Hui Sun1†
Le Yang1†
Ye Sun1
Xinya Zhang2
Xin Sun2
Xueping Zhao2Hui Sun2Qimeng Zhang2Guangli Yan2
Xijun Wang1,2*- 1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- 2State Key Laboratory of Integration and Innovation for Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin, China
Gout, a prevalent metabolic disorder driven by hyperuricemia, results in pathological deposition of monosodium urate (MSU) crystals in joints and soft tissues, stimulating intense inflammatory responses with systemic health consequences. Emerging evidence highlights dysregulated bile acid (BA) metabolism as a pivotal contributor to gout pathogenesis. Imbalances in BA influence disease progression through multiple mechanisms (1): modulating hepatic urate production via PPAR-α/XOD signaling (2), regulating immune responses through FXR/TGR5-dependent suppression of NLRP3 inflammasome activation, and (3) shaping the gut microbiota composition, which reciprocally affects uric acid homeostasis and inflammation. Despite these advances, the precise mechanistic networks linking BA dysmetabolism to gout remain incompletely understood. In this review, we systematically synthesizes current knowledge on BA-gout interactions, elucidated how BA disturbances exacerbate disease progression, discussed the factors contributing to metabolic disorders of BAs, and evaluated promising therapeutic strategies targeting BA pathways. For example, FXR antagonists facilitate the synthesis of BA by inhibiting the aberrant activation of FXR. TGR5 agonists suppress inflammation. Probiotics help restore the diversity of the gut microbiota and increase the abundance of beneficial bacteria, including Bifidobacterium and Lactobacillus. Moreover, traditional Chinese medicine works by improving structural disorders of the gut microbiota and activating CYP7A1 to enhance the BA synthesis pathway. By integrating metabolic, immunological, and microbial perspectives, this work provides a framework for developing novel, mechanism-based interventions against gout.
1 Introduction
Gout, a prevalent metabolic disorder characterized by hyperuricemic-induced monosodium urate (MSU) crystal deposition in joints and periarticular tissues, elicits intense inflammatory responses that cause significant morbidity (1, 2). In China, gout affects ~1.1% of the population (>16 million cases), with prevalence rising parallel to the surge in hyperuricemia (14.0% in 2019 vs. 11.1% in 2015) (3, 4). As the second most common metabolic disease after diabetes (5), gout manifests as acute arthritis (erythema, swelling, and debilitating pain) and, if untreated, progresses to chronic tophaceous joint destruction, nephrolithiasis, and cardiovascular complications (6–11). The available therapeutic agents (colchicine, non-steroidal anti-inflammatory (NSAIDs) and urate-lowering drugs) primarily alleviate symptoms but fail to modify disease progression and often cause adverse effects (12), underscoring the need for novel therapeutic strategies targeting underlying pathogenesis. Emerging evidence implicates bile acid (BA) metabolism as a critical regulator of gout pathophysiology. BAs, classically known for lipid digestion, are now recognized as pleiotropic signaling molecules modulating metabolic homeostasis, inflammation, and gut microbiota (13–15). Dysregulated BA profiles are linked to metabolic disorders including non-alcoholic fatty liver disease (NAFLD), diabetes, and atherosclerosis (16, 17), with reciprocal crosstalk between inflammation and BA synthesis (e.g., IL-1β-mediated suppression of cholesterol 7α-hydroxylase (CYP7A1)) (18, 19). Intriguingly, gout patients exhibit reduced BA synthesis and altered BA pools (20, 21), suggesting that BA dysmetabolism may orchestrate gout progression through multiple mechanisms: 1) Uric acid (UA) metabolism: BAs inhibit hepatic xanthine oxidase (XOD) via proliferator-activated receptor alpha (PPAR-α), reducing urate production; their deficiency exacerbates hyperuricemia (22). Impaired FXR activation due to low BAs also disrupts lipid metabolism, further diminishing renal urate excretion. Moreover, intestinal FXR deficiency increases intestinal XOD activity, resulting in higher UA production. 2) Inflammation: BA-activated FXR/TGR5 pathways suppress the NLRP3 inflammasome and release of cytokine (IL-1β and TNF-α) (23–25). The depletion of BAs in gout patients exacerbates MSU crystal-driven inflammation via unchecked immune cell (T lymphocyte/neutrophil/macrophage) activation. 3) Gut microbiota: Antimicrobial BAs shape microbial composition; their reduction in gout patients enriches pathobionts (e.g., Escherichia coli and Bacteroides) that promote urate accumulation and inflammation (26–28).
In this review, we synthesized existing information on BA-gout interactions, highlighting: the mechanistic interplay between BA dysregulation and gout pathogenesis across metabolic, immune, and microbial axes; the therapeutic potential of BA-targeted interventions (FXR antagonists, TGR5 agonists, and microbiota modulation) to concurrently address hyperuricemia and inflammation; and the clinical implications for gout management strategies. By elucidating BA-centric pathways, we aimed to advance gout therapeutics beyond symptomatic relief toward disease modification.
2 BA homeostasis in gout pathogenesis
2.1 Clinical manifestations
Studies have indicates that patients with hyperuricemia commonly exhibit impaired BA homeostasis (29). In male patients, serum unconjugated BA levels were significantly lower in the hyperuricemia group compared to the non-hyperuricemia group. Specifically, chenodeoxycholic acid (CDCA) levels in the hyperuricemia group were 34.1% lower than those in the non-hyperuricemia group (21). Gout patients have lower BA levels. A clinical study analyzing serum metabolites from 31 gout patients and 31 healthy controls revealed significantly decreased levels of 3α,7α-dihydroxycoprostanic acid, 7α-hydroxycholesterol, and 27-deoxy-5β-cyprinol in gout patients, indicating impaired primary BA biosynthesis (20).
2.2 Role of dysregulated BA metabolism in lipid metabolism
Reduced BA levels contribute to excessive lipid accumulation. Alterations in BA composition and concentration may impair the activity of hepatic FXR and TGR5 (30). CDCA is the most potent FXR agonist among BAs, followed by deoxycholic acid (DCA) = lithocholic acid (LCA) > cholic acid (CA) (31). Gout patients exhibit decreased CDCA levels, leading to weakened FXR activity. Furthermore, decreased BA levels attenuate the activation of FXR. Activation of FXR inhibits the expression of sterol regulatory element-binding protein 1c (SREBP-1c) by enhancing small heterodimer partner (SHP) expression (32), and reduces the activity of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1), thereby lowering triglyceride levels (32, 33). Additionally, FXR activation stimulates the expression of PPAR-α, a key regulator of triglyceride metabolism, thereby inhibiting hepatic lipid accumulation and enhancing fatty acid β-oxidation efficiency (34, 35). Consequently, reduced BA levels in gout impair the function of FXR receptors. A decrease in FXR activity reduces fatty acid β-oxidation capacity, leading to excessive lipid accumulation. These changes increase the risk of obesity and insulin resistance, resulting in dysregulated lipid metabolism and an increase in inflammation.
Excessive lipid accumulation contributes to elevated UA levels in gout patients. This lipid overload can induce insulin resistance, which further enhances renal urate reabsorption by activating the urate transporter 1 (URAT1) and sodium-dependent anion cotransporters in the proximal renal tubules. Consequently, renal UA clearance decreases (36), thereby increasing serum UA levels (37) and accelerating gout progression (Figure 1).
Figure 1. Dysregulated BA metabolism in gout disrupts lipid metabolism and impairs uric acid excretion. A decrease in BA levels attenuates FXR activity. FXR promotes hepatic TG synthesis and reduces fatty acid β-oxidation by upregulating the expression of SREBP-1c and inhibiting PPAR-α. This leads to the accumulation of lipids and metabolic disorders, thereby increasing serum UA levels. FXR, Farnesoid-X-receptor; SHP, Small heterodimer partner; PPAR-α, Proliferator-activated receptor alpha; SREBP-1c, Sterol regulatory element-binding protein 1c; TG, Triglyceride; FAS, Fatty acid synthase; ACC, Acetyl-CoA carboxylase; SCD-1, Stearoyl-CoA desaturase-1; UA, Uric acid; URAT1, Urate transporter 1.
2.3 Role of dysregulated BA metabolism in immune regulation
2.3.1 T lymphocytes
BAs attenuate gout inflammation by inhibiting T cell differentiation and activation. Specifically, the BA metabolites 3-oxolithocholic acid (3-oxoLCA) and iso-lithocholic acid (isoLCA) impede Th17 cell differentiation by directly binding to retinoic acid receptor-related orphan receptor gamma t (RORγt), a key transcriptional promoter of Th17 cells (38, 39). IL-17, a pro-inflammatory cytokine secreted by Th17 cells, plays a key role in gout pathogenesis (40, 41). Additionally, LCA interacts with the vitamin D receptor (VDR) to inhibit the activation of Th1 cells, thereby reducing the production of Th1 cytokines such as IFN-γ and TNF-α (42). Consequently, reduced BA levels promote the production of pro-inflammatory cytokines (IL-17 and TNF-α), thereby exacerbating inflammatory responses in gout (Figure 2).
Figure 2. Immune cell regulation by BA metabolic dysregulation in gout. BAs constrain T-cell differentiation, block neutrophil infiltration, and dampen macrophage-induced inflammation, thereby attenuating inflammatory responses. In gout, a decrease in BA levels compromises this suppressive function, resulting in pathological inflammation that propagates disease progression. 3-oxoLCA, 3-oxolithocholic acid; isoLCA, iso-lithocholic acid; RORγt, Retinoic acid receptor-related orphan receptor gamma t; VDR, Vitamin D receptor; FXR, Farnesoid-X-receptor; TGR5, Takeda G protein-coupled receptor 5; TLR4, Toll-like receptor 4; MyD88, Myeloid differentiation primary response gene 88; LPS, Lipopolysaccharide; MPO, Myeloperoxidase; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; ASC, Apoptosis-associated speck-like protein containing a CARD; Caspase-1, Cysteine-aspartic ase-1; IFN-γ, Interferon-γ; IL-1β, Interleukin-1β; TNF-α, Tumor Necrosis Factor-α; IL-6, Interleukin-6; IL-12, Interleukin-12; IL-17, Interleukin-17.
