The Farnesoid X receptor (FXR) serves as the central regulatory node for bile acid sensing, exhibiting ligand-dependent activation kinetics with distinct activation thresholds for different bile acids such as cholic acid. This molecular recognition event initiates a transcriptional cascade characterized by the transactivation of the small heterodimer partner (SHP) and the competitive displacement of HNF4α from the CYP7A1 promoter, thereby establishing an autoregulatory loop for cholic acid homeostasis. Notably, intestinal FXR activation induces the secretion of fibroblast growth factor 19 (FGF15 in mice), which subsequently activates hepatic FGFR4/β-Klotho receptor complexes via portal circulation. This enterohepatic signaling axis mediates CYP7A1 inhibition through an ERK1/2 phosphorylation cascade, demonstrating a critical cross-talk between intestinal and hepatic compartments (12).

FXR exerts pleiotropic anti-inflammatory effects through multilayered regulatory mechanisms: (1) Direct suppression of NF-κB signaling via p65 subunit sequestration coupled with proteasomal degradation pathways; and (2) Transcriptional repression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) through chromatin-bound SHP complexes (13). Furthermore, FXR coordinates hepatic detoxification processes by enhancing bile salt export pump (BSEP)-mediated biliary excretion while inhibiting basolateral uptake via the sodium taurocholate cotransporting polypeptide (NTCP), thereby preventing intracellular bile acid overload (14). NTCP serves as a multifunctional molecule with dual physiological roles: as the primary mediator of sodium-dependent bile acid uptake (15) and as the cellular entry receptor for hepatitis B virus through its interaction with the myristoylated preS1 domain. This vulnerability has been exploited therapeutically with agents like Myrcludex B, which simultaneously blocks viral entry while modulating bile acid-induced interferon responses (16, 17).

Intestinal FXR contributes to epithelial barrier integrity through two principal mechanisms: stabilization of tight junction proteins (claudin-1/occludin complexes) and angiopoietin-mediated antimicrobial peptide secretion. Additionally, FXR modulates gut microbial bile acid metabolism by regulating substrate availability (18). Emerging research has identified novel regulatory axes in FXR biology, including the discovery of liver-specific enhancer RNAs such as Fincor. This long non-coding RNA is induced by the FXR agonist tofexiflex, and CRISPR/Cas9-mediated ablation studies have established its essential role in NASH resolution. Genetic deletion of Fincor completely abrogates the therapeutic effects of tofexiflex, including: (1) attenuation of hepatic steatosis via SREBP1c downregulation; (2) inhibition of fibrogenesis through TGF-β pathway suppression; and (3) resolution of lobular inflammation via CCL2/MCP-1 inhibition (19).

TGR5 is a key bile acid receptor, which plays pivotal roles in inflammatory and immunomodulatory processes through metabolic and microbiota regulation. TGR5 downregulation in both non-alcoholic steatohepatitis (NASH) patients and murine models TGR5-knockout (TGR5^−/−) mice exhibited exacerbated hepatic injury, elevated proinflammatory cytokines, and enhanced M1 macrophage polarization. Mechanistically, TGR5 deficiency promoted NLRP3 inflammasome activation and caspase-1 cleavage, intensifying M1 polarization. Methionine-choline deficient (MCD) diet-induced NASH models revealed more severe hepatic steatosis and inflammation in TGR5^−/− mice compared to wild-type (WT) controls, with significantly higher NAFLD activity scores. Quantitative analysis showed TGR5 deletion increased hepatic levels of TNF-α and IL-6 while reducing IL-4 and IL-10 (20). Notably, TGR5^−/− livers displayed enhanced macrophage infiltration and M1 polarization. Further investigations identified TGR5-mediated suppression of NLRP3 inflammasome activation as the regulatory mechanism. Both TGR5^−/− mice and bone marrow-derived macrophages (BMDMs) exhibited upregulated NLRP3, caspase-1, IL-1β, and IL-18 expression under MCD diet or palmitic acid (PA) stimulation pharmacological inhibition of NLRP3 using CY-09 effectively suppressed inflammatory mediators and promoted M2 polarization. Clinical correlations in NASH patients confirmed inverse relationships between TGR5 expression and NLRP3 activation/M1 polarization (3, 20–22).

