2,973
Views
11
CrossRef citations to date
0
Altmetric
Review

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies

, , , , , , , , & show all
Article: 2181930 | Received 10 Oct 2022, Accepted 09 Feb 2023, Published online: 02 Mar 2023

References

  • Onofrio FQ, Hirschfield GM. The pathophysiology of cholestasis and its relevance to clinical practice. Clin Liver Dis (Hoboken). 2020;15(3):110–28. doi:10.1002/cld.894.
  • European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–267. doi:10.1016/j.jhep.2009.04.009.
  • Jungst C, Berg T, Cheng J, Green RM, Jia JD, Mason AL, Lammert F. Intrahepatic cholestasis in common chronic liver diseases. Eur J Clin Invest. 2013;43(10):1069–1083. doi:10.1111/eci.12128.
  • Hilscher MB, Kamath PS, Eaton JE. Cholestatic liver diseases: a primer for generalists and subspecialists. Mayo Clin Proc. 2020;95(10):2263–2279. doi:10.1016/j.mayocp.2020.01.015.
  • Afonso MB, Rodrigues PM, Simao AL, Ofengeim D, Carvalho T, Amaral JD, Gaspar MM, Cortez-Pinto H, Castro RE, Yuan J, et al. Activation of necroptosis in human and experimental cholestasis. Cell Death Dis. 2016;7(9):e2390. doi:10.1038/cddis.2016.280.
  • Goldstein J, Levy C. Novel and emerging therapies for cholestatic liver diseases. Liver Internat. 2018;38(9):1520–1535. doi:10.1111/liv.13880.
  • Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, Drenth JPH, Pockros PJ, Regula J, Beuers U, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631–643. doi:10.1056/NEJMoa1509840.
  • Harms MH, Lammers WJ, Thorburn D, Corpechot C, Invernizzi P, Janssen HLA, Battezzati PM, Nevens F, Lindor KD, Floreani A, et al. Major hepatic complications in Ursodeoxycholic acid-treated patients with primary biliary cholangitis: risk factors and time trends in incidence and outcome. Am J Gastroenterol. 2018;113(2):254–264. doi:10.1038/ajg.2017.440.
  • Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015;62(1):S25–S37. doi:10.1016/j.jhep.2015.02.023.
  • Xiong K, Cai J, Liu PY, Wang JY, Zhao SL, Xu L, Yang Y, Liu J, Ma A. Lactobacillus casei alleviated the abnormal increase of cholestasis-related liver indices during tuberculosis treatment: a post hoc analysis of randomized controlled trial. Mol Nutr Food Res. 2021;65(16):e2100108. doi:10.1002/mnfr.202100108.
  • Rijkers GT, Bengmark S, Enck P, Haller D, Herz U, Kalliomaki M, Kudo S, Lenoir-Wijnkoop I, Mercenier A, Myllyluoma E, et al. Guidance for substantiating the evidence for beneficial effects of probiotics: current status and recommendations for future research. J Nutr. 2010;140(3):671S–6S. doi:10.3945/jn.109.113779.
  • Pavlovic N, Stankov K, Mikov M. Probiotics-interactions with bile acids and impact on cholesterol metabolism. Appl Biochem Biotechnol. 2012;168(7):1880–1895. doi:10.1007/s12010-012-9904-4.
  • Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. J Hepatol. 2017;67(6):1298–1323. doi:10.1016/j.jhep.2017.07.022.
  • Palmer KR, Liu X, Mol BW. Management of intrahepatic cholestasis in pregnancy. Lancet. 2019;393(10174):853–854. doi:10.1016/S0140-6736(18)32323-7.
  • Trauner M, Fuchs CD. Novel therapeutic targets for cholestatic and fatty liver disease. Gut. 2022;71(1):194–209. doi:10.1136/gutjnl-2021-324305.
  • Chen Q-W, Li Q-R, Cao M-W, Yan J-H, Zhang X-Z. Hierarchy-assembled dual probiotics system ameliorates cholestatic drug-induced liver injury via gut-liver axis modulation. Adv Sci (Weinh). 2022;9(17):e2200986. doi:10.1002/advs.202200986.
  • Liu YH, Chen KF, Li FY, Gu ZL, Liu Q, He LQ, Shao T, Song Q, Zhu F, Zhang L, 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. doi:10.1002/hep.30975.
  • Bhamidimarri KR, Schiff E. Drug-induced cholestasis. Clin Liver Dis. 2013;17(4):519. doi:10.1016/j.cld.2013.07.015.
  • Shen T, Liu Y, Shang J, Xie Q, Li J, Yan M, Xu J, Niu J, Liu J, Watkins PB, et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 2019;19(1):156(8):2230-2241.e11. doi:10.1053/j.gastro.2019.02.002.
  • Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatol (Baltimore, Md). 2005;42(2):481–489. doi:10.1002/hep.20800.
  • Vinken M. In vitro prediction of drug-induced cholestatic liver injury: a challenge for the toxicologist. Arch Toxicol. 2018;92(5):1909–1912. doi:10.1007/s00204-018-2201-4.
  • Gijbels E, Vilas-Boas V, Deferm N, Devisscher L, Jaeschke H, Annaert P, Vinken M. Mechanisms and in vitro models of drug-induced cholestasis. Arch Toxicol. 2019;93(5):1169–1186. doi:10.1007/s00204-019-02437-2.
  • Gulamhusein AF, Hirschfield GM. Primary biliary cholangitis: pathogenesis and therapeutic opportunities. Nat Rev Gastroenterol Hepatol. 2020;17(2):93–110. doi:10.1038/s41575-019-0226-7.
  • Younossi ZM, Bernstein D, Shiffman ML, Kwo P, Kim WR, Kowdley KV, Jacobson IM. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48–63. doi:10.1038/s41395-018-0390-3.
  • Zeng N, Duan W, Chen S, Wu S, Ma H, Ou X, You H, Kong Y, Jia J. Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis. Hepatol Int. 2019;13(6):788–799. doi:10.1007/s12072-019-09984-x.
  • Sarcognato S, Sacchi D, Grillo F, Cazzagon N, Fabris L, Cadamuro M, Cataldo I, Covelli C, Mangia A, Guido M, et al. Autoimmune biliary diseases: primary biliary cholangitis and primary sclerosing cholangitis. Pathologica. 2021;113(3):170–184. doi:10.32074/1591-951X-245.
