Objective To elucidate the therapeutic mechanism of Yudantong decoction (YDTD) in cholestatic liver disease (CLD), focusing on the gut microbiota-bile acid-intestinal farnesoid X receptor (FXR) axis.
Methods A CLD mouse model induced by α-naphthylisothiocyanate was treated with YDTD. Hepatic injury, gut microbiota composition (16S rRNA sequencing), bile acid profiles (high-performance liquid chromatography–tandem mass spectrometry, HPLC-MS/MS), intestinal FXR/NLRP3 signaling, and barrier function were assessed. Fecal microbiota transplantation, bile salt hydrolase (BSH) inhibition, and FXR antagonism were employed for mechanistic validation.
Results CLD mice exhibited hepatocellular steatosis, lobular necrosis, and elevated serum markers. These pathological changes were associated with gut dysbiosis, impaired bile acid metabolism via bile salt hydrolase (BSH) suppression, FXR signaling inhibition, and NLRP3 inflammasome activation. YDTD restored BSH activity and bile acid homeostasis, upregulated FXR expression, suppressed NLRP3 inflammasome activation, and improved intestinal barrier integrity. Fecal microbiota transplantation experiments confirmed that YDTD-modified microbiota mediated these therapeutic benefits, whereas pharmacological inhibition of BSH or FXR attenuated YDTD’s therapeutic effects.
Conclusion YDTD alleviates CLD, at least in part, by targeting the gut microbiota-bile acid-FXR signaling pathway, highlighting the gut microbiota as a promising therapeutic target for CLD.
| [1] |
Sutton H, Karpen SJ, Kamath BM. Pediatric cholestatic diseases: common and unique pathogenic mechanisms. Annu Rev Pathol., 2024, 19: 319-344
|
| [2] |
Pinon M, Kamath BM. What’s new in pediatric genetic cholestatic liver disease: advances in etiology, diagnostics and therapeutic approaches. Curr Opin Pediatr., 2024, 36(5): 524-536
|
| [3] |
Wagner M, Fickert P. Drug therapies for chronic cholestatic liver diseases. Annu Rev Pharmacol Toxicol., 2020, 60: 503-527
|
| [4] |
Hu Y, Chen L, Shu J, et al.. Clinical study on treatment of infantile cytomegalovirus hepatitis with integrated Chinese and Western medicine. Chin J Integr Med., 2012, 18(2): 100-105
|
| [5] |
Sun D, Xie C, Zhao Y, et al.. The gut microbiota-bile acid axis in cholestatic liver disease. Mol Med., 2024, 30(1): 104
|
| [6] |
Tang B, Tang L, Li S, et al.. Gut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy. Nat Commun., 2023, 14(1): 1305
|
| [7] |
Foley MH, Walker ME, Stewart AK, et al.. Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut. Nat Microbiol., 2023, 8(4): 611-628
|
| [8] |
You M, Zhou L, Wu F, et al.. Probiotics for the treatment of hyperlipidemia: Focus on gut-liver axis and lipid metabolism. Pharmacol Res., 2025, 214 Article ID: 107694
|
| [9] |
Hu S, Tang B, Lu C, et al.. Lactobacillus rhamnosus GG ameliorates triptolide-induced liver injury through modulation of the bile acid-FXR axis. Pharmacol Res., 2024, 206 Article ID: 107275
|
| [10] |
Feng S, Xie X, Li J, et al.. Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation. Hepatol Int., 2024, 18(3): 1040-1052
|
| [11] |
Yang L, Li W, Zhao Q, et al.. Saccharomyces boulardii alleviates colitis by regulating FXR-NLRP3 mediated macrophage pyroptosis. J Inflamm Res., 2025, 18: 3161-3176
|
| [12] |
Schneider KM, Candels LS, Hov JR, et al.. Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling. Nat Metab., 2021, 3(9): 1228-1241
|
| [13] |
Liu Y, Chen K, Li F, et al.. Probiotic lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice. Hepatology., 2020, 71(6): 2050-2066
|
| [14] |
Wu X, Hou L, Liu J, et al.. Network pharmacology and experimental analysis of Yudantong decoction, a multi-immunomodulator for the treatment of intractable cholestatic liver disease: Identification of active agents, molecular targets, and mechanisms of action. Int J Clin Pharmacol Ther., 2025, 63(5): 220-238
|
| [15] |
Luo YS, Zheng XT, Zhang HY, et al.. The cholestatic fibrosis induced by α-naphthylisothiocyanate in mice and the inflammation pathway. Chin J Appl Physiol., 2020, 36(2): 152-156
|
| [16] |
Wang Y, Tang J, Lv Q, et al.. Establishment and resilience of transplanted gut microbiota in aged mice. iScience., 2022, 25(1): 103654
|
| [17] |
Ko K, Lokteva LM, Akuffo GA, et al.. A comparative study of extraction free detection of HBV DNA using sodium dodecyl sulfate, N-lauroylsarcosine sodium salt, and sodium dodecyl benzene sulfonate. Sci Rep., 2024, 14(1): 25442
|
| [18] |
Gao F, Su J, Li J, et al.. Study on the effects of the atractylodes macrocephala koidz-raphanus sativus l herb pair in alleviating senile constipation via the gut microbiota-SCFAs-5-HT axis. Phytomedicine., 2025, 145 Article ID: 156977
|
| [19] |
Liu J, Sun J, Yu J, et al.. Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism. NPJ Biofilms Microbiomes., 2023, 9(1): 29
|
| [20] |
Beuers U, Banales JM, Karpen SJ, et al.. The history and future of bile acid therapies. J Hepatol., 2025, 83(5): 1172-1188