2.3.2 Neutrophils
BAs suppress neutrophil infiltration into inflammatory sites, thereby inhibiting the onset of acute gout. Myeloperoxidase (MPO) activity serves as a biomarker for neutrophil infiltration at inflammatory loci. Studies demonstrate that BAs attenuate lipopolysaccharide (LPS)-induced upregulation of NLRP3, ASC, and Caspase-1, thereby reducing MPO activity, inhibit neutrophil infiltration, and alleviate inflammatory responses (43). In contrast, diminished BA levels promote Th17 differentiation, leading to greater production of the pro-inflammatory cytokine IL-17, which enhances neutrophil recruitment (44). Neutrophils are known to produce IL-1β, a key pro-inflammatory cytokine responsible for initiating acute gout attacks characterized by joint redness, swelling, warmth, and pain (45) (Figure 2).
2.3.3 Macrophages
BAs attenuate inflammatory responses in gout by suppressing macrophage-mediated inflammation. Macrophages play an important role in the initiation, progression, and resolution of gout (46). It is reported that LPS activates the TLR4 receptor, which signals through MyD88, followed by the activation of different transcription factors, resulting in expression of pro-inflammatory (47). Studies have shown that BAs reduce the LPS-induced expression of pro-inflammatory cytokines, such as IL-6, tumour necrosis factor (TNF) and IL-12 in human macrophages (48). Additionally, the activation of TGR5 and FXR (receptors for BAs) inhibits the effector functions of macrophages and promotes their polarization toward the anti-inflammatory M2 phenotype (49). Consequently, a decrease in BA levels lead to enhanced pro-inflammatory cytokine production and impaired polarization towards the M2 anti-inflammatory phenotype, thereby exacerbating inflammatory responses in gout (Figure 2).
This chapter delineates the function of BA homeostasis in the pathogenesis of gout. We investigated how the dysregulation of BA metabolism can precipitate lipid metabolic disorders in gout patients, contribute to increased UA levels, and stimulate the production of pro-inflammatory factors by immune cells, including T cells, macrophages, and neutrophils, thereby exacerbating the progression of the disease. We subsequently examined the mechanisms underlying BA metabolic dysregulation in gout, building upon existing research.
3 Mechanisms underlying the dysregulation BA metabolism in gout
3.1 BA synthesis
BA synthesis in the liver occurs via two pathways: the classical pathway and the alternative pathway (50). The classical pathway is initiated by CYP7A1, the rate-limiting enzyme in primary BA synthesis. This cytochrome P450 enzyme catalyzes the conversion of cholesterol to 7α-hydroxycholesterol (51), and subsequently converted to CA through the action of cytochrome P450 12α-hydroxylase B1 (CYP8B1) and mitochondrial cytochrome P450 27A1 (CYP27A1). The intermediates are instead converted into CDCA when CYP8B1 is lacking (52). CYP8B1 is the essential enzyme for CA synthesis (53, 54). Next, 7α-hydroxycholesterol undergoes a series of modifications to generate CA and CDCA (55). This classical pathway primarily produces CA and CDCA (56, 57). The alternative pathway is initiated by CYP27A1. The intermediate 27-hydroxycholesterol undergoes 7α-hydroxylation by oxysterol 7α-hydroxylase (cytochrome P450 family 7 subfamily B member 1 (CYP7B1)), followed by a series of modifications to produce CDCA (58, 59).
In the gout state, abnormal activation of FXR and pro-inflammatory cytokines can suppress BA production, leading to the dysregulation of BA metabolism. Aberrant activation of hepatic FXR in gout inhibits the expression of CYP7A1. This reduces the conversion rate of cholesterol to BAs, consequently increasing cholesterol levels and decreasing the synthesis of BA (29). A clinical study revealed impaired primary BA biosynthesis and confirmed reduced BA biosynthesis in the gout state (20). Furthermore, IL-1β suppresses CYP7A1 transcription in human hepatocytes via the c-Jun N-terminal kinase/c-Jun signaling pathway (19). TNF-α significantly inhibits the expression of the CYP7A1 protein in hepatocytes (F = 47.92, P < 0.01) (60), thereby reducing BA synthesis (Figure 3).
Figure 3. Mechanisms underlying BA metabolism dysregulation in gout. In gout, dysregulated hepatic FXR activation combined with elevated IL-1β and TNF-α levels collectively suppresses CYP7A1 expression, thereby reducing BA synthesis. Concurrently, an increase in the production of hepatic pro-inflammatory cytokines (TNF-α and IL-1β) downregulates the transcription of NTCP, impairing the function of NTCP and decelerating BA enterohepatic circulation. Furthermore, gout-associated gut dysbiosis decreases microbial consortia producing BSH and 7α-dehydroxylase, leading to reduced free and secondary BA proportions. BSH, bile salt hydrolase. CA, Cholic acid; CDCA, Chenodeoxycholic acid; LCA, Lithocholic acid; DCA, Deoxycholic acid; SHP, Small heterodimer partner; FXR, Farnesoid-X-receptor; IL-1β, Interleukin-1β; TNF-α, Tumor Necrosis Factor-α; CYP8B1, Cytochrome P450 12α-hydroxylase B1; CYP7A1, Cholesterol 7 alpha-hydroxylase; CYP27A1, Cytochrome P450 27A1; CYP7B1, Cytochrome P450 family 7 subfamily B member 1; BSEP, Bile salt export pump; ASBT, Apical sodium-dependent bile acid transporter; OSTα/β, Organic solute transporter alpha/beta; NTCP, Sodium taurocholate cotransporting polypeptide; FGF15/19, Fibroblast growth factor 15/19; FGFR4, Fibroblast growth factor receptor 4; BSH, Bile salt hydrolase.
3.2 BA transportation
Multiple transport proteins facilitate the circulation of BAs between the liver and intestines. For example, most synthesized free BAs are conjugated to glycine or taurine and are subsequently secreted into the gallbladder via the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) (61). In the intestine, conjugated BAs are metabolized by the gut microbiota to generate secondary BAs (50, 62). About 95% of BAs in the intestinal lumen are subsequently reabsorbed primarily in the terminal ileum by the apical sodium-dependent bile acid transporter (ASBT). The reabsorbed BAs are then transported across enterocytes to the portal circulation by the organic solute transporter alpha/beta (OSTα/β) located on the basolateral membrane. These BAs return to the liver via the portal vein and re-enter hepatocytes under the action of the sodium taurocholate cotransporting polypeptide (NTCP) (13, 63, 64) (Figure 3). About 5% of BAs are excreted in feces. Under physiological conditions, the size of the BA pool remains stable through the coordinated function of this enterohepatic transport system (65).
In the gout state, UA induces endoplasmic reticulum (ER) stress in hepatic cells, activating SREBP-1c. This triggers overexpression of lipogenic enzymes, increasing intrahepatic fat production and promoting hepatic inflammation (66, 67). An increase in the production of hepatic pro-inflammatory cytokines (TNF-α and IL-1β) reduces the transcription of the NTCP gene, consequently decreasing both NTCP mRNA and protein levels. This ultimately impairs the function of NTCP and reduces the enterohepatic circulation rate of BAs (68, 69).
3.3 BA targets
3.3.1 FXR
In the gout state, aberrant activation of hepatic FXR decreases BA synthesis. FXR is a nuclear receptor activated by BAs. Its primary function involves regulating BA synthesis and enterohepatic circulation to maintain BA homeostasis (70). In the liver, the activation of FXR suppresses BA synthesis while promoting BA transport into bile ducts (71). FXR directly activates transcription of the SHP, which subsequently negatively regulates the expression of CYP7A1. In the intestine, FXR plays a crucial role in enterohepatic circulation. Upon activation in the ileum, FXR induces the release of fibroblast growth factor 15 (FGF15). This enterokine reaches the liver via the enterohepatic circulation, where it binds to the fibroblast growth factor receptor 4 (FGFR4). The FGF19-FGFR4 complex then inhibits the expression of hepatic CYP7A1 (72, 73), ultimately suppressing BA synthesis (Figure 3).
Activation of FXR can inhibit the assembly of the NLRP3 inflammasome and, through the activation of SHP, suppress the NF-κB pathway. This process consequently reduces the production of pro-inflammatory factors (e.g., IL-1β, TNF-α) and mitigates inflammation (23, 49, 74, 75). Furthermore, research has demonstrated that increased local TNF-α level driven by intestinal FXR deficiency induces the overexpression and hyperactivity of intestinal XO, leading to elevated intestinal uric acid synthesis, ultimately resulting in hyperuricemia (21) (Figure 4).
Figure 4. The roles of BA target FXR, TGR5, and VDR in gout BA metabolism disorders. A reduction in BA levels weakens the signaling of receptors FXR, TGR5, and VDR. This attenuation subsequently reduces the inhibitory tone on key inflammatory pathways, NLRP3 and NF-κB, thereby further promoting the generation of pro-inflammatory cytokines such as IL-1β and TNF-α. Furthermore, crosstalk exists between FXR and TGR5. FXR activation induces TGR5 gene transcription, and the activation of either receptor promotes the secretion of GLP-1 from intestinal L cells. The released GLP-1, in turn, exerts anti-inflammatory effects by attenuating the production of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, forming a potential negative feedback loop. Notably, the elevated local TNF-α level, which is partly driven by intestinal FXR deficiency, induces the overexpression and hyperactivity of intestinal XOD, leading to increased intestinal uric acid synthesis. Consequently, the dysregulation of bile acid metabolism modulates FXR, TGR5, and VDR receptors, thereby enhancing inflammatory responses and uric acid synthesis, which exacerbates the progression of gout. FXR, Farnesoid-X-receptor; SHP, Small heterodimer partner; IL-1β, Interleukin-1β; TNF-α, Tumor Necrosis Factor-α; IL-6, Interleukin-6; UA, Uric acid; VDR, Vitamin D receptor; TGR5, Takeda G protein-coupled receptor 5; XOD, Xanthine oxidase; LCA, Lithocholic acid; glyco-LCA, Glycolithocholic acid; keto-LCA, Ketolithocholic acid.