By studying the endoplasmic reticulum (ER)-mitochondrial coupling mediated by grp75, the protective mechanism of TGR5 in diabetic retinopathy. After TGR5 is activated, it will destroy the IP3R1-GRP75-VDAC1 axis, thus weakening the situation of diabetic retinopathy. It can also reduce the Ca ^{2 +} flux from the endoplasmic reticulum to the mitochondria, and the subsequent problem of mitochondrial Ca ^{2 +} overload. This regulatory effect can prevent the opening of mitochondrial permeability transition pores, prevent the release of mitochondrial DNA, and inhibit CGAS-STING-mediated inflammation. TGR5 agonists can improve retinal damage in diabetic models, while STING inhibitors can improve retinal damage in diabetic models (23). Microbial deoxycholic acid can alleviate mastitis induced by Staphylococcus aureus through the TGR5-cAMP-PKA-NF-κB/NLRP3 signaling pathway (21, 24). Ursodeoxycholic acid can reduce mastitis induced by Staphylococcus aureus by activating TGR5-NF-κB. And restore short-chain fatty acids to reduce neonatal calf colitis induced by enteric aggregative Escherichia coli that produces ultra-broad spectrum beta-lactamase (25). Intestinal microbiota - bile acid - fxr/TGR5 axis can improve intestinal barrier function, and can also inhibit colon inflammation (26).

Activated T cell family nuclear factors have become key mediators in bile acid-induced inflammatory processes. Studies on the mechanism have shown that human and mouse hepatocytes exposed to bile acid concentrations related to pathological simulation can induce nuclear translocation of NFATC3. It is also accompanied by upregulation of IL-8, CXCL2 and CXCL10 chemokine networks (27). Pharmacological NFAT inhibition or NFATC3 genetic ablation substantially attenuates this inflammatory cascade, establishing causal linkage. It has been clinically confirmed that nuclear NFATC3 accumulation exists in PBC/PSC liver specimens. It showed a strong positive correlation with IL-8 expression gradient. Molecular validation by luciferase reporter gene assay and CHIP-seq confirmation demonstrated that bile acids are directly involved in the NFAT response element within the IL-8 promoter, and site-specific mutations of this cis-regulatory motif would eliminate bile acid-driven transcriptional activation, thus delineating the molecular logic of the mechanism (27, 28). This axis of inflammation mediated by fat is not only limited to hepatobiliary pathology, but also contributes to ZTHE development of colorectal cancer and the progression of viral hepatitis through conserved regulatory topology (29, 30).

The expression of intestinal antimicrobial peptides has prominent spatial and temporal heterogeneity, and its regulatory structure has not yet been determined (31). Cutting-edge single-cell transcriptomics uncovers bile acid transcription factors as chromatin topological determinants of AMP heterogeneity, which is different from the typical signaling paradigm (32). BATF regulates amp by means of atypical, bile acid-independent mechanisms related to lineage commitment decisions rather than direct receptor activation. Single-cell ATAC-seq analysis also found that the chromatin accessibility landscape predetermines the regulatory potential of BATF through epigenetic prepatterns, and that this double-layer regulatory pattern, that is, the combination of chromatin topology and BATF activity, controls AMP zoning after birth and coordinates the ontogenetic process of fetal intestinal immunity (32). The discovery of bile acid-mediated epigenetic priming provides mechanistic insight into how microbial metabolites shape mucosal defense systems during developmental window.

