Bile salt hydrolase: a key player in gut microbiota and its implications for metabolic dysfunction-associated steatotic liver disease

Abstract

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global public health challenge. Bile acids (BAs), synthesized in the liver and further metabolized in the gut, are essential in maintaining host metabolic homeostasis. Bile salt hydrolase (BSH), an enzyme produced by the gut microbiota, catalyzes the hydrolysis of conjugated BAs, thus regulating the balance between primary and secondary BAs. Growing evidence suggests that BSH activity is intricately linked to the pathogenesis of MASLD. This review comprehensively examines the structural and functional properties of BSH enzymes, their distribution among gut microbial communities, and current methodologies for assessing BSH expression and activity. Furthermore, it highlights the alterations in BSH observed in MASLD and explores the potential mechanistic pathways involved, offering a foundation for the development of novel diagnostic and therapeutic strategies.

Keywords

Bile salt hydrolase / gut microbiota / bile acids / metabolic dysfunction-associated steatotic liver disease

References

[1] Loomba R,Shulman GI.Mechanisms and disease consequences of nonalcoholic fatty liver disease.Cell2021;184:2537-64

[2] Miao L,Byrne CD,Zheng MH.Current status and future trends of the global burden of MASLD.Trends Endocrinol Metab2024;35:697-707

[3] Chan KE,Tang ASP.Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: a meta-analysis and systematic review of 10 739 607 individuals.J Clin Endocrinol Metab2022;107:2691-700

[4] Sharpton SR,Knight R.Current concepts, opportunities, and challenges of gut microbiome-based personalized medicine in nonalcoholic fatty liver disease.Cell Metab2021;33:21-32 PMCID:PMC8414992

[5] Collins SL,Bisanz JE,Patterson AD.Bile acids and the gut microbiota: metabolic interactions and impacts on disease.Nat Rev Microbiol2023;21:236-47

[6] Lee MH,Mohanty I.How bile acids and the microbiota interact to shape host immunity.Nat Rev Immunol2024;24:798-809

[7] Perino A.Metabolic messengers: bile acids.Nat Metab2022;4:416-23

[8] Foley MH,Stewart AK.Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut.Nat Microbiol2023;8:611-28 PMCID:PMC10066039

[9] Jia B,Hahn Y.Metagenomic analysis of the human microbiome reveals the association between the abundance of gut bile salt hydrolases and host health.Gut Microbes2020;11:1300-13 PMCID:PMC7524343

[10] Sun L,Cai J.Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer.Nat Commun2023;14:755 PMCID:PMC9918522

[11] Smirnova E,Narayan N.Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD.Hepatology2022;76:1811-24 PMCID:PMC9653520

[12] Begley M,Gahan CGM.Bile salt hydrolase activity in probiotics.Appl Environ Microbiol2006;72:1729-38 PMCID:PMC1393245

[13] Xu F,Singh W,Tikhonova IG.The complex structure of bile salt hydrolase from Lactobacillus salivarius reveals the structural basis of substrate specificity.Sci Rep2019;9:12438 PMCID:PMC6711994

[14] Rimal B,Tanes CE.Bile salt hydrolase catalyses formation of amine-conjugated bile acids.Nature2024;626:859-63 PMCID:PMC10881385

[15] Bustos AY,Fadda S.New insights into bacterial bile resistance mechanisms: the role of bile salt hydrolase and its impact on human health.Food Res Int2018;112:250-62

[16] Song Z,Lao X.Taxonomic profiling and populational patterns of bacterial bile salt hydrolase (BSH) genes based on worldwide human gut microbiome.Microbiome2019;7:9 PMCID:PMC6345003

[17] Zhong XC,Gao XX.Caffeic acid phenethyl ester suppresses intestinal FXR signaling and ameliorates nonalcoholic fatty liver disease by inhibiting bacterial bile salt hydrolase activity.Acta Pharmacol Sin2023;44:145-56 PMCID:PMC9813015