In the context of gout, a decrease in BA levels leads to attenuated FXR activity, consequently diminishes the inhibitory effect on NLRP3 and NF-κB signaling pathways and promotes enhanced activity and expression of intestinal XOD, thereby triggering inflammatory responses and elevated UA levels, which exacerbate the progression of gout (Figure 4).
3.3.2 TGR5
TGR5 is a G protein-coupled receptor activated by BAs. LCA is the most potent TGR5 agonist, followed by DCA, CDCA, CA (76). Notably, there exists crosstalk between FXR and TGR5, and FXR activation induce TGR5 gene transcription, thereby promoting glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells (77, 78). Moreover, TGR5 activation also induces the release of GLP-1. Studies indicate that GLP-1 attenuates the production of the inflammatory cytokines TNF-α, IL-6, and IL-1β, thereby exerting anti-inflammatory effects (13, 79, 80). Furthermore, TGR5 activation inhibits the phosphorylation of IκBα in macrophages, thereby suppressing the NF-κB pathway. It also increases ubiquitination of the NLRP3 inflammasome, collectively dampening inflammatory responses (81, 82).
Conversely, in gout, reduced bile acid levels lead to diminished TGR5 activity, which in turn results in reduced GLP-1 secretion, and weakened inhibition of both the NF-κB pathway and NLRP3 inflammasome. These changes collectively promote inflammatory responses, thereby exacerbating the progression of gout (Figure 4).
3.3.3 VDR
The nuclear receptor VDR is activated by BAs. VDR can be activated by BAs such as LCA, glycolithocholic acid (glyco-LCA), and ketolithocholic acid (keto-LCA) (83). VDR participates in the regulation of inflammatory responses. BAs exert anti-inflammatory effects by activating the VDR receptor to inhibit NF-κB signaling and suppress TNF-α expression (84).
In gout, diminished levels of secondary BAs lead to decreased VDR activation, which results in attenuated inhibition of NF-κB signaling. This effect ultimately disrupts bile acid synthesis and promotes inflammatory responses, thereby accelerating the progression of gout (Figure 4).
3.4 Gut microbiota dysbiosis
Gut microbiota dysbiosis in gout lead to reduced production of both free and secondary BAs. Gout patients have a greater abundance of Bacteroides (85) along with decreased levels of Bifidobacterium and Lactobacillus (26, 27). Additionally, hyperuricemic mice present reduced abundances of beneficial Clostridium bacteria and Lactobacillus (86, 87), and hyperuricemic rats present decreased abundances of Lactobacillus, Streptococcus, and Clostridium (88). The intestinal microbiota including Lactobacillus, Lactococcus, Streptococcus, Bacillus, Enterococcus, Bifidobacterium, and Bacteroides, expresses bile salt hydrolase (BSH) (89–91). This enzyme converts conjugated BAs to free forms by hydrolyzing the C24 N-acyl amide bond, which links BAs to their amino acid conjugates (taurine or glycine) (92). The secondary BAs generated through BSH-mediated deconjugation exhibit potent bactericidal activity (93, 94), thereby diversifying the structure and function of BAs while facilitating their fecal excretion (95). Clostridium species play a crucial roles in dehydroxylation, producing bile acid 7α-dehydroxylase, which converts primary BAs (CA and CDCA) into secondary BAs (DCA and LCA) (96, 97). Reduced abundance of Clostridium results in diminished synthesis of secondary BAs (98). Clostridium strain S2 produces sulfatase enzymes that catalyze the desulfation of BAs. Bacterial desulfation facilitates the reabsorption of BAs and is essential for maintaining homeostasis of the BA pool (30). As evidenced above, gut dysbiosis in gout reduces microbial populations producing BSH and 7α-dehydroxylase, leading to a decreased proportion of free and secondary BAs (Figure 3).
Research indicates that compared to conjugated BAs, free BAs exert stronger inhibitory effects on bacterial growth, with significantly greater potency against gram-negative bacteria than gram-positive bacteria (99). A reduction in free BAs in gout promote the proliferation of gram-negative pathogens, such as Escherichia coli and Bacteroides. LPS, a key component of Gram-negative bacterial cell walls, potentiates both the synthesis and activity of XOD, leading to the excessive production of UA and exacerbating gout progression (26, 100). Additionally, secondary BAs exhibit strong antimicrobial activity (93, 94), and exert protective effects on gout by suppressing inflammatory responses through TGR5-mediated downregulation of the NF-κB signaling pathway (101). In gout, the levels of secondary BAs decrease, compromising intestinal barrier integrity and increasing the risk of intestinal inflammation (102). This compromised barrier function facilitates the translocation of LPS into systemic circulation. Consequently, LPS activates the TLR4/NF-κB inflammatory signaling pathway, leading to the upregulation of pro-inflammatory cytokines (103) and precipitating gout attacks (Figure 5).
Figure 5. A mechanistic diagram summarizing the interactions of BA and UA metabolism, immune regulation, gut microbiota, and gout. This diagram outlines the causes of BA metabolic disorders in gout. Abnormal hepatic FXR activation lowers BA synthesis, while gut microbiota disruption reduces free and secondary BAs. Additionally, IL-1β and TNF-α further decrease bile acid production. Together, these factors reduce BA levels in gout, negatively impacting UA metabolism, immune regulation, and gut microbiota. UA Metabolism: Reduced BA levels can lead to increased expression or activity of xanthine oxidase in both the liver and intestine, as well as disrupt lipid metabolism, ultimately resulting in excessive uric acid productio; Immune Regulation: Decreased BA levels diminish the activity of FXR, TGR5, and VDR receptors, thereby weakening their inhibitory effects on NLRP3 and NF-κB. Concurrently, they modulate immune cells, such as altering T cell differentiation and promoting neutrophil infiltration, which collectively exacerbates the inflammatory response. Gut Microbiota: Reduced levels of free and secondary BAs promote the proliferation of gram-negative bacteria (e.g., Escherichia coli) and compromise intestinal barrier integrity. This, in turn, fosters increased UA production and enhances the inflammatory response. In summary, BA metabolic dysregulation exacerbates the progression of gout by collectively impacting UA metabolism, immune regulation, and the gut microbiota. FXR, Farnesoid-X-receptor; SHP, Small heterodimer partner; IL-1β, Interleukin-1β; TNF-α, Tumor Necrosis Factor-α; IL-6, Interleukin-6; UA, Uric acid; VDR, Vitamin D receptor; TGR5, Takeda G protein-coupled receptor 5; XOD, Xanthine oxidase; BAs, Bile acids. PPAR-α, Proliferator-activated receptor alpha; IFN-γ, Interferon-γ; IL-12, Interleukin-12; IL-17, Interleukin-17; CYP7A1, Cholesterol 7 alpha-hydroxylase; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; LPS, Lipopolysaccharide; CA, Cholic acid; CDCA, Chenodeoxycholic acid.
This chapter investigates the mechanisms underlying BA metabolic dysregulation in gout. The aberrant activation of hepatic FXR in gout is identified as a significant contributor to the reduction in BA synthesis. some studies suggest that pro-inflammatory cytokines IL-1β and TNF-α suppress the expression of CYP7A1 and NTCP, leading to decreased BA synthesis and a reduction in the hepatic-enterohepatic circulation rate, thereby contributing to BA metabolic disorders. Moreover, gut microbiota dysbiosis in gout results in a reduction of microbial populations responsible for producing BSH and 7α-dehydroxylase. This reduction leads to a low ratio of free to secondary BAs, thereby altering the BA pool. The combined effects of decreased BA synthesis and an altered BA pool decrease the activities of FXR, TGR5, and VDR, which subsequently induce or promote inflammatory responses, thereby exacerbating the progression of gout. Building upon the previously discussed factors contributing to BA metabolic disorders, we aim to identify and assess potential therapeutic agents for gout by modulating BA metabolism.
4 Potential therapeutic agents for gout treatment that target BA metabolism
4.1 FXR antagonists
FXR antagonists ameliorate reduced BA synthesis in gout by inhibiting aberrant activation of FXR. BA synthesis is regulated through two primary pathways: the FXR/SHP pathway and the FXR/FGF19/FGFR4 pathway. Blocking both FXR-mediated pathways with FXR antagonists upregulates the expression of CYP7A1, thereby increasing BA synthesis and fundamentally addressing the impaired synthesis observed in gout (104). Both UDCA and glycine-conjugated ursodeoxycholic acid (GUDCA) function as FXR antagonists (105). UDCA can be used in cases where BA production is impaired, and it has anti-inflammatory properties (14). It can inhibit the growth of the pathogenic bacterium Clostridium difficile, reduce the damage caused by the pathogen to intestinal epithelial cells, improve intestinal barrier damage, and suppress inflammatory responses (106) and the occurrence of gout. GUDCA selectively antagonizes intestinal FXR signaling, ameliorates insulin resistance (107), enhances renal UA excretion, and reduces serum urate levels - thereby exerting therapeutic effects against gout. FXR antagonists represent potential therapeutic agents for treating gout through the regulation of BA metabolism (as summarized in Table 1).
Table 1. Potential therapeutic agents targeting bile acid metabolism in gout: FXR antagonists and TGR5 agonists.
4.2 TGR5 agonists
TGR5 agonists treat gout by promoting the excretion of UA and suppressing inflammation. The potent TGR5 agonist 6α-ethyl-23(S)-methylcholic acid (INT-777) inhibits inflammation in macrophages through TGR5-mediated targeting of cAMP and NF-κB signaling pathways (117). Furthermore, INT-777 induces the release of GLP-1 in enteroendocrine cells, ameliorating insulin resistance (122) and thereby promoting the excretion of UA. Additionally, the secondary bile acids 3-oxoLCA and isoLCA function as TGR5 agonists that suppress the differentiation of Th17 cells in vitro through two mechanisms: (1) directly inhibiting the expression of RORγt, and (2) promoting the polarization of M2 macrophages, which indirectly inhibits the development of Th17 cells (119). TGR5 agonists are promising therapeutic agents for treating gout (as summarized in Table 1).