The changes in the gut microbiota during cholestasis also affect BA The gut microbiota serves as a central regulator of bile acid (BA) homeostasis through enzymatic activity within the intestinal lumen. Wang et al. (43) systematically investigated microbial-BA interactions in infants with cholestatic jaundice (CJ) via integrated 16S rRNA sequencing and fecal BA profiling. Their analysis revealed significant reductions in primary and secondary BA levels, accompanied by a metabolic shift from classical to alternative BA synthesis pathways. Notably, CJ infants exhibited microbial communities enriched with Clostridium and Streptococcus alongside depleted Bifidobacterium, with these dysbiotic patterns strongly correlating to disrupted BA profiles and elevated hepatic dysfunction markers. Liu et al. (44) further dissected microbiome differences across biliary atresia, non- biliary atresia cholestasis (IC), and healthy cohorts using 16S rDNA sequencing. The IC group displayed a distinct microbial architecture dominated by Enterobacteriaceae, showing positive associations with serum transaminases and total bilirubin. These findings underscore divergent enterohepatic BA cycling mechanisms between obstructive and metabolic cholestasis. In addition, the changes of bile acid metabolism mediated by Lactobacillus and clostridium are also an important part of the treatment of IBD (26).

The gut microbiota exerts enzymatic control over bile acid pool composition through three phylogenetically conserved biotransformation cascades. First, bile salt hydrolase (BSH) produced by commensal Clostridium and Bacteroides catalyzes the hydrolytic deconjugation of primary BAs, cleaving glycine/taurine moieties from steroid cores to generate unconjugated species with enhanced membrane permeability and signaling potential (45). Second, hydroxysteroid dehydrogenase (HSDH) derived from Lactobacillus mediates stereoselective 7β-epimerization via NADPH-dependent redox cycling, converting CDCA into its 7β-hydroxy isoform DCA - a secondary BA with increased hydrophobicity and receptor-binding selectivity (46). Third, The specialized anaerobic 7α-dehydroxylation of Bacteroides, which irreversibly removes the C7 hydroxyl group from cholic acid, relies on sequential ketoenol tautomerism and reduction elimination steps to produce cholic acid, resulting in the most hydrophobic and cytotoxic BA species, which has been documented in relevant studies (9, 11). These three microbial enzymes work together to determine the structural diversity, physical and chemical properties and endocrine functions of the enterohepatic BA pools.

Bifidobacterium depletion potentiates FXR signaling through diminished tauro-β-muricholate and elevated FGF15 production (47), thereby suppressing primary bile acid synthesis while promoting the dominance of alternative acidic biosynthetic pathways - ultimately reducing CA/CDCA ratios (43). Under cholestatic conditions, Clostridium/Enterococcus/Clostridioides difficile expansion elevates DCA levels that drive TLR2-mediated macrophage polarization, exacerbating intestinal inflammation and microbiota dysbiosis (40, 48). The BAIA1 gene encoded by Firmicutes critically mediates the enzymatic reduction of 3-oxo-allo-deoxycholic acid (3-oxo-allo-DCA) to allo-deoxycholic acid (allo-DCA), and similarly converts 3-oxo-allo-lithocholic acid to allo-LCA. Besides, BAIA1 overexpression demonstrates a significant association with colorectal carcinogenesis (29, 49).

The hepatoprotective capacity of commensal microbiota is evidenced in bile duct ligation (BDL) models: Germ-free mice exhibit exacerbated cholestatic injury compared to conventionalized counterparts, with microbial colonization attenuating bile infarct progression through coordinated activation of hepatic regenerative programs, maintenance of inflammatory homeostasis, lipidomic reprogramming, and optimization of mitochondrial respiratory efficiency (50). Concurrent Kupfer cell activation propagates hepatobiliary injury feedforward through bilirubine-induced inflammatory cascade initiation, cytokine storm cascade disruption of the intestinal barrier, and secondary cholic acid metabolism disorders (7, 51).Pathological microbial shifts facilitate endotoxin translocation across compromised intestinal epithelium, establishing a self-perpetuating gut-liver injury axis that perpetuates cholestasis and hyperbilirubinemia (52, 53) ( Figure 1 ).