  • Li H, Guan YL, Han CC, Zhang Y, Liu Q, Wei W, Ma Y. The pathogenesis, models and therapeutic advances of primary biliary cholangitis. Biomed Pharmacother. 2021;140:111754. doi:10.1016/j.biopha.2021.111754.
  • de Vries E, Beuers U. Management of cholestatic disease in 2017. Liver Int. 2017;37:123–129. doi:10.1111/liv.13306.
  • Tanaka A, Takikawa H. Geoepidemiology of primary sclerosing cholangitis: a critical review. J Autoimmun. 2013;46:35–40. doi:10.1016/j.jaut.2013.07.005.
  • Gidwaney NG, Pawa S, Das KM. Pathogenesis and clinical spectrum of primary sclerosing cholangitis. World J Gastroenterol. 2017;23(14):2459–2469. doi:10.3748/wjg.v23.i14.2459.
  • Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol. 2011;25(6):727–739. doi:10.1016/j.bpg.2011.10.009.
  • Chapman R, Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol. 2008;14(21):3350–3359. doi:10.3748/wjg.14.3350.
  • Ovadia C, Williamson C. Intrahepatic cholestasis of pregnancy: recent advances. Clin Dermatol. 2016;34(3):327–334. doi:10.1016/j.clindermatol.2016.02.004.
  • Wood AM, Livingston EG, Hughes BL, Kuller JA. Intrahepatic cholestasis of pregnancy: a review of diagnosis and management. Obstet Gynecol Surv. 2018;73(2):103–109. doi:10.1097/OGX.0000000000000524.
  • Hay JE. Liver disease in pregnancy. Hepatol (Baltimore, Md). 2008;47(3):1067–1076. doi:10.1002/hep.22130.
  • Henkel SAF, Squires JH, Ayers M, Ganoza A, McKiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol. 2019;11(5):450–463. doi:10.4254/wjh.v11.i5.450.
  • Srivastava A. Progressive familial intrahepatic cholestasis. J Clin Exp Hepatol. 2014;4(1):25–36. doi:10.1016/j.jceh.2013.10.005.
  • Gunaydin M, Cil ATB. Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment. Hepat Med-Evidence Res. 2018;10:95–104. doi:10.2147/HMER.S137209.
  • Vinayagamoorthy V, Srivastava A, Sarma M.S. Newer variants of progressive familial intrahepatic cholestasis. World J Hepatol. 2021;13(12):2024-2038. doi:10.4254/wjh.v13.i12.2024.
  • Baker A, Kerkar N, Todorova L, Kamath BM, Houwen RHJ. Systematic review of progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2019;43(1):20–36. doi:10.1016/j.clinre.2018.07.010.
  • Carter BA, Shulman RJ. Mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5):277–287. doi:10.1038/ncpgasthep0796.
  • Nandivada P, Carlson SJ, Chang MI, Cowan E, Gura KM, Puder M. Treatment of parenteral nutrition-associated liver disease: the role of lipid emulsions. Adv Nutr. 2013;4(6):711–717. doi:10.3945/an.113.004770.
  • Tazuke Y, Kiristioglu I, Heidelberger KP, Eisenbraun MD, Teitelbaum DH. Hepatic P-glycoprotein changes with total parenteral nutrition administration. J Parenter Ent Nut. 2004;28(1):1–6. doi:10.1177/014860710402800101.
  • Tazuke Y, Drongowski RA, Btaiche I, Coran AG, Teitelbaum DH. Effects of lipid administration on liver apoptotic signals in a mouse model of total parenteral nutrition (TPN). Pediatr Surg Int. 2004;20(4):224–228. doi:10.1007/s00383-003-1115-1.
  • Lauriti G, Zani A, Aufieri R, Cananzi M, Chiesa PL, Eaton S, Pierro A. Incidence, prevention, and treatment of parenteral nutrition-associated cholestasis and intestinal failure-associated liver disease in infants and children: a systematic review. JPEN J Parenter Enteral Nutr. 2014;38(1):70–85. doi:10.1177/0148607113496280.
  • Fernandez-Murga ML, Petrov PD, Conde I, Castell JV, Gomez-Lechon MJ, Jover R. Advances in drug-induced cholestasis: clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol. 2018;120:196–212. doi:10.1016/j.fct.2018.07.017.
  • Kis E, Ioja E, Rajnai Z, Jani M, Méhn D, Herédi-Szabó K, Krajcsi P. BSEP inhibition: in vitro screens to assess cholestatic potential of drugs. Toxicol In Vitro. 2012;26(8):1294–1299. doi:10.1016/j.tiv.2011.11.002.
  • Fernández-Murga ML, Petrov PD, Conde I, Castell JV, Goméz-Lechón MJ, Jover R. Advances in drug-induced cholestasis: clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol. 2018;120:196–212. doi:10.1016/j.fct.2018.07.017.
  • Padda MS, Sanchez M, Akhtar AJ, Boyer JL. Drug-induced cholestasis. Hepatol (Baltimore, Md). 2011;53(4):1377–1387. doi:10.1002/hep.24229.
  • Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology. 2004;126(1):322–342. doi:10.1053/j.gastro.2003.06.005.
  • Pauli-Magnus C, Meier PJ. Hepatobiliary transporters and drug-induced cholestasis. Hepatol (Baltimore, Md). 2006;44(4):778–787. doi:10.1002/hep.21359.
  • Sharanek A, Burban A, Burbank M, Le Guevel R, Li R, Guillouzo A, Guguen-Guillouzo C. Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs. Sci Rep. 2016;6(1):24709. doi:10.1038/srep24709.
  • Yu TZ, Wang L, Lee H, O’Brien DK, Bronk SF, Gores GJ, Yoon Y. Decreasing mitochondrial fission prevents cholestatic liver injury. J Biological Chem. 2014;289(49):34074–34088. doi:10.1074/jbc.M114.588616.
  • Halilbasic E, Baghdasaryan A, Trauner M. nuclear receptors as drug targets in cholestatic liver diseases. Clin Liver Dis. 2013;17(2):161–+. doi:10.1016/j.cld.2012.12.001.
  • Lleo A, Wang G-Q, Gershwin ME, Hirschfield GM. Primary biliary cholangitis. Lancet (London, England). 2020;396(10266):1915–1926. doi:10.1016/S0140-6736(20)31607-X.