|
| [21] |
Jia W, Xie G, Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol., 2018, 15(2): 111-128
|
| [22] |
Chen Z, Chen H, Huang W, et al.. Bacteroides fragilis alleviates necrotizing enterocolitis through restoring bile acid metabolism balance using bile salt hydrolase and inhibiting FXR-NLRP3 signaling pathway. Gut Microbes., 2024, 16(1): 2379566
|
| [23] |
Cai Y, Zheng Q, Sun R, et al.. Recent progress in the study of Artemisiae Scopariae Herba (Yin Chen), a promising medicinal herb for liver diseases. Biomed Pharmacother., 2020, 130 Article ID: 110513
|
| [24] |
Liu S, Luorong Q, Hu K, et al.. Aqueous extract of Lysimachia christinae hance prevents cholesterol gallstone in mice by affecting the intestinal microflora. J Microbiol Biotechnol., 2021, 31(9): 1272-1280
|
| [25] |
Hu Y, Chen LL, Ye Z, et al.. Indigo naturalis as a potential drug in the treatment of ulcerative colitis: a comprehensive review of current evidence. Pharm Biol., 2024, 62(1): 818-832
|
| [26] |
Xu H, Wang S, Jiang Y, et al.. Poria cocos polysaccharide ameliorated antibiotic-associated diarrhea in mice via regulating the homeostasis of the gut microbiota and intestinal mucosal barrier. Int J Mol Sci., 2023, 24(2): 1423
|
| [27] |
Ping Y, Li C, Wang L, et al.. Effects of Atractylodes Macrocephala Rhizoma polysaccharide on intestinal microbiota composition in rats with mammary gland hyperplasia. Front Endocrinol., 2022, 13: 1102605
|
| [28] |
Cheng H, Zhang D, Wu J, et al.. Atractylodes macrocephala Koidz. volatile oil relieves acute ulcerative colitis via regulating gut microbiota and gut microbiota metabolism. Front Immunol., 2023, 14: 1127785
|
| [29] |
Duan Y, Huang J, Sun M, et al.. Poria Cocos polysaccharide improves intestinal barrier function and maintains intestinal homeostasis in mice. Int J Biol Macromol., 2023, 249 Article ID: 125953
|
| [30] |
Kang Y, Kuang X, Yan H, et al.. A novel synbiotic alleviates autoimmune hepatitis by modulating the gut microbiota-liver axis and inhibiting the hepatic TLR4/NF-κB/NLRP3 signaling pathway. mSystems., 2023, 8(2): Article ID: e0112722
|
| [31] |
Pan F, Zhang L, Li M, et al.. Predominant gut Lactobacillus murinus strain mediates anti-inflammaging effects in calorie-restricted mice. Microbiome., 2018, 6(1): 54
|
| [32] |
Wang H, He S, Xin J, et al.. Psychoactive effects of Lactobacillus johnsonii against restraint stress-induced memory dysfunction in mice through modulating intestinal inflammation and permeability-a study based on the gut-brain axis hypothesis. Front Pharmacol., 2021, 12 Article ID: 662148
|
| [33] |
Zhang H, Liu M, Liu X, et al.. Bifidobacterium animalis ssp. lactis 420 mitigates autoimmune hepatitis through regulating intestinal barrier and liver immune cells. Front Immunol., 2020, 11 Article ID: 569104
|
| [34] |
Mangin I, Dossou-Yovo F, Lévêque C, et al. Oral administration of viable Bifidobacterium pseudolongum strain Patronus modified colonic microbiota and increased mucus layer thickness in rat. FEMS Microbiol Ecol. 2018;94(11).
|
| [35] |
Qu S, Zheng Y, Huang Y, et al.. Excessive consumption of mucin by over-colonized Akkermansia muciniphila promotes intestinal barrier damage during malignant intestinal environment. Front Microbiol., 2023, 14: 1111911
|
| [36] |
Seregin SS, Golovchenko N, Schaf B, et al.. NLRP6 protects Il10-/- mice from colitis by limiting colonization of Akkermansia muciniphila. Cell Rep., 2017, 19(4): 733-745
|
| [37] |
Li X, Yang J, Zhou X, et al.. Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption. Nat Metab., 2024, 6(7): 1397-1414
|
| [38] |
Liu Y, Kuang W, Li M, et al.. Cholesterol-lowering mechanism of Lactobacillus bile salt hydrolase through regulation of Bifidobacterium pseudolongum in the gut microbiota. Nutrients., 2025, 17(18): 3019
|
| [39] |
Tyagi A, Kumar V. The gut microbiota-bile acid axis: a crucial regulator of immune function and metabolic health. World J Microbiol Biotechnol., 2025, 41(7): 215
|
| [40] |
Wu L, Zhou J, Zhou A, et al.. Lactobacillus acidophilus ameliorates cholestatic liver injury through inhibiting bile acid synthesis and promoting bile acid excretion. Gut Microbes., 2024, 16(1): 2390176
|
| [41] |
Verbeke L, Farre R, Verbinnen B, et al.. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol., 2015, 185(2): 409-419
|
| [42] |
Hao H, Cao L, Jiang C, et al.. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab., 2017, 25(4): 856-867.e5
|
| [43] |
Ravichandra A, Schwabe RF. Mouse Models of Liver Fibrosis. Methods Mol Biol., 2021, 2299: 339-356
|
| [44] |
Wu B, Tian X, Wang W, et al.. Upregulation of cadherin-11 contributes to cholestatic liver fibrosis. Pediatr Investig., 2022, 6(2): 100-110
|
Funding
Beijing Municipal Natural Science Foundation(Grant No. L222131)
National Natural Science Foundation of China (NSFC)(82104926)
RIGHTS & PERMISSIONS
The Author(s)
PDF
