelial barrier is mediated by the vitamin D receptor via a SIRT1/Nrf2 and NF-κB dependent mechanism in Caco-2 cells. Toxicol. Lett. 316, 109–118. doi: 10.1016/j.toxlet.2019.08.024
Yu, C. L. M., and Kiat, H. H. (2024). Pharmacological modulation of cholesterol 7α-hydroxylase (CYP7A1) as a therapeutic strategy for hypercholesterolemia. Biochem. Pharmacol. 220:115985. doi: 10.1016/j.bcp.2023.115985
Zhang, Y., An, G., and Wang, S. (2025). Advances in the biological functions and applications of inulin in animal production (J/OL). Feed Res. 170–173. doi: 10.13557/j.cnki.issn1002-2813.2025.19.030
Zhang, Y., Li, J., and Wang, Y. (2020). Role ofbile acid metabolism and its receptors in the development of D recep in non-alcoholic fatty liver disease. J. Clin. Hepatobil. Dis. 36, 1374–1377. doi: 10.3969/j.issn.1001-5256.2020.06.040
Zhang, Y., Yin, L., Anderson, J., Ma, H., Gonzalez, F. J., Willson, T. M., et al. (2010). Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia. J. Biol. Chem. 285:30353043. doi: 10.1074/jbc.M109.083899
Zhou, Q., Cai, C., and Li, J. (2023). Intestine-liver axis: gut microbial homeostasis and hepatocellular carcinoma. J. Clin. Hepatobil. Dis. 39, 2710–2717. doi: 10.3969/j.issn.1001-5256.2023.11.029
Zhuang, Z., Xie, Y., and Fang, J. (2023). Advances in the bile acid farnesol X receptor in colorectal cancer. Tumors 43, 607–613.
Keywords: gut microbiota, bile acids, lipid metabolism, signal pathway, enterohepatic circulation
Citation: Liu M, He C, Lv X, Zheng W, Yin J, Li Y and Ma J (2026) Bile acid signaling mediates gut microbiota regulation of host lipid metabolism. Front. Microbiol. 16:1696213. doi: 10.3389/fmicb.2025.1696213
Received: 01 September 2025; Accepted: 31 October 2025;
Published: 13 January 2026.
Edited by:
Guijie Chen, Nanjing Agricultural University, ChinaReviewed by:
Yaroslav Shansky, Federal Medical & Biological Agency of Russia, RussiaHongwang Dong, Academy of National Food and Strategic Reserves Administration, China
Copyright © 2026 Liu, He, Lv, Zheng, Yin, Li and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jie Ma, bWFqaWUyMDIzQGd4dS5lZHUuY24=