  • Patel A, Seetharam A. Primary biliary cholangitis: disease pathogenesis and implications for established and novel therapeutics. J Clin Exp Hepatol. 2016;6(4):311–318. doi:10.1016/j.jceh.2016.10.001.
  • Visseren T, Murad SD. Recurrence of primary sclerosing cholangitis, primary biliary cholangitis and auto-immune hepatitis after liver transplantation. Best Pract Res Clin Gastroenterol. 2017;31(2):187–198. doi:10.1016/j.bpg.2017.04.004.
  • Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet. 2018;391(10139):2547–2559. doi:10.1016/S0140-6736(18)30300-3.
  • Kaplan GG, Laupland KB, Butzner D, Urbanski SJ, Lee SS. The burden of large and small duct primary sclerosing cholangitis in adults and children: a population-based analysis. Am J Gastroenterol. 2007;102(5):1042–1049. doi:10.1111/j.1572-0241.2007.01103.x.
  • Lazaridis KN, LaRusso NF, Ingelfinger JR. Primary Sclerosing Cholangitis. N Engl J Med. 2016;375(12):1161–1170. doi:10.1056/NEJMra1506330.
  • Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BWM, Poen AC, van Nieuwkerk KM, Drenth JP, Witteman BJ, Tuynman HA, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology. 2013;58(6):2045–2055. doi:10.1002/hep.26565.
  • Dean G, Hanauer S, Levitsky J. The role of the intestine in the pathogenesis of primary sclerosing cholangitis: evidence and therapeutic implications. Hepatol (Baltimore, Md). 2020;72(3):1127–1138. doi:10.1002/hep.31311.
  • Kummen M, Thingholm LB, Rühlemann MC, Holm K, Hansen SH, Moitinho-Silva L, Tian C, McIntyre M, Bing N, Hung K, et al. Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis. Gastroenterology. 2021;21(1):160. doi:10.1186/s12876-021-01740-6.
  • Nakamoto N, Sasaki N, Aoki R, Miyamoto K, Suda W, Teratani T, Suzuki T, Koda Y, Chu P-S, Taniki N, et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol. 2019;4(3):492–503. doi:10.1038/s41564-018-0333-1.
  • Yan C, Koda S, Wu J, Zhang BB, Yu Q, Netea MG, Tang R-X, Zheng K-Y. Roles of trained immunity in the pathogenesis of cholangiopathies: a therapeutic target. Hepatology. 2020;72(5):1838–1850. doi:10.1002/hep.31395.
  • Kremer AE, Wolf K, Stander S. Intrahepatic cholestasis of pregnancy. Rare but Important Hautarzt. 2017;68:95–102.
  • Dixon PH, Williamson C. The pathophysiology of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol. 2016;40(2):141–153. doi:10.1016/j.clinre.2015.12.008.
  • Roediger R, Fleckenstein J. Intrahepatic cholestasis of pregnancy: natural history and current management. Semin Liver Dis. 2021;41(1):103–108. doi:10.1055/s-0040-1722264.
  • Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev. 2020;7(7). doi:10.1002/14651858.CD000493.pub3.
  • Xiao JP, Li ZY, Song YJ, Sun YH, Shi H, Chen DZ, Zhang Y. Molecular pathogenesis of intrahepatic cholestasis of pregnancy. Can J Gastroenterol Hepatol. 2021;2021:6679322. doi:10.1155/2021/6679322.
  • Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2014;124(1):120–133. doi:10.1097/AOG.0000000000000346.
  • Reichert MC, Lammert F. ABCB4 gene aberrations in human liver disease: an evolving spectrum. Semin Liver Dis. 2018;38(4):299–307. doi:10.1055/s-0038-1667299.
  • Piątek K, Kurzawińska G, Magiełda J, Drews K, Barlik M, Malewski Z, Ożarowski M, Maciejewska M, Seremak-Mrozikiewicz A. The role of ABC transporters’ gene polymorphism in the etiology of intrahepatic cholestasis of pregnancy. Ginekol Pol. 2018;89(7):393–397. doi:10.5603/GP.a2018.0067.
  • Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali S, et al. Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol. 2010;53(1):170–178. doi:10.1016/j.jhep.2010.01.034.
  • Jacquemin E. Progressive familial intrahepatic cholestasis. Clin Res Hepatol Gastroenterol. 2012;36:S26–S35. doi:10.1016/S2210-7401(12)70018-9.
  • Paulusma CC, Folmer DE, Ho-Mok KS, de Waart DR, Hilarius PM, Verhoeven AJ, Oude Elferink RPJ. ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity. Hepatol (Baltimore, Md). 2008;47(1):268–278. doi:10.1002/hep.21950.
  • Harris MJ, Le Couteur DG, Arias IM. Progressive familial intrahepatic cholestasis: genetic disorders of biliary transporters. J Gastroenterol Hepatol. 2005;20(6):807–817. doi:10.1111/j.1440-1746.2005.03743.x.
  • Alam S, Lal BB. Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: outcome and therapeutic strategies. World J Hepatol. 2022;14(1):98-118. doi:10.4254/wjh.v14.i1.98.
  • Carter BA, Shulman RJ. Mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2007;4(5):277–287. doi:10.1038/ncpgasthep0796.
  • Alkharfy TM, Ba-Abbad R, Hadi A, Sobaih BH, AlFaleh KM. Total parenteral nutrition-associated cholestasis and risk factors in preterm infants. Saudi J Gastroenterol. 2014;20(5):293–296. doi:10.4103/1319-3767.141688.
  • Kelly DA. Intestinal failure-associated liver disease: what do we know today? Gastroenterology. 2006;130(2):S70–S7. doi:10.1053/j.gastro.2005.10.066.
  • Orso G, Mandato C, Veropalumbo C, Cecchi N, Garzi A, Vajro P. Pediatric parenteral nutrition-associated liver disease and cholestasis: novel advances in pathomechanisms-based prevention and treatment. Dig Liver Dis. 2016;48(3):215–222. doi:10.1016/j.dld.2015.11.003.
  • El Kasmi KC, Vue PM, Anderson AL, Devereaux MW, Ghosh S, Balasubramaniyan N, Fillon SA, Dahrenmoeller C, Allawzi A, Woods C, et al. Macrophage-derived IL-1β/NF-κB signaling mediates parenteral nutrition-associated cholestasis. Nat Commun. 2018;9(1):1393. doi:10.1038/s41467-018-03764-1.