4.3 Probiotics and prebiotics
Probiotics and prebiotics exert therapeutic effects on gout by promoting BA synthesis and reducing BA excretion. In a randomized controlled trial of 160 gout patients, the anti-inflammatory effects of probiotic supplementation were associated with BA-mediated inhibition of the activation of the NLRP3 inflammasome and reduced PGE2 expression via butaprost modulation (123). Wu et al. found that the administration of JS-3 in hyperuricemic quails increased the intestinal abundance of beneficial bacteria including Bifidobacterium, Bacteroides unclassified_f-Lachnospiraceae, and norank_fynorank_o-Clostridia_UCG-014, while reducing the abundance of pathogenic bacteria. This restored the diversity and function of gut microbiota and enhanced the production of α-cholic acid and ursodeoxycholic acid 3-sulfate, consequently alleviating hyperuricemia (124). Furthermore, prebiotics modulate BA metabolism, as evidenced by inulin increasing fecal concentrations of DCA and LCA in dogs (125). Insoluble dietary fiber from soybean hulls (a recognized prebiotic) significantly increases the abundance of Bifidobacterium and Lactobacillus abundance (126). Dietary fibers such as β-galactooligosaccharides reduce the fecal excretion of CA, α-rhamnolic acid, and DCA in mice (127). Thus, probiotics and prebiotics are promising therapeutic agents for correcting BA dysmetabolism in gout.
4.4 Traditional Chinese medicine
Traditional Chinese medicine (TCM) alleviates gout by modulating BA metabolism. Astragalus membranaceus restored the impairments structure of the microbiota in hyperuricemic mice by increasing the relative abundances of beneficial bacteria (Lactobacillaceae and Lactobacillus murine) but decreasing the relative abundances of pathogenic bacteria (Prevotellaceae, Rikenellaceae and Bacteroidaceae). This elevates levels of chenodeoxycholic acid, sulfolithocholylglycine, 3α,6β,7β-trihydroxy-5β-cholanic acid, and nutriacholic acid, thereby ameliorating metabolic disorders (128). Phellinus igniarius, a medicinal and edible fungus, modulates BA metabolism via its polysaccharides. It upregulates the expression of CYP8B1 and increases tauroursodeoxycholic acid (TUDCA) levels, which in turn inhibits the expression and activity of XOD, ultimately leading to a reduction in the production of UA (129). Poria cocos treats hyperuricemia by regulating BA metabolism, which involves an increase in chenodeoxycholic acid and a decrease in glycylcholic acid, restoring their balance (130). Atractylenolides II and III from Atractylodes macrocephala antagonize the FXR receptor, activating CYP7A1 to increase BA synthesis (131) and counter BA deficiency in gout. Therefore, TCM has broad therapeutic potential for gout management (Table 2).
Table 2. Potential therapeutic agents from traditional Chinese medicine for gout-induced bile acid metabolic dysregulation.
This chapter primarily evaluates potential drugs for the treating of gout by targeting BA metabolism. Key approaches include, FXR antagonists, which mitigate the underlying issue of decreased BA synthesis by inhibiting FXR receptor activation; TGR5 agonists, which provide anti-inflammatory benefits through the activation of TGR5; prebiotics and probiotics, which address BA metabolic disorders by modifying the gut microbiota; TCM, which ameliorates BA metabolic disorders by restoring gut microbiota structure and enhancing BA synthesis. These approaches aim to treat gout by modulating BA metabolic disorders.
5 Challenges and prospects of clinical translation
The clinical application of TCM in the management of gout is extensive, highlighting its ability to alleviate symptoms and reduce side effects. Clinical research has demonstrated that the Huangqin Qingrechubi capsule significantly enhances lipid metabolism disorders and inflammatory responses in patients with gouty arthritis by modulating the lncRNA H19/APN/PI3K/AKT pathway, thereby effectively mitigating gout symptoms (134). Compared to conventional Western medicine, compound TCM formulations exhibit greater overall efficacy in the treatment of acute gouty arthritis. These findings indicate that TCM compounds significantly improve serum UA levels, erythrocyte sedimentation rates, and C-reactive protein levels while also decreasing the incidence of adverse reactions (135). These studies provide substantial evidence supporting the application of TCM gout in treatment. However, the multi-component nature of TCM makes the identification of bioactive components and the clarification of synergistic or antagonistic relationships among them particularly complex, which remains a significant challenge in TCM. Additionally, interest in the application of probiotics for gout management has increased in recent years. Probiotics fermented apple juice can ameliorate hyperuricemia by reversing gut microbiota dysbiosis and increasing the abundance of beneficial bacteria, such as Lactobacillush, Faecalibaculum, and Lachnospiraceae_NK4A136_group (87). Moreover, a clinical trial revealed that, compared to the control group using febuxostat alone, the combination with Probio-X probiotics significantly reduced serum UA levels and the frequency of acute gout attacks. The study also highlighted that the efficacy of probiotics is highly individualized (123). Therefore, although probiotics hold broad prospects in gout treatment, further clinical research is still necessary to explore their potential in personalized therapy. Moreover, strategies aimed at targeting BA metabolism for disease treatment present promising application prospects. In a study focused on liver cancer therapy, the nanodelivery of BA receptor modulators significantly modified the immune microenvironment in mouse liver tumors, thereby inducing a robust anti-tumor immune response and offering a novel approach for the precise treatment of liver cancer (136). Similarly, the application of nanoemulsion-loaded obeticholic acid (OCA) to precisely manipulate liver sinusoidal endothelial cells enhances the secretion of chemokine ligand 16, which in turn activates natural killer T cell-mediated immunotherapy for liver cancer (137). Similarly, although the clinical translation of treating gout by regulating BA metabolism currently faces some challenges, such as the limited number of clinical studies on modulating BA metabolic disorders for gout treatment, as well as concerns regarding the safety and efficacy of this approach, which requires further clinical research, it provides a new method and approach for treating gout.
6 Conclusion and prospects
BAs are synthesized primarily in the liver through classical and alternative pathways (138), followed by microbial metabolism and transformation in the gut (58, 139). In the intestine, the gut microbiota converts primary BAs into secondary BAs (50, 62)(e.g., DCA, LCA, and UDCA) (52, 140). As pivotal metabolic regulators, BAs play an essential role in maintaining metabolic homeostasis. Gout, a clinically prevalent metabolic disorder, is characterized by inflammatory responses triggered by the deposition of MSU crystals in joints and surrounding tissues (141). Chronic recurrence of gout attacks can lead to joint deformities, renal impairment, and cardiovascular complications, posing a significant threat to human health (142). Dysregulation of BA metabolism occurs when any component of BA synthesis, secretion, or reabsorption, or microbial modification becomes impaired. Clinical studies have demonstrated pervasive BA metabolic disturbances in gout patients (29).
BA dysmetabolism is a critical pathological indicator of gout, actively promoting its onset and progression. Studies have demonstrated that BA synthesis is reduced and BA levels are decreased in gout. With respect to UA metabolism, BAs downregulate XOD mRNA expression via the inhibition of PPARα receptor, thereby reducing UA production. Consequently, decreased BA levels in gout increase serum urate concentrations (22). Furthermore, decreased BA availability impairs FXR activation, disrupting lipid metabolism and reducing UA excretion. Moreover, intestinal FXR deficiency increases intestinal XOD activity, resulting in higher uric acid production. ultimately inducing hyperuricemia. Concerning immune responses, weakened activation of FXR and TGR5 via the depletion of BAs increases the levels of pro-inflammatory cytokines, amplifying inflammatory cascades. BAs also suppress the differentiation of T-cells into Th17 cells (reducing inflammatory cytokine secretion), neutrophil infiltration, and macrophage-driven inflammation. Thus, reduced BA levels in gout exacerbate inflammatory responses, accelerating disease progression. Regarding gut microbiota, BAs actively shape its composition and structure, thereby modulating UA metabolism and inflammatory responses to and contributing to the progression of gout. To date, the pathogenesis of gout primarily involves multiple aspects including disorders of purine and UA metabolism, inflammatory responses, and gut microbiota dysbiosis, with BA metabolism permeating these processes and playing a crucial role in the onset and progression of gout.
This review further elucidates the mechanisms underlying BA dysmetabolism in gout. In the gout state, aberrant FXR activation and pro-inflammatory cytokines (IL-1β, and TNF-α) suppress BA synthesis. Some studies suggest that the pro-inflammatory cytokines IL-1β and TNF-α also suppress the expression of NTCP, and impaired function of NTCP affect BA transport. Moreover, the gut microbiota plays a pivotal role in BA metabolism. In gout, gut dysbiosis reduces microbial populations producing BSH and 7α-dehydroxylase, thereby decreasing the proportion of free and secondary BAs. The subsequent decline in the production of these free and secondary BAs leads to increased UA production and compromises intestinal barrier, ultimately contributing to gout pathogenesis. Consequently, the dysregulation of BA metabolism in gout may stem from disruptions in BA biosynthesis, transport systems, and the composition of the gut microbiota.
Based on the underlying causes of BA metabolism abnormalities in gout, in this review, we summarized several potential therapeutic drugs for treating BA metabolic disorders in gout. Although preclinical studies have elucidated the mechanisms by which drugs can treat gout through modulation of BA metabolism, their efficacy still requires validation in large-scale clinical trials. Given the complex interplay between BA metabolism and gut microbiota, treatments such as TCM and probiotics for gout may lead to variable therapeutic outcomes due to individual differences in gut microbiota. Future studies should focus on an in-depth investigation the gut microbiota-BA relationship to develop more precise probiotic formulations and TCM compounds, thereby enhancing treatment efficacy. Moreover, owing to the widespread distribution of FXR/TGR5 receptors in the human body, future targeted therapies for these receptors should explore advanced drug delivery technologies to develop more precise targeted formulations that minimize adverse effects. For example, in the treatment of hepatocellular carcinoma, researchers have designed a polyoxazole-based nanosystem for the delivery of OCA and 5β−CA to the liver to minimize the adverse effects of these BA modulators (136).