[18] Zhao Q,Huang RY.Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.Nat Commun2023;14:1829 PMCID:PMC10067939

[19] Liu X,Shi M.Melatonin improves cholestatic liver disease via the gut-liver axis.J Pineal Res2024;76:e12929

[20] Wan Y,Li J.Unconjugated and secondary bile acid profiles in response to higher-fat, lower-carbohydrate diet and associated with related gut microbiota: a 6-month randomized controlled-feeding trial.Clin Nutr2020;39:395-404

[21] Jiao N,Chapa-Rodriguez A.Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.Gut2018;67:1881-91

[22] He X,Hong Y.High fat diet and high sucrose intake divergently induce dysregulation of glucose homeostasis through distinct gut microbiota-derived bile acid metabolism in mice.J Agric Food Chem2024;72:230-44

[23] Parasar B,Xiao X,Brito IL.Chemoproteomic profiling of gut microbiota-associated bile salt hydrolase activity.ACS Cent Sci2019;5:867-73 PMCID:PMC6535767

[24] Khodakivskyi PV,Yevtodiyenko A.Noninvasive imaging and quantification of bile salt hydrolase activity: from bacteria to humans.Sci Adv2021;7:eaaz9857 PMCID:PMC7857686

[25] Yu J,Chen L,Chen Y.Disease-associated gut microbiota reduces the profile of secondary bile acids in pediatric nonalcoholic fatty liver disease.Front Cell Infect Microbiol2021;11:698852 PMCID:PMC8459332

[26] Li Y,He X.Zhi-Kang-Yin formula attenuates high-fat diet-induced metabolic disorders through modulating gut microbiota-bile acids axis in mice.Chin Med2024;19:145 PMCID:PMC11490013

[27] Jia W,Zheng X.Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism.J Mol Cell Biol2021;13:460-2 PMCID:PMC8436671

[28] Zhao WW,Wu X.Ilexsaponin A₁ Ameliorates diet-induced nonalcoholic fatty liver disease by regulating bile acid metabolism in mice.Front Pharmacol2021;12:771976 PMCID:PMC8712733

[29] Xu H,Niu K.Involvement of bile acid metabolism and gut microbiota in the amelioration of experimental metabolism-associated fatty liver disease by nobiletin.Molecules2024;29:976 PMCID:PMC10935266

[30] Li X,Xiao M.Penthorum chinense Pursh. extract attenuates non-alcholic fatty liver disease by regulating gut microbiota and bile acid metabolism in mice.J Ethnopharmacol2022;294:115333

[31] Li DK,Lee Y.Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury.Sci Adv2022;8:eabo2794 PMCID:PMC9417178

[32] Li ZM,Mao YQ.Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis.Pharmacol Res2023;196:106902

[33] Gao X,Xin Y.Dietary cholesterol drives the development of nonalcoholic steatohepatitis by altering gut microbiota mediated bile acid metabolism in high-fat diet fed mice.J Nutr Biochem2023;117:109347

[34] Zhuge A,Yuan Y.Microbiota-induced lipid peroxidation impairs obeticholic acid-mediated antifibrotic effect towards nonalcoholic steatohepatitis in mice.Redox Biol2023;59:102582 PMCID:PMC9830314

[35] Shen B,Gu T.Kuhuang alleviates liver fibrosis by modulating gut microbiota-mediated hepatic IFN signaling and bile acid synthesis.Front Pharmacol2022;13:1080226 PMCID:PMC9792617

[36] Takimoto Y,Nakamoto N.Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis.iScience2023;26:106220 PMCID:PMC9982274

[37] Liu Y,Li F.Probiotic Lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice.Hepatology2020;71:2050-66 PMCID:PMC7317518

[38] Qin N,Li A.Alterations of the human gut microbiome in liver cirrhosis.Nature2014;513:59-64