  • Whitington PF. Cholestasis associated with total parenteral nutrition in infants. Hepatol (Baltimore, Md). 1985;5(4):693–696. doi:10.1002/hep.1840050428.
  • Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol. 2006;3(6):318–328. doi:10.1038/ncpgasthep0521.
  • Paumgartner G. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–531. doi:10.1053/jhep.2002.36088.
  • Almasio P, Bortolini M, Pagliaro L, Coltorti M. Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. Drugs. 1990;40(Suppl 3):111–123. doi:10.2165/00003495-199000403-00011.
  • Binder T, Salaj P, Zima T, Vitek L. Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis of pregnancy. J Perinat Med. 2006;34(5):383–391. doi:10.1515/JPM.2006.077.
  • Roncaglia N, Locatelli A, Arreghini A, Assi F, Cameroni I, Pezzullo JC, Ghidini A. A randomised controlled trial of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of gestational cholestasis. Bjog-an Int J Obstetrics Gynaecol. 2004;111(1):17–21. doi:10.1046/j.1471-0528.2003.00029.x.
  • Kjaergaard K, Frisch K, Sorensen M, Munk OL, Hofmann AF, Horsager J, Schacht AC, Erickson M, Shapiro D, Keiding S, et al. Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. J Hepatol. 2021;74(1):58–65. doi:10.1016/j.jhep.2020.07.028.
  • Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol. 2001;21(11):1840–1845. doi:10.1161/hq1101.098228.
  • Ghonem NS, Ananthanarayanan M, Soroka CJ, Boyer JL. Peroxisome proliferator-activated receptor α activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion. Hepatol (Baltimore, Md). 2014;59(3):1030–1042. doi:10.1002/hep.26894.
  • Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000;275(47):36703–36707. doi:10.1074/jbc.M004045200.
  • Corpechot C, Chazouillères O, Rousseau A, Le Gruyer A, Habersetzer F, Mathurin P, Goria O, Potier P, Minello A, Silvain C, et al. A placebo-controlled trial of bezafibrate in primary biliary cholangitis. N Engl J Med. 2018;378(23):2171–2181. doi:10.1056/NEJMoa1714519.
  • Levy C, Peter JA, Nelson DR, Keach J, Petz J, Cabrera R, Clark V, Firpi RJ, Morelli G, Soldevila-Pico C, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther. 2011;33(2):235–242. doi:10.1111/j.1365-2036.2010.04512.x.
  • Schramm C, Hirschfield G, Mason AL, Wedemeyer H, Klickstein L, Neelakantham S, Koo P, Sanni J, Badman M, Jones D, et al. Early assessment of safety and efficacy of tropifexor, a potent non bile-acid FXR agonist, in patients with primary biliary cholangitis: an interim analysis of an ongoing phase 2 study. J Hepatol. 2018;68:S103–S. doi:10.1016/S0168-8278(18)30426-4.
  • Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C, Eksteen B, Agarwal K, Muir A, Rushbrook S, et al. The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis. Hepatol (Baltimore, Md). 2019;70(3):788–801. doi:10.1002/hep.30509.
  • Erstad DJ, Farrar CT, Ghoshal S, Masia R, Ferreira DS, Chen Y-CI, Choi J-K, Wei L, Waghorn PA, Rotile NJ, et al. Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP-305, a novel farnesoid X receptor agonist. Hepatol Commun. 2018;2(7):821–835. doi:10.1002/hep4.1193.
  • Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered fibroblast growth factor 19 reduces liver injury and resolves sclerosing cholangitis in Mdr2-Deficient mice. Hepatology. 2016;63(3):914–929. doi:10.1002/hep.28257.
  • Zhou M, Wang XY, Phung V, Lindhout DA, Mondal K, Hsu JY, Yang H, Humphrey M, Ding X, Arora T, et al. Separating tumorigenicity from bile acid regulatory activity for endocrine hormone FGF19. Cancer Res. 2014;74(12):3306–3316. doi:10.1158/0008-5472.CAN-14-0208.
  • Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, Vecchiotti S, Gonzalez FJ, Schoonjans K, Strazzabosco M, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2 −/− (Abcb4 −/−) mouse cholangiopathy model by promoting biliary HCO 3− output. Hepatol (Baltimore, Md). 2011;54(4):1303–1312. doi:10.1002/hep.24537.
  • Xiang JW, Zhang ZY, Xie HY, Zhang CC, Bai Y, Cao H, Che QS, Guo J, Su ZQ. Effect of different bile acids on the intestine through enterohepatic circulation based on FXR. Gut Microbes. 2021;13(1):1949095. doi:10.1080/19490976.2021.1949095.
  • Tonin F, Arends I. Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review. Beilstein J Org Chem. 2018;14:470–483. doi:10.3762/bjoc.14.33.
  • Robles-Diaz M, Nezic L, Vujic-Aleksic V, Bjornsson ES. Role of ursodeoxycholic acid in treating and preventing idiosyncratic drug-induced liver injury. A Systematic Review. Front Pharmacol. 2021;12:744488. doi:10.3389/fphar.2021.744488.
  • Noureddin M, Sander-Struckmeier S, Mato JM. Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: a systematic review. World J Hepatol. 2020;12(2):46-63. doi:10.4254/wjh.v12.i2.46.
  • Lu SC, Mato JM. S -adenosylmethionine in Liver Health, Injury, and Cancer. Physiol Rev. 2012;92(4):1515–1542. doi:10.1152/physrev.00047.2011.
  • Testino G, Leone S, Fagoonee S, Pellicano R. The role of adenosyl-methionine in alcoholic liver disease and intrahepatic cholestasis. Minerva Gastroenterol Dietol. 2018;64(3):187–189. doi:10.23736/S1121-421X.18.02484-4.
  • Hardy ML, Coulter I, Morton SC, Favreau J, Venuturupalli S, Chiappelli F, Rossi F, Orshansky G, Jungvig LK, Roth EA, et al. S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Evid Rep Technol Assess (Summ). 2003;(64):1-3.
  • Li M, Luo Q, Tao YY, Sun X, Liu CH. Pharmacotherapies for drug-induced liver injury: a current literature review. Front Pharmacol. 2022;12:806249. doi:10.3389/fphar.2021.806249.
  • Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM. 6 alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45(17):3569–3572. doi:10.1021/jm025529g.