In conclusion, BA metabolism dysregulation contributes significantly to the pathogenesis of gout. The improvement of BA dysregulation holds promise as a potential therapeutic target or pathway for preventing and treating gout. However, considering the existing constraints in clinical gout management and the paucity of research regarding both the involvement of BA abnormalities in gout progression and the therapeutic efficacy of BA-targeted interventions, it is imperative that future studies should aim to elucidate the underlying molecular mechanisms of BA metabolism in gout. Additionally, conducting relevant clinical trials is essential. Such research endeavors may reveal novel pathways and strategies for the treatment of gout.
Author contributions
HS (1st author): Writing – review & editing, Writing – original draft, Investigation. LY: Writing – review & editing, Investigation, Writing – original draft. YS: Visualization, Writing – review & editing. XYZ: Visualization, Writing – review & editing. XS: Writing – review & editing, Software. XPZ: Writing – review & editing, Data curation. HS (7th author): Funding acquisition, Writing – review & editing, Supervision. QZ: Methodology, Writing – review & editing. GY: Supervision, Writing – review & editing, Methodology. XW: Writing – review & editing, Supervision, Funding acquisition, Conceptualization.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. This work was supported by the National Natural Science Foundation of China (U23A20501, 82404816), the Guangdong Basic and Applied Basic Research Found Project (2023A1515110703), the key research and development plan projects of Heilongjiang Province (2022ZX02C04), the State Key Laboratory of Dampness Syndrome of Chinese Medicine (SZ2021ZZ49, SZ2022KF16), and the Guangdong Academy of Traditional Chinese Medicine “Young Talents Program” Project (SZ2024QN06).
Acknowledgments
We are very grateful to Home for Researchers (www.home-for-researchers.com) for providing drawing assistance.
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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References
1. Jiang Y-J, Cheng Y-H, Zhu H-Q, Wu Y-L, Nan J-X, and Lian L-H. Palmatine, an isoquinoline alkaloid from Phellodendron amurense Rupr., ameliorated gouty inflammation by inhibiting pyroptosis via NLRP3 inflammasome. J Ethnopharmacology. (2025) 340:119231. doi: 10.1016/j.jep.2024.119231
2. Ni X, Wang Q, Ning Y, Liu J, Su Q, Lv S, et al. Anemoside B4 targets NEK7 to inhibit NLRP3 inflammasome activation and alleviate MSU-induced acute gouty arthritis by modulating the NF-κB signaling pathway. Phytomedicine. (2025) 138:156407. doi: 10.1016/j.phymed.2025.156407
3. Dehlin M, Jacobsson L, and Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. (2020) 16:380–90. doi: 10.1038/s41584-020-0441-1
4. Zhang M, Zhu X, Wu J, Huang Z, Zhao Z, Zhang X, et al. Prevalence of hyperuricemia among chinese adults: findings from two nationally representative cross-sectional surveys in 2015–16 and 2018–19. Front Immunol. (2022) 12:791983. doi: 10.3389/fimmu.2021.791983
5. Xu L, Cheng J, Lu J, Lin G, Yu Q, Li Y, et al. Integrating network pharmacology and experimental validation to clarify the anti-hyperuricemia mechanism of cortex phellodendri in mice. Front Pharmacol. (2022) 13:964593. doi: 10.3389/fphar.2022.964593
6. Luo Z, Yang F, Hong S, Wang J, Chen B, Li L, et al. Role of microRNA alternation in the pathogenesis of gouty arthritis. Front Endocrinol (Lausanne). (2022) 13:967769. doi: 10.3389/fendo.2022.967769
7. Singh JA and Gaffo A. Gout epidemiology and comorbidities. Semin Arthritis Rheumatism. (2020) 50:S11–6. doi: 10.1016/j.semarthrit.2020.04.008
8. Wen S, Arakawa H, and Tamai I. Uric acid in health and disease: From physiological functions to pathogenic mechanisms. Pharmacol Ther. (2024) 256:108615. doi: 10.1016/j.pharmthera.2024.108615
9. Liu W, Liu W, Wang S, Tong H, Yuan J, Zou Z, et al. Prevalence and risk factors associated with hyperuricemia in the pearl river delta, guangdong province, China. RMHP. (2021) 14:655–63. doi: 10.2147/RMHP.S293913
10. Feig DI and Johnson RJ. Hyperuricemia in childhood primary hypertension. Hypertension. (2003) 42:247–52. doi: 10.1161/01.HYP.0000085858.66548.59
11. De Vera MA, Rahman MM, Bhole V, Kopec JA, and Choi HK. Independent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study. Ann Rheumatic Diseases. (2010) 69:1162–4. doi: 10.1136/ard.2009.122770
12. Yokose C, McCormick N, Lu N, Jiang B, Tan K, Chigurupati S, et al. Comparative cardiovascular safety of NSAID versus colchicine use when initiating urate-lowering therapy among patients with gout: target trial emulations. Arthritis Rheumatol. (2025), 43259. doi: 10.1002/art.43259
13. Lun W, Yan Q, Guo X, Zhou M, Bai Y, He J, et al. Mechanism of action of the bile acid receptor TGR5 in obesity. Acta Pharm Sin B. (2024) 14:468–91. doi: 10.1016/j.apsb.2023.11.011
14. Francini E, Badillo Pazmay GV, Fumarola S, Procopio AD, Olivieri F, and Marchegiani F. Bi-directional relationship between bile acids (BAs) and gut microbiota (GM): UDCA/TUDCA, probiotics, and dietary interventions in elderly people. Int J Mol Sci. (2025) 26:1759. doi: 10.3390/ijms26041759
15. Li Y, Hou H, Wang X, Dai X, Zhang W, Tang Q, et al. Diammonium glycyrrhizinate ameliorates obesity through modulation of gut microbiota-conjugated BAs-FXR signaling. Front Pharmacol. (2021) 12:796590. doi: 10.3389/fphar.2021.796590
16. Cai J, Rimal B, Jiang C, Chiang JYL, and Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther. (2022) 237:108238. doi: 10.1016/j.pharmthera.2022.108238
17. Chávez-Talavera O, Tailleux A, Lefebvre P, and Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology. (2017) 152:1679–1694.e3. doi: 10.1053/j.gastro.2017.01.055
18. Lackey DE and Olefsky JM. Regulation of metabolism by the innate immune system. Nat Rev Endocrinol. (2016) 12:15–28. doi: 10.1038/nrendo.2015.189
19. Li T, Jahan A, and Chiang JYL. Bile acids and cytokines inhibit the human cholesterol 7α-hydroxylase gene via the JNK/c-Jun pathway. Hepatology. (2006) 43:1202–10. doi: 10.1002/hep.21183
20. Zhong Z, Huang Y, Huang Q, Zheng S, Huang Z, Deng W, et al. Serum metabolic profiling analysis of gout patients based on UPLC-Q-TOF/MS. Clinica Chimica Acta. (2021) 515:52–60. doi: 10.1016/j.cca.2020.12.028
21. Bao R, Chen B, Wang A, Wang D, Pan J, Chen Q, et al. Intestinal FXR deficiency induces dysregulation of xanthine oxidase and accounts for sex difference in hyperuricemia. Free Radical Biol Med. (2025) 226:374–88. doi: 10.1016/j.freeradbiomed.2024.11.040
22. Kanemitsu T, Tsurudome Y, Kusunose N, Oda M, Matsunaga N, Koyanagi S, et al. Periodic variation in bile acids controls circadian changes in uric acid via regulation of xanthine oxidase by the orphan nuclear receptor PPARα. J Biol Chem. (2017) 292:21397–406. doi: 10.1074/jbc.m117.791285
23. Liu L, Miao Z-W, Wei Y-Z, Bu S, Gu X, Xu Y, et al. New Baitouweng Decoction alleviated DSS-induced colitis through the FXR/NLRP3 signaling pathway by regulating gut microbiota and bile acids. Gastroenterol Rep (Oxf). (2025) 13:goaf055. doi: 10.1093/gastro/goaf055
24. Sun X, Chen Z, Yu L, Zeng W, Sun B, Fan H, et al. Bacteroides dorei BDX-01 alleviates DSS-induced experimental colitis in mice by regulating intestinal bile salt hydrolase activity and the FXR-NLRP3 signaling pathway. Front Pharmacol. (2023) 14:1205323. doi: 10.3389/fphar.2023.1205323
25. Zheng B-X, Yi Y, Wang X-W, Li C-Y, Zhao Y, Tian J-Z, et al. Geniposide via enema alleviates colitis by modulating intestinal flora and bile acid metabolites, inhibiting S100A8/S100A9/NF-κB, and promoting TGR5 inhibition of NLRP3 inflammasome. Phytomedicine. (2025) 142:156791. doi: 10.1016/j.phymed.2025.156791
26. Xiao N, Zhang X, Xi Y, Li Z, Wei Y, Shen J, et al. Study on the effects of intestinal flora on gouty arthritis. Front Cell Infect Microbiol. (2024) 14:1341953. doi: 10.3389/fcimb.2024.1341953
27. Bian M, Zhu C, Nie A, and Zhou Z. Guizhi Shaoyao Zhimu Decoction ameliorates gouty arthritis in rats via altering gut microbiota and improving metabolic profile. Phytomedicine. (2024) 131:155800. doi: 10.1016/j.phymed.2024.155800