[39] Kobyliak N,Falalyeyeva T.Beneficial effects of probiotic combination with omega-3 fatty acids in NAFLD: a randomized clinical study.Minerva Med2018;109:418-28

[40] Fogelson KA,Zarrinpar A.The gut microbial bile acid modulation and its relevance to digestive health and diseases.Gastroenterology2023;164:1069-85 PMCID:PMC10205675

[41] Chen ML,Zhang Y.Resveratrol attenuates trimethylamine- N -oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota.mBio2016;7:e02210-15 PMCID:PMC4817264

[42] Pontes KSDS,Cunha MRD.Effects of probiotics on body adiposity and cardiovascular risk markers in individuals with overweight and obesity: a systematic review and meta-analysis of randomized controlled trials.Clin Nutr2021;40:4915-31

[43] Agolino G,Vaccalluzzo A.Bile salt hydrolase: the complexity behind its mechanism in relation to lowering-cholesterol lactobacilli probiotics.J Funct Foods2024; 120:106357

[44] Kumar R,Batish VK.Bile salt hydrolase (Bsh) activity screening of lactobacilli: in vitro selection of indigenous lactobacillus strains with potential bile salt hydrolysing and cholesterol-lowering ability.Probiotics Antimicro Prot2012;4:162-72

[45] Yang Y,Zhou S,Chen Y.Bile salt hydrolase can improve Lactobacillus plantarum survival in gastrointestinal tract by enhancing their adhesion ability.FEMS Microbiol Lett2019;366:fnz100

[46] Li F,Krausz KW.Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity.Nat Commun2013;4:2384 PMCID:PMC6595219

[47] Huang F,Ma X.Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism.Nat Commun2019;10:4971 PMCID:PMC6823360

[48] Liang C,Gong PM.Lactiplantibacillus plantarum H-87 prevents high-fat diet-induced obesity by regulating bile acid metabolism in C57BL/6J mice.Food Funct2021;12:4315-24

[49] Watanabe M,Wang L.Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.J Clin Invest2004;113:1408-18 PMCID:PMC406532

[50] Zhang H,Liu X.Obeticholic acid ameliorates obesity and hepatic steatosis by activating brown fat.Exp Ther Med2021;22:991 PMCID:PMC8311225

[51] Münzker J,Till A.Functional changes of the gastric bypass microbiota reactivate thermogenic adipose tissue and systemic glucose control via intestinal FXR-TGR5 crosstalk in diet-induced obesity.Microbiome2022;10:96 PMCID:PMC9229785

[52] Zhang J,He Z.Salidroside attenuates NASH through regulating bile acid-FXR/TGR5 signaling pathway via targeting gut microbiota.Int J Biol Macromol2025;307:142276

[53] Sun H,Wang H.Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis.Gut2023;72:1664-77

[54] Gong Z,Zhao S.Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis.Oncotarget7:83951-63 PMCID:PMC5356637

[55] Yue H,Cai W,Dong P.Antarctic krill peptide alleviates liver fibrosis via downregulating the secondary bile acid mediated NLRP3 signaling pathway.Food Funct2022;13:7740-9

[56] Sun X,Yu L.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 Pharmacol2023;14:1205323 PMCID:PMC10244678

[57] Puri P,Joyce A.The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids.Hepatology2018;67:534-48 PMCID:PMC5764808

[58] Liu C,Abuduaini R.Enlightening the taxonomy darkness of human gut microbiomes with a cultured biobank.Microbiome2021;9:119 PMCID:PMC8140505

[59] Abu-Ali GS,Lloyd-Price J.Metatranscriptome of human faecal microbial communities in a cohort of adult men.Nat Microbiol2018;3:356-66

[60] Loomba R,Li W.Gut microbiome-based metagenomic signature for non-invasive detection of advanced fibrosis in human nonalcoholic fatty liver disease.Cell Metab2017;25:1054-62.e5 PMCID:PMC5502730