  • Fiorucci S, Clerici C, Antonelli E, Orlandi S, Goodwin B, Sadeghpour BM, Sabatino G, Russo G, Castellani D, Willson TM, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther. 2005;313(2):604–612. doi:10.1124/jpet.104.079665.
  • Kowdley KV, Vuppalanchi R, Levy C, Floreani A, Andreone P, LaRusso NF, Shrestha R, Trotter J, Goldberg D, Rushbrook S, et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J Hepatol. 2020;73(1):94–101. doi:10.1016/j.jhep.2020.02.033.
  • Schaap FG, van der Gaag NA, Gouma DJ, Jansen PLM. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology. 2009;49(4):1228–1235. doi:10.1002/hep.22771.
  • Piglionica M, Cariello M, Moschetta A. The gut-liver axis in hepatocarcinoma: a focus on the nuclear receptor FXR and the enterokine FGF19. Curr Opin Pharmacol. 2018;43:93–98. doi:10.1016/j.coph.2018.08.005.
  • Cariello M, Piglionica M, Gadaleta RM, Moschetta A. The enterokine fibroblast growth factor 15/19 in bile acid metabolism. Handb Exp Pharmacol. 2019;256:73–93.
  • Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, To C, Learned RM, Tian H, DePaoli AM, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014;6(247):247ra100. doi:10.1126/scitranslmed.3009098.
  • Hirschfield GM, Chazouilleres O, Drenth JP, Thorburn D, Harrison SA, Landis CS, Mayo MJ, Muir AJ, Trotter JF, Leeming DJ, et al. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: a multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol. 2019;70(3):483–493. doi:10.1016/j.jhep.2018.10.035.
  • Hasegawa S, Yoneda M, Kurita Y, Nogami A, Honda Y, Hosono K, Nakajima A. Cholestatic liver disease: current treatment strategies and new therapeutic agents. Drugs. 2021;81(10):1181–1192. doi:10.1007/s40265-021-01545-7.
  • Marschall H-U, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, SILBERT D, Fuchsbichler A, Benthin L, Grundstrom R, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology. 2005;129(2):476–485. doi:10.1016/j.gastro.2005.05.009.
  • Dilger K, Denk A, Heeg MHJ, Beuers U. No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatol (Baltimore, Md). 2005;41(3):595–602. doi:10.1002/hep.20568.
  • Arenas F, Hervias I, Uriz M, Joplin R, Prieto J, Medina JF. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J Clin Invest. 2008;118(2):695–709. doi:10.1172/JCI33156.
  • Gao L, Wang L, Woo E, He X, Yang G, Bowlus C, Leung PSC, Gershwin ME. Clinical management of primary biliary cholangitis-strategies and evolving trends. Clin Rev Allergy Immunol. 2020;59(2):175–194. doi:10.1007/s12016-019-08772-7.
  • Qin JJ, Li RQ, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65. doi:10.1038/nature08821.
  • Chopyk DM, Grakoui A. Contribution of the intestinal microbiome and gut barrier to hepatic disorders. Gastroenterology. 2020;159(3):849–863. doi:10.1053/j.gastro.2020.04.077.
  • Kummen M, Hov JR. The gut microbial influence on cholestatic liver disease. Liver Int. 2019;39(7):1186–1196. doi:10.1111/liv.14153.
  • Li Y, Tang RQ, Leung PSC, Gershwin ME, Ma X. Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases. Autoimmun Rev. 2017;16(9):885–896. doi:10.1016/j.autrev.2017.07.002.
  • Tang RQ, Wei YR, Li YM, Chen WH, Chen HY, Wang QX, Yang F, Miao Q, Xiao X, Zhang H, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 2018;67(3):534–541. doi:10.1136/gutjnl-2016-313332.
  • Kummen M, Holm K, Anmarkrud JA, Nygard S, Vesterhus M, Hoivik ML, Trøseid M, Marschall H-U, Schrumpf E, Moum B, et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut. 2017;66(4):611–619. doi:10.1136/gutjnl-2015-310500.
  • Dhillon AK, Kummen M, Troseid M, Akra S, Liaskou E, Moum B, Vesterhus M, Karlsen TH, Seljeflot I, Hov JR, et al. Circulating markers of gut barrier function associated with disease severity in primary sclerosing cholangitis. Liver Int. 2019;39(2):371–381. doi:10.1111/liv.13979.
  • Balmer ML, Slack E, de Gottardi A, Lawson MAE, Hapfelmeier S, Miele L, Grieco A, Van Vlierberghe H, Fahrner R, Patuto N, et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med. 2014;6(237):237ra66. doi:10.1126/scitranslmed.3008618.
  • Sabino J, Vieira-Silva S, Machiels K, Joossens M, Falony G, Ballet V, Ferrante M, Van Assche G, Van der Merwe S, Vermeire S, et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut. 2016;65(10):1681–1689. doi:10.1136/gutjnl-2015-311004.
  • Rossen NG, Fuentes S, Boonstra K, D’Haens GR, Heilig HG, Zoetendal EG, de Vos WM, Ponsioen CY. The mucosa-associated microbiota of psc patients is characterized by low diversity and low abundance of uncultured clostridiales II. Journal of Crohns & Colitis. 2015;9(4):342–348. doi:10.1093/ecco-jcc/jju023.
  • Zhan QT, Qi XC, Weng RP, Xi FF, Chen Y, Wang YY, Hu W, Zhao BH, Luo Q. Alterations of the human gut microbiota in intrahepatic cholestasis of pregnancy. Front Cell Infect Microbiol. 2021;11:635680. doi:10.3389/fcimb.2021.635680.
  • Ovadia C, Perdones-Montero A, Fan HM, Mullish BH, McDonald JAK, Papacleovoulou G, Wahlström A, Ståhlman M, Tsakmaki A, Clarke LCD, et al. Ursodeoxycholic acid enriches intestinal bile salt hydrolase-expressing bacteroidetes in cholestatic pregnancy. Sci Rep. 2020;10(1):3895. doi:10.1038/s41598-019-56089-4.
  • Hourigan SK, Moutinho TJ, Berenz A, Papin J, Guha P, Bangiolo L, Oliphant S, Provenzano M, Baveja R, Baker R, et al. Gram-negative microbiota blooms in premature twins discordant for parenteral nutrition-associated cholestasis. J Pediatr Gastroenterol Nutr. 2020;70(5):640–644. doi:10.1097/MPG.0000000000002617.