28. Bian M, Wang J, Wang Y, Nie A, Zhu C, Sun Z, et al. Chicory ameliorates hyperuricemia via modulating gut microbiota and alleviating LPS/TLR4 axis in quail. Biomedicine Pharmacotherapy. (2020) 131:110719. doi: 10.1016/j.biopha.2020.110719
29. Bao R, Wang W, Chen B, Pan J, Chen Q, Liu M, et al. Dioscin ameliorates hyperuricemia-induced atherosclerosis by modulating of cholesterol metabolism through FXR-signaling pathway. Nutrients. (2022) 14:1983. doi: 10.3390/nu14091983
30. Rochoń J, Kalinowski P, Szymanek-Majchrzak K, and Grąt M. Role of gut-liver axis and glucagon-like peptide-1 receptor agonists in the treatment of metabolic dysfunction-associated fatty liver disease. World J Gastroenterol. (2024) 30:2964–80. doi: 10.3748/wjg.v30.i23.2964
31. Guan B, Tong J, Hao H, Yang Z, Chen K, Xu H, et al. Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases. Acta Pharm Sin B. (2022) 12:2129–49. doi: 10.1016/j.apsb.2021.12.011
32. Peng A, Liu S, Fang L, Zhu Z, Zhou Y, Yue S, et al. Inonotus obliquus and its bioactive compounds alleviate non-alcoholic fatty liver disease via regulating FXR/SHP/SREBP-1c axis. Eur J Pharmacol. (2022) 921:174841. doi: 10.1016/j.ejphar.2022.174841
33. Duan X, Meng Q, Wang C, Liu Z, Liu Q, Sun H, et al. Calycosin attenuates triglyceride accumulation and hepatic fibrosis in murine model of non-alcoholic steatohepatitis via activating farnesoid X receptor. Phytomedicine. (2017) 25:83–92. doi: 10.1016/j.phymed.2016.12.006
34. Chen S, Sun S, Feng Y, Li X, Yin G, Liang P, et al. Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. Eur J Pharmacol. (2023) 952:175808. doi: 10.1016/j.ejphar.2023.175808
35. Zhu Y, Liu H, Zhang M, and Guo GL. Fatty liver diseases, bile acids, and FXR. Acta Pharm Sin B. (2016) 6:409–12. doi: 10.1016/j.apsb.2016.07.008
36. Fujii W, Yamazaki O, Hirohama D, Kaseda K, Kuribayashi-Okuma E, Tsuji M, et al. Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12. J Clin Invest. (2025) 135:e186633. doi: 10.1172/JCI186633
37. Su M, Sun L, Li W, Liu H, Liu Y, Wei Y, et al. Metformin alleviates hyperuricaemia-induced serum FFA elevation and insulin resistance by inhibiting adipocyte hypertrophy and reversing suppressed white adipose tissue beiging. Clin Sci (Lond). (2020) 134:1537–53. doi: 10.1042/CS20200580
38. Hang S, Paik D, Yao L, Kim E, Jamma T, Lu J, et al. Bile acid metabolites control Th17 and Treg cell differentiation. Nature. (2019) 576:143–8. doi: 10.1038/s41586-019-1785-z
39. Paik D, Yao L, Zhang Y, Bae S, D’Agostino GD, Zhang M, et al. Human gut bacteria produce TH17-modulating bile acid metabolites. Nature. (2022) 603:907–12. doi: 10.1038/s41586-022-04480-z
40. Mansour AA, Raucci F, Saviano A, Tull S, Maione F, and Iqbal AJ. Galectin-9 regulates monosodium urate crystal-induced gouty inflammation through the modulation of treg/th17 ratio. Front Immunol. (2021) 12:762016. doi: 10.3389/fimmu.2021.762016
41. Conforti-Andreoni C, Spreafico R, Qian HL, Riteau N, Ryffel B, Ricciardi-Castagnoli P, et al. Uric acid-driven th17 differentiation requires inflammasome-derived IL-1 and IL-18. J Immunol. (2011) 187:5842–50. doi: 10.4049/jimmunol.1101408
42. Pols TWH, Puchner T, Korkmaz HI, Vos M, Soeters MR, and de Vries CJM. Lithocholic acid controls adaptive immune responses by inhibition of Th1 activation through the Vitamin D receptor. PloS One. (2017) 12:e0176715. doi: 10.1371/journal.pone.0176715
43. Yang M, Liu S, Cai J, Sun X, Li C, Tan M, et al. Bile acids ameliorates lipopolysaccharide-induced endometritis in mice by inhibiting NLRP3 inflammasome activation. Life Sci. (2023) 331:122062. doi: 10.1016/j.lfs.2023.122062
44. Wang Y and Liu Y. Neutrophil-induced liver injury and interactions between neutrophils and liver sinusoidal endothelial cells. Inflammation. (2021) 44:1246–62. doi: 10.1007/s10753-021-01442-x
45. Fu X, Liu H, Huang G, and Dai S. The emerging role of neutrophils in autoimmune-associated disorders: effector, predictor, and therapeutic targets. MedComm. (2021) 2:402–13. doi: 10.1002/mco2.69
46. Ma C, Jiang Y, Xiang Y, Li C, Xie X, Zhang Y, et al. Metabolic reprogramming of macrophages by biomimetic melatonin-loaded liposomes effectively attenuates acute gouty arthritis in a mouse model. Adv Sci (Weinh). (2024) 12:2410107. doi: 10.1002/advs.202410107
47. Wammers M, Schupp A-K, Bode JG, Ehlting C, Wolf S, Deenen R, et al. Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids. Sci Rep. (2018) 8:255. doi: 10.1038/s41598-017-18305-x
48. Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L, et al. Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. J Leukocyte Biol. (2013) 94:1253–64. doi: 10.1189/jlb.0812396
49. Fiorucci S, Baldoni M, Ricci P, Zampella A, Distrutti E, and Biagioli M. Bile acid-activated receptors and the regulation of macrophages function in metabolic disorders. Curr Opin Pharmacol. (2020) 53:45–54. doi: 10.1016/j.coph.2020.04.008
50. Collins SL, Stine JG, Bisanz JE, Okafor CD, and Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol. (2023) 21:236–47. doi: 10.1038/s41579-022-00805-x
51. Fan M, Yang Z, Jin L, and Huang W. Differential roles of individual bile acid in physiology and disease. Pharmacol Res. (2025) 218:107845. doi: 10.1016/j.phrs.2025.107845
52. Jiang X, Ren J, Yu G, Wu W, Chen M, Zhao Y, et al. Targeting bile-acid metabolism: nutritional and microbial approaches to alleviate ulcerative colitis. Nutrients. (2025) 17:1174. doi: 10.3390/nu17071174
53. Li J, Guo C, Liu Y, Han B, Lv Z, Jiang H, et al. Chronic arsenic exposure-provoked biotoxicity involved in liver-microbiota-gut axis disruption in chickens based on multi-omics technologies. J Adv Res. (2024) 67:373–86. doi: 10.1016/j.jare.2024.01.019
54. Chen L, Jiao T, Liu W, Luo Y, Wang J, Guo X, et al. Hepatic cytochrome P450 8B1 and cholic acid potentiate intestinal epithelial injury in colitis by suppressing intestinal stem cell renewal. Cell Stem Cell. (2022) 29:1366–1381.e9. doi: 10.1016/j.stem.2022.08.008
55. Fleishman JS and Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Sig Transduct Target Ther. (2024) 9:97. doi: 10.1038/s41392-024-01811-6
56. Jia W, Li Y, Cheung KCP, and Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. Sci China Life Sci. (2024) 67:865–78. doi: 10.1007/s11427-023-2353-0
57. Jia W, Wei M, Rajani C, and Zheng X. Targeting the alternative bile acid synthetic pathway for metabolic diseases. Protein Cell. (2021) 12:411–25. doi: 10.1007/s13238-020-00804-9
58. Jia W, Xie G, and Jia W. Bile acid–microbiota cross-talk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. (2018) 15:111–28. doi: 10.1038/nrgastro.2017.119
59. Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, et al. Immunology of bile acids regulated receptors. Prog Lipid Res. (2024) 95:101291. doi: 10.1016/j.plipres.2024.101291
60. Jin C-G, Jiang F-R, Zhang J, Ma J-R, and Ling X-F. Role of osteopontin in diet-induced brown gallstone formation in rats. Chin Med J (Engl). (2021) 134:1093–100. doi: 10.1097/CM9.0000000000001519
61. Di Ciaula A, Garruti G, Lunardi Baccetto R, Molina-Molina E, Bonfrate L, Wang DQ-H, et al. Bile acid physiology. Ann Hepatology. (2017) 16:S4–S14. doi: 10.5604/01.3001.0010.5493
62. Zhang P, Zheng L, Duan Y, Gao Y, Gao H, Mao D, et al. Gut microbiota exaggerates triclosan-induced liver injury via gut-liver axis. J Hazardous Materials. (2022) 421:126707. doi: 10.1016/j.jhazmat.2021.126707
63. Ticho AL, Malhotra P, Dudeja PK, Gill RK, and Alrefai WA. Intestinal absorption of bile acids in health and disease. Compr Physiol. (2019) 10:21–56. doi: 10.1002/cphy.c190007
64. Dawson PA. Roles of ileal ASBT and OSTα-OSTβ in regulating bile acid signaling. Dig Dis. (2017) 35:261–6. doi: 10.1159/000450987
65. Chow MD, Lee Y-H, and Guo GL. The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mol Aspects Med. (2017) 56:34–44. doi: 10.1016/j.mam.2017.04.004
66. Choi Y-J, Shin H-S, Choi HS, Park J-W, Jo I, Oh E-S, et al. Uric acid induces fat accumulation via generation of endoplasmic reticulum stress and SREBP-1c activation in hepatocytes. Lab Invest. (2014) 94:1114–25. doi: 10.1038/labinvest.2014.98
67. Spiga R, Marini MA, Mancuso E, Di Fatta C, Fuoco A, Perticone F, et al. Uric acid is associated with inflammatory biomarkers and induces inflammation via activating the NF-κB signaling pathway in hepG2 cells. ATVB. (2017) 37:1241–9. doi: 10.1161/ATVBAHA.117.309128