  • Quraishi MN, Acharjee A, Beggs AD, Horniblow R, Tselepis C, Gkoutos G, Ghosh S, Rossiter AE, Loman N, van Schaik W, et al. A pilot integrative analysis of colonic gene expression, gut microbiota, and immune infiltration in primary sclerosing cholangitis-inflammatory bowel disease: association of disease with bile acid pathways. J Crohns Colitis. 2020;14(7):935–947. doi:10.1093/ecco-jcc/jjaa021.
  • Vieira-Silva S, Sabino J, Valles-Colomer M, Falony G, Kathagen G, Caenepeel C, Cleynen I, van der Merwe S, Vermeire S, Raes J, et al. Quantitative microbiome profiling disentangles inflammation- and bile duct obstruction-associated microbiota alterations across PSC/IBD diagnoses. Nat Microbiol. 2019;4(11):1826–1831. doi:10.1038/s41564-019-0483-9.
  • Jiang B, Yuan G, Wu J, Wu Q, Li L, Jiang P. Prevotella copri ameliorates cholestasis and liver fibrosis in primary sclerosing cholangitis by enhancing the FXR signalling pathway. Biochim Biophys Acta Mol Basis Dis. 2022;1868(3):166320. doi:10.1016/j.bbadis.2021.166320.
  • Juanola O, Hassan M, Kumar P, Yilmaz B, Keller I, Simillion C, Engelmann C, Tacke F, Dufour JF, De Gottardi A, et al. Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns. Gut Microbes. 2021;13(1):1-20. doi:10.1080/19490976.2021.1911534.
  • Guo C, Li Y, Wang P, Li Y, Qiu C, Li M, Wang D, Zhao R, Li D, Wang Y, et al. Alterations of gut microbiota in cholestatic infants and their correlation with hepatic function. Front Microbiol. 2018;9:2682. doi:10.3389/fmicb.2018.02682.
  • Lee J-Y, Arai H, Nakamura Y, Fukiya S, Wada M, Yokota A. Contribution of the 7β-hydroxysteroid dehydrogenase from Ruminococcus gnavus N53 to ursodeoxycholic acid formation in the human colon. J Lipid Res. 2013;54(11):3062–3069. doi:10.1194/jlr.M039834.
  • Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. 2018;18(2):71–87. doi:10.3727/105221618X15156018385515.
  • Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol. 2017;101(1):47–64. doi:10.1007/s00253-016-8006-6.
  • Li RM, Andreu-Sanchez S, Kuipers F, Fu JY. Gut microbiome and bile acids in obesity-related diseases. Best Pract Res Clin Endocrinol Metab. 2021;35(3):101493. doi:10.1016/j.beem.2021.101493.
  • Biagioli M, Carino A. Signaling from Intestine to the host: how bile acids regulate intestinal and liver immunity. Handb Exp Pharmacol. 2019;256:95-108. doi:10.1007/164_2019_225.
  • Slijepcevic D, van de Graaf SFJ. van de Graaf SFJ. Bile acid uptake transporters as Targets for therapy. Dig Dis. 2017;35(3):251–258. doi:10.1159/000450983.
  • Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24(1):41–50. doi:10.1016/j.cmet.2016.05.005.
  • Y-JY W, Sheng L. Regulation of bile acid receptor activity. Liver Res. 2018;2(4):180–185. doi:10.1016/j.livres.2018.09.008.
  • Jiang CT, Xie C, Li F, Zhang LM, Nichols RG, Krausz KW, Cai J, Qi Y, Fang -Z-Z, Takahashi S, et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest. 2015;125(1):386–402. doi:10.1172/JCI76738.
  • Modica S, Petruzzelli M, Bellafante E, Murzilli S, Salvatore L, Celli N, Di Tullio G, Palasciano G, Moustafa T, Halilbasic E, et al. Selective activation of nuclear bile acid receptor fxr in the intestine protects mice against cholestasis. Gastroenterology. 2012;142(2):355-65.e1-4. doi:10.1053/j.gastro.2011.10.028.
  • Malhi H, Camilleri M. Modulating bile acid pathways and TGR5 receptors for treating liver and GI diseases. Curr Opin Pharmacol. 2017;37:80–86. doi:10.1016/j.coph.2017.09.008.
  • Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009;89(1):147–191. doi:10.1152/physrev.00010.2008.
  • Keitel V, Dröge C, Häussinger D. Targeting FXR in Cholestasis. Handb Exp Pharmacol. 2019;256:299–324.
  • Zollner G, Trauner M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol. 2009;156(1):7-27. doi:10.1111/j.1476-5381.2008.00030.x.
  • Perino A, Schoonjans K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci. 2015;36(12):847–857. doi:10.1016/j.tips.2015.08.002.
  • Duboc H, Tache Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis. 2014;46(4):302–312. doi:10.1016/j.dld.2013.10.021.
  • Merlen G, Kahale N, Ursic-Bedoya J, Bidault-Jourdainne V, Simerabet H, Doignon I, Tanfin Z, Garcin I, Péan N, Gautherot J, et al. TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function. Gut. 2020;69(1):146–157. doi:10.1136/gutjnl-2018-316975.
  • Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, Deutschmann K, Höhne J, Liaskou E, Hov JR, Karlsen TH, et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J Hepatol. 2021;75(3):634–646. doi:10.1016/j.jhep.2021.03.029.
  • Klindt C, Reich M, Hellwig B, Stindt J, Rahnenführer J, Hengstler JG, Xiong L. The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signaling in liver. Cells. 2019;9(1):8. doi:10.3390/cells9010008.
  • Bidault-Jourdainne V, Merlen G, Glénisson M, Doignon I, Garcin I, Péan N, Boisgard R, Ursic-Bedoya J, Serino M, Ullmer C, et al. TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload. JHEP Rep. 2021;3(2):100214. doi:10.1016/j.jhepr.2020.100214.
  • Deutschmann K, Reich M, Klindt C, Droge C, Spomer L, Haussinger D, Keitel V. Bile acid receptors in the biliary tree: TGR5 in physiology and disease. Biochim Biophys Acta Mol Basis Dis. 2018;1864(4):1319–1325. doi:10.1016/j.bbadis.2017.08.021.
  • Keitel V, Häussinger D. Role of TGR5 (GPBAR1) in liver disease. Semin Liver Dis. 2018;38(4):333–339. doi:10.1055/s-0038-1669940.
  • Yang H, Luo F, Wei Y, Jiao Y, Qian J, Chen S, Gong Y, Tang L. TGR5 protects against cholestatic liver disease via suppressing the NF-κB pathway and activating the Nrf2/HO-1 pathway. Ann Transl Med. 2021;9(14):1158. doi:10.21037/atm-21-2631.
  • Rao J, Yang C, Yang S, Lu H, Hu Y, Lu L, Cheng F, Wang X. Deficiency of TGR5 exacerbates immune-mediated cholestatic hepatic injury by stabilizing the β-catenin destruction complex. Int Immunol. 2020;32(5):321–334. doi:10.1093/intimm/dxaa002.
  • Keitel V, Reich M, Häussinger D. TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis? Clin Rev Allergy Immunol. 2015;48(2–3):218–225. doi:10.1007/s12016-014-8443-x.
  • Gruner N, Mattner J, Bagnato VS, Romero MP. Bile acids and microbiota: multifaceted and versatile regulators of the liver-gut axis. Int J Mol Sci. 2021;23(1):22. doi:10.3390/ijms23010022.
  • Horackova S, Plockova M, Demnerova K. Importance of microbial defence systems to bile salts and mechanisms of serum cholesterol reduction. Biotechnol Adv. 2018;36(3):682–690. doi:10.1016/j.biotechadv.2017.12.005.
  • Long SL, Gahan CGM, Joyce SA. Interactions between gut bacteria and bile in health and disease. Mol Aspects Med. 2017;56:54–65. doi:10.1016/j.mam.2017.06.002.
  • Ren SJ, Zhou YP, Xuan RR. Research progress in the role of gut microbiota and its metabolites in intrahepatic cholestasis of pregnancy. Expert Rev Gastroenterol Hepatol. 2021;15(12):1361–1366. doi:10.1080/17474124.2021.2011211.
  • Ovadia C, Perdones-Montero A, Spagou K, Smith A, Sarafian MH, Gomez-Romero M, Bellafante E, Clarke LCD, Sadiq F, Nikolova V, et al. Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis. Hepatology. 2019;70(1):276–293. doi:10.1002/hep.30661.
  • Fan HM, Mitchell AL, Williamson C. Metabolic impact of bile acids in gestation. Eur J Endocrinol. 2021;184(3):R69–R83. doi:10.1530/EJE-20-1101.
  • Zhan K, Zheng H, Li JQ, Wu HM, Qin SM, Luo L, Huang SG. Gut microbiota-bile acid crosstalk in diarrhea-irritable bowel syndrome. In: Biomed research international. 2020;2020:3828249. doi:10.1155/2020/3828249.
  • Wu LW, Feng J, Li JJ, Yu Q, Ji J, Wu JY, Dai WQ, Guo CY. The gut microbiome-bile acid axis in hepatocarcinogenesis. Biomedicine & Pharmacotherapy. 2021;133:111036. doi:10.1016/j.biopha.2020.111036.
  • Molinero N, Ruiz L, Sanchez B, Margolles A. Intestinal bacteria interplay with bile and cholesterol metabolism: implications on host physiology. Front Physiol. 2019;10:10. doi:10.3389/fphys.2019.00010.
  • Behr C, Slopianka M, Haake V, Strauss V, Sperber S, Kamp H, Walk T, Beekmann K, Rietjens IMCM, van Ravenzwaay B, et al. Analysis of metabolome changes in the bile acid pool in feces and plasma of antibiotic-treated rats. Toxicol Appl Pharmacol. 2019;363:79–87. doi:10.1016/j.taap.2018.11.012.
  • Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyötyläinen T, Orešič M, Bäckhed F, 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(2):225–235. doi:10.1016/j.cmet.2013.01.003.
  • Li F, Jiang C, Krausz KW, Li Y, Albert I, Hao H, Fabre KM, Mitchell JB, Patterson AD, Gonzalez FJ, et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun. 2013;4(1):2384. doi:10.1038/ncomms3384.
  • Peck SC, Denger K, Burrichter A, Irwin SM, Balskus EP, Schleheck D. A glycyl radical enzyme enables hydrogen sulfide production by the human intestinal bacterium. Proc Natl Acad Sci U S A 2019; 116:3171–3176.
  • Hu H, Shao W, Liu Q, Liu N, Wang Q, Xu J, Zhang X, Weng Z, Lu Q, Jiao L, et al. Gut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion. Nat Commun. 2022;13(1):252. doi:10.1038/s41467-021-27758-8.
  • Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72(1):137–174. doi:10.1146/annurev.biochem.72.121801.161712.
  • Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther. 2022;237:108238. doi:10.1016/j.pharmthera.2022.108238.
  • Chiang JYL. Negative feedback regulation of bile acid metabolism: impact on liver metabolism and diseases. Hepatol (Baltimore, Md). 2015;62(4):1315–1317. doi:10.1002/hep.27964.
  • Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17(13):1581–1591. doi:10.1101/gad.1083503.
  • Y-f N, Hu J, X- H Y. Cross-talk between bile acids and intestinal microbiota in host metabolism and health. J Zhejiang Univ Sci B. 2015;16(6):436–446. doi:10.1631/jzus.B1400327.
  • Kim I, Ahn SH, Inagaki T, Choi M, Ito S, Guo GL, Kliewer SA, Gonzalez FJ. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007;48:2664–2672. doi:10.1194/jlr.M700330-JLR200.
  • Coppola CP, Gosche JR, Arrese M, Ancowitz B, Madsen J, Vanderhoof J, SHNEIDER B. Molecular analysis of the adaptive response of intestinal bile acid transport after ileal resection in the rat. Gastroenterology. 1998;115(5):1172–1178. doi:10.1016/S0016-5085(98)70088-5.
  • Sinha J, Chen F, Miloh T, Burns RC, Yu Z, Shneider BL. beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G996-G1003. doi:10.1152/ajpgi.90343.2008.
  • Begley M, Gahan CGM, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29(4):625–651. doi:10.1016/j.femsre.2004.09.003.
  • Heuman DM, Bajaj RS, Lin Q. Adsorption of mixtures of bile salt taurine conjugates to lecithin-cholesterol membranes: implications for bile salt toxicity and cytoprotection. J Lipid Res. 1996;37(3):562–573. doi:10.1016/S0022-2275(20)37599-4.