68. Trauner M, Fickert P, and Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol. (1999) 14:946–59. doi: 10.1046/j.1440-1746.1999.01982.x
69. Kosters A and Karpen SJ. The role of inflammation in cholestasis – clinical and basic aspects. Semin Liver Dis. (2010) 30:186–94. doi: 10.1055/s-0030-1253227
70. Guo Y, Xie G, and Zhang X. Role of FXR in renal physiology and kidney diseases. Int J Mol Sci. (2023) 24:2408. doi: 10.3390/ijms24032408
71. Sheng Y, Meng G, Zhang M, Chen X, Chai X, Yu H, et al. Dan-shen Yin promotes bile acid metabolism and excretion to prevent atherosclerosis via activating FXR/BSEP signaling pathway. J Ethnopharmacology. (2024) 330:118209. doi: 10.1016/j.jep.2024.118209
72. Nerild HH, Gilliam-Vigh H, Ellegaard A-M, Forman JL, Vilsbøll T, Sonne DP, et al. Expression of bile acid receptors and transporters along the intestine of patients with type 2 diabetes and controls. J Clin Endocrinol Metab. (2025) 110:e660–6. doi: 10.1210/clinem/dgae261
73. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. (2005) 2:217–25. doi: 10.1016/j.cmet.2005.09.001
74. Jiao Y, Ren J, Xie S, Yuan N, Shen J, Yin H, et al. Raffinose-metabolizing bacteria impair radiation-associated hematopoietic recovery via the bile acid/FXR/NF-κB signaling pathway. Gut Microbes. (2025) 17:2488105. doi: 10.1080/19490976.2025.2488105
75. Li YTY, Swales KE, Thomas GJ, Warner TD, and Bishop-Bailey D. Farnesoid X receptor ligands inhibit vascular smooth muscle cell inflammation and migration. ATVB. (2007) 27:2606–11. doi: 10.1161/atvbaha.107.152694
76. Perino A, Demagny H, Velazquez-Villegas L, and Schoonjans K. Molecular physiology of bile acid signaling in health, disease, and aging. Physiol Rev. (2021) 101:683–731. doi: 10.1152/physrev.00049.2019
77. Pathak P, Liu H, Boehme S, Xie C, Krausz KW, Gonzalez F, et al. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem. (2017) 292:11055–69. doi: 10.1074/jbc.M117.784322
78. Kim H and Fang S. Crosstalk between FXR and TGR5 controls glucagon-like peptide 1 secretion to maintain glycemic homeostasis. Lab Anim Res. (2018) 34:140. doi: 10.5625/lar.2018.34.4.140
79. Guo Q, Hou X, Cui Q, Li S, Shen G, Luo Q, et al. Pectin mediates the mechanism of host blood glucose regulation through intestinal flora. Crit Rev Food Sci Nutr. (2024) 64:6714–36. doi: 10.1080/10408398.2023.2173719
80. Zheng X, Chen T, Jiang R, Zhao A, Wu Q, Kuang J, et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metab. (2021) 33:791–803.e7. doi: 10.1016/j.cmet.2020.11.017
81. Zhang Z, Guo X, Liu J, Gu Y, Ji X, Zhu S, et al. Conjugated bile acids alleviate acute pancreatitis through inhibition of TGR5 and NLRP3 mediated inflammation. J Transl Med. (2024) 22:1124. doi: 10.1186/s12967-024-05922-0
82. Li B, Zhang Y, Liu X, Zhang Z, Zhuang S, Zhong X, et al. Traditional Chinese medicine Pien-Tze-Huang ameliorates LPS-induced sepsis through bile acid-mediated activation of TGR5-STAT3-A20 signalling. J Pharm Analysis. (2024) 14:100915. doi: 10.1016/j.jpha.2023.12.005
83. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, et al. Vitamin D receptor as an intestinal bile acid sensor. Science. (2002) 296:1313–6. doi: 10.1126/science.1070477
84. Fang Y, Qin M, Zheng Q, Wang K, Han X, Yang Q, et al. Role of bile acid receptors in the development and function of diabetic nephropathy. Kidney Int Rep. (2024) 9:3116–33. doi: 10.1016/j.ekir.2024.08.002
85. Chu Y, Sun S, Huang Y, Gao Q, Xie X, Wang P, et al. Metagenomic analysis revealed the potential role of gut microbiome in gout. NPJ Biofilms Microbiomes. (2021) 7:66. doi: 10.1038/s41522-021-00235-2
86. Xu D, Lv Q, Wang X, Cui X, Zhao P, Yang X, et al. Hyperuricemia is associated with impaired intestinal permeability in mice. Am J Physiology-Gastrointestinal Liver Physiol. (2019) 317:G484–92. doi: 10.1152/ajpgi.00151.2019
87. Li H, Shen N, Ren J, Yang S, Chen Y, and Gao Z. Biotransformation characteristics of urate-lowering probiotic fermented apple juice and potential regulatory mechanisms for ameliorating hyperuricemia via mediating gut microbiota and metabolic pathways. Food Chem. (2024) 460:140462. doi: 10.1016/j.foodchem.2024.140462
88. Yu Y, Liu Q, Li H, Wen C, and He Z. Alterations of the gut microbiome associated with the treatment of hyperuricaemia in male rats. Front Microbiol. (2018) 9:2233. doi: 10.3389/fmicb.2018.02233
89. Song Z, Cai Y, Lao X, Wang X, Lin X, Cui Y, et al. Taxonomic profiling and populational patterns of bacterial bile salt hydrolase (BSH) genes based on worldwide human gut microbiome. Microbiome. (2019) 7:9. doi: 10.1186/s40168-019-0628-3
90. Chiang JYL and Ferrell JM. Bile acids as metabolic regulators and nutrient sensors. Annu Rev Nutr. (2019) 39:175–200. doi: 10.1146/annurev-nutr-082018-124344
91. Fan Y and Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. (2021) 19:55–71. doi: 10.1038/s41579-020-0433-9
92. Begley M, Hill C, and Gahan CGM. Bile salt hydrolase activity in probiotics. Appl Environ Microbiol. (2006) 72:1729–38. doi: 10.1128/AEM.72.3.1729-1738.2006
93. Islam KBMS, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. (2011) 141:1773–81. doi: 10.1053/j.gastro.2011.07.046
94. Choi S-B, Lew L-C, Yeo S-K, Nair Parvathy S, and Liong M-T. Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Crit Rev Biotechnol. (2015) 35:392–401. doi: 10.3109/07388551.2014.889077
95. Ridlon JM and Gaskins HR. Another renaissance for bile acid gastrointestinal microbiology. Nat Rev Gastroenterol Hepatol. (2024) 21:348–64. doi: 10.1038/s41575-024-00896-2
96. Li T and Chiang JYL. Bile acids as metabolic regulators: an update. Curr Opin Gastroenterol. (2023) 39:249–55. doi: 10.1097/MOG.0000000000000934
97. Urdaneta V and Casadesús J. Interactions between bacteria and bile salts in the gastrointestinal and hepatobiliary tracts. Front Med (Lausanne). (2017) 4:163. doi: 10.3389/fmed.2017.00163
98. Li H, Liang J, Han M, and Gao Z. Polyphenols synergistic drugs to ameliorate non-alcoholic fatty liver disease via signal pathway and gut microbiota: A review. J Advanced Res. (2025) 68:43–62. doi: 10.1016/j.jare.2024.03.004
99. Thibaut MM and Bindels LB. Crosstalk between bile acid-activated receptors and microbiome in entero-hepatic inflammation. Trends Mol Med. (2022) 28:223–36. doi: 10.1016/j.molmed.2021.12.006
100. Shu S and Mi W. Regulatory mechanisms of lipopolysaccharide synthesis in Escherichia coli. Nat Commun. (2022) 13:4576. doi: 10.1038/s41467-022-32277-1
101. Zheng Y, Yue C, Zhang H, Chen H, Liu Y, and Li J. Deoxycholic acid and lithocholic acid alleviate liver injury and inflammation in mice with klebsiella pneumoniae-induced liver abscess and bacteremia. J Inflammation Res. (2021) 14:777–89. doi: 10.2147/JIR.S298495
102. Tian M, Li D, Ma C, Feng Y, Hu X, and Chen F. Barley leaf insoluble dietary fiber alleviated dextran sulfate sodium-induced mice colitis by modulating gut microbiota. Nutrients. (2021) 13:846. doi: 10.3390/nu13030846
103. Liu Z-Q, Sun X, Liu Z-B, Zhang T, Zhang L-L, and Wu C-J. Phytochemicals in traditional Chinese medicine can treat gout by regulating intestinal flora through inactivating NLRP3 and inhibiting XOD activity. J Pharm Pharmacol. (2022) 74:919–29. doi: 10.1093/jpp/rgac024
104. Yu Cai Lim M and Kiat Ho H. Pharmacological modulation of cholesterol 7α-hydroxylase (CYP7A1) as a therapeutic strategy for hypercholesterolemia. Biochem Pharmacol. (2024) 220:115985. doi: 10.1016/j.bcp.2023.115985
105. Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall H-U, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. (2013) 17:225–35. doi: 10.1016/j.cmet.2013.01.003
106. Golden JM, Escobar OH, Nguyen MVL, Mallicote MU, Kavarian P, Frey MR, et al. Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. (2018) 315:G259–71. doi: 10.1152/ajpgi.00354.2017
107. Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. (2018) 24:1919–29. doi: 10.1038/s41591-018-0222-4
108. Floreani A and Mangini C. Primary biliary cholangitis: Old and novel therapy. Eur J Internal Med. (2018) 47:1–5. doi: 10.1016/j.ejim.2017.06.020
109. Paolini M, Pozzetti L, Montagnani M, Potenza G, Sabatini L, Antelli A, et al. Ursodeoxycholic acid (UDCA) prevents DCA effects on male mouse liver via up-regulation of CXP and preservation of BSEP activities. Hepatology. (2002) 36:305–14. doi: 10.1053/jhep.2002.34939