  • Winston JA, Theriot CM. Diversification of host bile acids by members of the gut microbiota. Gut Microbes. 2020;11(2):158–171. doi:10.1080/19490976.2019.1674124.
  • Cremers CM, Knoefler D, Vitvitsky V, Banerjee R, Jakob U. Bile salts act as effective protein-unfolding agents and instigators of disulfide stress in vivo. Proc Natl Acad Sci U S A. 2014;111(16):E1610–E9. doi:10.1073/pnas.1401941111.
  • Devkota S, Chang EB. Interactions between diet, bile acid metabolism, gut microbiota, and inflammatory bowel diseases. Dig Dis. 2015;33(3):351–356. doi:10.1159/000371687.
  • Gahan CGM, Hill C, Sendi P, Linnér A, Thulin P, Linder A, Treutiger C-J, Norrby-Teglund A. Listeria monocytogenes: survival and adaptation in the gastrointestinal tract. Front Cell Infect Microbiol. 2014;4:4. doi:10.3389/fcimb.2014.00004.
  • Islam K, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, Ogura Y, Hayashi T, Yokota A. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141(5):1773–1781. doi:10.1053/j.gastro.2011.07.046.
  • Kakiyama G, Pandak WM, Gillevet PM, Hylemon PB, Heuman DM, Daita K, Takei H, Muto A, Nittono H, Ridlon JM, et al. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol. 2013;58(5):949–955. doi:10.1016/j.jhep.2013.01.003.
  • Watanabe M, Fukiya S, Yokota A. Comprehensive evaluation of the bactericidal activities of free bile acids in the large intestine of humans and rodents. J Lipid Res. 2017;58(6):1143–1152. doi:10.1194/jlr.M075143.
  • Kurdi P, Kawanishi K, Mizutani K, Yokota A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J Bacteriol. 2006;188(5):1979–1986. doi:10.1128/JB.188.5.1979-1986.2006.
  • Inagaki T, Moschetta A, Lee YK, Peng L, Zhao GX, Downes M, Yu RT, Shelton JM, Richardson JA, Repa JJ, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(10):3920-5. doi:10.1073/pnas.0509592103.
  • Parséus A, Sommer N, Sommer F, Caesar R, Molinaro A, Ståhlman M, Greiner TU, Perkins R, Bäckhed F. Microbiota-induced obesity requires farnesoid X receptor. Gut. 2017;66(3):429–437. doi:10.1136/gutjnl-2015-310283.
  • D’Aldebert E, Biyeyeme Bi Mve M-J, Mergey M, Wendum D, Firrincieli D, Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. Gastroenterology. 2009;136(4):1435–1443. doi:10.1053/j.gastro.2008.12.040.
  • Choi SB, Lew LC, Yeo SK, Parvathy SN, Liong MT. Probiotics and the BSH-related cholesterol lowering mechanism: a Jekyll and Hyde scenario. Crit Rev Biotechnol. 2015;35(3):392–401. doi:10.3109/07388551.2014.889077.
  • Tanaka H, Doesburg K, Iwasaki T, Mierau I. Screening of lactic acid bacteria for bile salt hydrolase activity. J Dairy Sci. 1999;82(12):2530–2535. doi:10.3168/jds.S0022-0302(99)75506-2.
  • Degirolamo C, Rainaldi S, Bovenga F, Murzilli S, Moschetta A. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the Fxr-Fgf15 axis in mice. Cell Rep. 2014;7(1):12–18. doi:10.1016/j.celrep.2014.02.032.
  • Martoni CJ, Labbe A, Ganopolsky JG, Prakash S, Jones ML. Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242. Reuteri NCIMB 30242. Gut Microbes. 2015;6(1):57–65. doi:10.1080/19490976.2015.1005474.
  • Zhang Z, Zhou H, Zhou XH, Sun JZ, Liang X, Lv YY, Bai L, Zhang J, Gong P, Liu T, et al. Lactobacillus casei YRL577 ameliorates markers of non-alcoholic fatty liver and alters expression of genes within the intestinal bile acid pathway. Br J Nutr. 2021;125(5):521–529. doi:10.1017/S0007114520003001.
  • Chen ML, Yi L, Zhang Y, Zhou X, Ran L, Yang J, Zhu JD, Zhang QY, Mi MT. Resveratrol attenuates Trimethylamine-N-Oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. Mbio. 2016;7(2):e02210-15. doi:10.1128/mBio.02210-15.
  • Koutnikova H, Genser B, Monteiro-Sepulveda M, Faurie JM, Rizkalla S, Schrezenmeir J, Clément K. Impact of bacterial probiotics on obesity, diabetes and non-alcoholic fatty liver disease related variables: a systematic review and meta-analysis of randomised controlled trials. Bmj Open. 2019;9(3):e017995. doi:10.1136/bmjopen-2017-017995.
  • Dhiman RK, Rana B, Agrawal S, Garg A, Chopra M, Thumburu KK, Khattri A, Malhotra S, Duseja A, Chawla YK. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology. 2014;147(6):1327-37.e3. doi:10.1053/j.gastro.2014.08.031.
  • Ren L, Song Q, Liu YH, Zhang LH, Hao ZM, Feng WK. Probiotic Lactobacillus rhamnosus GG prevents progesterone metabolite epiallaopregnanolone sulfate-induced hepatic bile acid accumulation and liver injury. Biochem Biophys Res Commun. 2019;520(1):67–72. doi:10.1016/j.bbrc.2019.09.103.
  • Lin Z, Wu J, Wang J, Levesque CL, Ma X. Dietary Lactobacillus reuteri prevent from inflammation mediated apoptosis of liver via improving intestinal microbiota and bile acid metabolism. Food Chem. 2023;404:134643. doi:10.1016/j.foodchem.2022.134643.
  • Liu H, Wang H, Zhang M, Abdulhay E. CT image features under reconstruction algorithm in analysis of the effect of probiotics combined with ursodeoxycholic acid in treatment of intrahepatic cholestasis of pregnancy. J Healthc Eng. 2021;2021:1709793. doi:10.1155/2021/1709793.
  • Vleggaar FR, Monkelbaan JF, van Erpecurn KJ. Probiotics in primary sclerosing cholangitis: a randomized placebo-controlled crossover pilot study. Eur J Gastroenterol Hepatol. 2008;20(7):688–692. doi:10.1097/MEG.0b013e3282f5197e.