110. Chen B, Bai Y, Tong F, Yan J, Zhang R, Zhong Y, et al. Glycoursodeoxycholic acid regulates bile acids level and alters gut microbiota and glycolipid metabolism to attenuate diabetes. Gut Microbes. (2023) 15:2192155. doi: 10.1080/19490976.2023.2192155
111. Agnihotri P, Saquib M, Joshi L, Malik S, Chakraborty D, Sarkar A, et al. Integrative metabolomic-proteomic analysis uncovers a new therapeutic approach in targeting rheumatoid arthritis. Arthritis Res Ther. (2024) 26:227. doi: 10.1186/s13075-024-03429-z
112. Li T, Ding N, Guo H, Hua R, Lin Z, Tian H, et al. A gut microbiota-bile acid axis promotes intestinal homeostasis upon aspirin-mediated damage. Cell Host Microbe. (2024) 32:191–208.e9. doi: 10.1016/j.chom.2023.12.015
113. Zhao T. Mebhydrolin ameliorates glucose homeostasis in type 2 diabetic mice by functioning as a selective FXR antagonist. (2021) 119:154771. doi: 10.1016/j.metabol.2021.154771
114. Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, Von Furstenberg R, Moore DD, et al. Stigmasterol, a soy lipid–derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res. (2007) 62:301–6. doi: 10.1203/pdr.0b013e3181256492
115. Xin Y, Li X, Zhu X, Lin X, Luo M, Xiao Y, et al. Stigmasterol protects against steatohepatitis induced by high-fat and high-cholesterol diet in mice by enhancing the alternative bile acid synthesis pathway. J Nutr. (2023) 153:1903–14. doi: 10.1016/j.tjnut.2023.05.026
116. Urizar NL, Liverman AB, Dodds DT, Silva FV, Ordentlich P, Yan Y, et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science. (2002) 296:1703–6. doi: 10.1126/science.1072891
117. Pols TWH, Nomura M, Harach T, Sasso GL, Oosterveer MH, Thomas C, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. (2011) 14:747–57. doi: 10.1016/j.cmet.2011.11.006
118. Wang XX, Edelstein MH, Gafter U, Qiu L, Luo Y, Dobrinskikh E, et al. G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes. JASN. (2016) 27:1362–78. doi: 10.1681/asn.2014121271
119. Sun H, Guo Y, Wang H, Yin A, Hu J, Yuan T, et al. Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis. Gut. (2023) 72:1664–77. doi: 10.1136/gutjnl-2022-327756
120. Wang Y, Chen X, Huws SA, Xu G, Li J, Ren J, et al. Ileal microbial microbiome and its secondary bile acids modulate susceptibility to nonalcoholic steatohepatitis in dairy goats. Microbiome. (2024) 12:247. doi: 10.1186/s40168-024-01964-0
121. Zhou W, Wu W, Si Z, Liu H, Wang H, Jiang H, et al. The gut microbe Bacteroides fragilis ameliorates renal fibrosis in mice. Nat Commun. (2022) 13:6081. doi: 10.1038/s41467-022-33824-6
122. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. (2009) 10:167–77. doi: 10.1016/j.cmet.2009.08.001
123. Zhao F, Tie N, Kwok L-Y, Ma T, Wang J, Man D, et al. Baseline gut microbiome as a predictive biomarker of response to probiotic adjuvant treatment in gout management. Pharmacol Res. (2024) 209:107445. doi: 10.1016/j.phrs.2024.107445
124. Wu J, Aga L, Tang L, Li H, Wang N, Yang L, et al. Lacticaseibacillus paracasei JS-3 Isolated from “Jiangshui” Ameliorates Hyperuricemia by Regulating Gut Microbiota and iTS Metabolism. Foods. (2024) 13:1371. doi: 10.3390/foods13091371
125. Alexander C, Cross T-WL, Devendran S, Neumer F, Theis S, Ridlon JM, et al. Effects of prebiotic inulin-type fructans on blood metabolite and hormone concentrations and faecal microbiota and metabolites in overweight dogs. Br J Nutr. (2018) 120:711–20. doi: 10.1017/s0007114518001952
126. Yang L, Zhao Y, Huang J, Zhang H, Lin Q, Han L, et al. Insoluble dietary fiber from soy hulls regulates the gut microbiota in vitro and increases the abundance of bifidobacteriales and lactobacillales. J Food Sci Technol. (2020) 57:152–62. doi: 10.1007/s13197-019-04041-9
127. Mistry RH, Liu F, Borewicz K, Lohuis MAM, Smidt H, Verkade HJ, et al. Long-term β-galacto-oligosaccharides supplementation decreases the development of obesity and insulin resistance in mice fed a western-type diet. Mol Nutr Food Res. (2020) 64:1900922. doi: 10.1002/mnfr.201900922
128. Deng S, Cai K, Pei C, Zhang X, Xiao X, Chen Y, et al. 16S rRNA and metagenomics combined with UPLC-Q/TOF-MS metabolomics analysis reveals the potential mechanism of radix astragali against hyperuricemia in mice. Drug Des Devel Ther. (2023) 17:1371–86. doi: 10.2147/DDDT.S407983
129. Gan Y, Zeng Y, Huang J, Li Y, Zhu Q, and Wang L. Polysaccharide extracted from Phellinus igniarius attenuated hyperuricemia by modulating bile acid metabolism and inhibiting uric acid synthesis in adenine/potassium oxonate-treated mice. J Ethnopharmacology. (2025) 342:119365. doi: 10.1016/j.jep.2025.119365
130. Wang Y, Yu Z, Zhang Z, Mu R, Song J, Yang Z, et al. Integrating metabolomics with network pharmacology to reveal the mechanism of Poria cocos in hyperuricemia treatment. J Ethnopharmacology. (2025) 337:118977. doi: 10.1016/j.jep.2024.118977
131. Tsai C-J, Liang J-W, and Lin H-R. Sesquiterpenoids from Atractylodes macrocephala act as farnesoid X receptor and progesterone receptor modulators. Bioorganic Medicinal Chem Letters. (2012) 22:2326–9. doi: 10.1016/j.bmcl.2012.01.048
132. Liu Z, Zhang Y, Zhang R, Gu L, and Chen X. Promotion of classic neutral bile acids synthesis pathway is responsible for cholesterol-lowing effect of Si-miao-yong-an decoction: Application of LC–MS/MS method to determine 6 major bile acids in rat liver and plasma. J Pharm Biomed Analysis. (2017) 135:167–75. doi: 10.1016/j.jpba.2016.12.021
133. Deng Z, Ouyang Z, Mei S, Zhang X, Li Q, Meng F, et al. Enhancing NKT cell-mediated immunity against hepatocellular carcinoma: Role of XYXD in promoting primary bile acid synthesis and improving gut microbiota. J Ethnopharmacology. (2024) 318:116945. doi: 10.1016/j.jep.2023.116945
134. Zhang X, Liu J, Sun Y, Zhou Q, Ding X, and Chen X. Chinese herbal compound Huangqin Qingrechubi capsule reduces lipid metabolism disorder and inflammatory response in gouty arthritis via the LncRNA H19/APN/PI3K/AKT cascade. Pharm Biol. (2023) 61:541–55. doi: 10.1080/13880209.2023.2191641
135. Zhao X, Fan Y, Sun J, Chen H, Nwafor E-O, Wang H, et al. Efficacy and safety of Chinese herbal compound in the treatment of acute gouty arthritis: A systematic review and meta-analysis of randomized controlled trials. Int Immunopharmacol. (2025) 149:114223. doi: 10.1016/j.intimp.2025.114223
136. Ji G, Si X, Dong S, Xu Y, Li M, Yang B, et al. Manipulating liver bile acid signaling by nanodelivery of bile acid receptor modulators for liver cancer immunotherapy. Nano Lett. (2021) 21:6781–91. doi: 10.1021/acs.nanolett.1c01360
137. Ji G, Ma L, Yao H, Ma S, Si X, Wang Y, et al. Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy. Acta Pharm Sin B. (2020) 10:2171–82. doi: 10.1016/j.apsb.2020.09.004
138. Crosignani A, Zuin M, Allocca M, and Del Puppo M. Oxysterols in bile acid metabolism. Clinica Chimica Acta. (2011) 412:2037–45. doi: 10.1016/j.cca.2011.07.028
139. Režen T, Rozman D, Kovács T, Kovács P, Sipos A, Bai P, et al. The role of bile acids in carcinogenesis. Cell Mol Life Sci. (2022) 79:243. doi: 10.1007/s00018-022-04278-2
140. Li J and Dawson PA. Animal models to study bile acid metabolism. Biochim Biophys Acta Mol Basis Dis. (2019) 1865:895–911. doi: 10.1016/j.bbadis.2018.05.011
141. Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda J, et al. 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Ann Rheumatic Dis. (2020) 79:31–8. doi: 10.1136/annrheumdis-2019-215315
Keywords: gout, bile acid metabolism, uric acid homeostasis, NLRP3 inflammasome, gut-joint axis, FXR antagonists
Citation: Sun H, Yang L, Sun Y, Zhang X, Sun X, Zhao X, Sun H, Zhang Q, Yan G and Wang X (2025) Dysregulated bile acid metabolism as a novel player in gout progression: emerging therapeutic strategies. Front. Endocrinol. 16:1676017. doi: 10.3389/fendo.2025.1676017
Received: 30 July 2025; Accepted: 20 October 2025;
Published: 03 November 2025.
Edited by:
Christopher Gerner, University of Vienna, AustriaReviewed by:
Wang Lin, Yunnan University of Traditional Chinese Medicine, ChinaHongcai Li, Northwest A&F University, China
Yuan Luo, Air Force Medical Center, China
Copyright © 2025 Sun, Yang, Sun, Zhang, Sun, Zhao, Sun, Zhang, Yan and Wang. 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: Xijun Wang, eGlqdW53QHNpbmEuY29t
†These authors have contributed equally to this work