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Abstract: Over the past decade, there has been increasing attention on the interaction between microbiota and bile acid metabolism. bile acids are not only involved in the metabolism of nutrients, but are also important in signal transduction for the regulation of host physiological activities. Microbial-regulated bile acid metabolism has been proven to affect many diseases, but there have not been many studies of disease regulation by microbial receptor signaling pathways. This review considers findings of recent research on the core roles of farnesoid X receptor (FXR), G protein-coupled bile acid receptor (TGR5), and vitamin D receptor (VDR) signaling pathways in microbial–host interactions in health and disease. Studying the relationship between these pathways can help us understand the pathogenesis of human diseases, and lead to new solutions for their treatments.

肠道微生物调节疾病中胆汁酸代谢相关的信号通路

[1]Alexeev EE, Lanis JM, Kao DJ, et al., 2018. Microbiota-derived indole metabolites promote human and murine intestinal homeostasis through regulation of interleukin-10 receptor. Am J Pathol, 188(5):1183-1194.

[2]Alnouti Y, 2009. Bile acid sulfation: a pathway of bile acid elimination and detoxification. Toxicol Sci, 108(2):225-246.

[3]Ananthanarayanan M, Balasubramanian N, Makishima M, et al., 2001. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem, 276(31):28857-28865.

[4]Baggio LL, Drucker DJ, 2007. Biology of incretins: GLP-1 and GIP. Gastroenterology, 132(6):2131-2157.

[5]Begley M, Gahan CGM, Hill C, 2005. The interaction between bacteria and bile. FEMS Microbiol Rev, 29(4):625-651.

[6]Bustos AY, de Valdez GF, Fadda S, et al., 2018. New insights into bacterial bile resistance mechanisms: the role of bile salt hydrolase and its impact on human health. Food Res Int, 112:250-262.

[7]Cariello M, Piccinin E, Garcia-Irigoyen O, et al., 2017. Nuclear receptor FXR, bile acids and liver damage: introducing the progressive familial intrahepatic cholestasis with FXR mutations. Biochim Biophys Acta Mol Basis Dis, 1864(4):1308-1318.

[8]Cariou B, van Harmelen K, Duran-Sandoval D, et al., 2006. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem, 281(16):11039-11049.

[9]Carr RM, Reid AE, 2015. FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr Atheroscler Rep, 17(4):16.

[10]Cheng J, Fang ZZ, Kim JH, et al., 2014. Intestinal CYP3A4 protects against lithocholic acid-induced hepatotoxicity in intestine-specific VDR-deficient mice. J Lipid Res, 55(3):455-465.

[11]Degirolamo C, Modica S, Palasciano G, et al., 2011. Bile acids and colon cancer: solving the puzzle with nuclear receptors. Trends Mol Med, 17(10):564-572.

[12]Degirolamo C, Rainaldi S, Bovenga F, et al., 2014. Microbiota modification with probiotics induces hepatic bile acid synthesis via downregulation of the FXR-FGF15 axis in mice. Cell Rep, 7(1):12-18.

[13]Devkota S, Wang YW, Musch MW, et al., 2012. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in IL10^−/− mice. Nature, 487(7405):104-108.

[14]Duran-Sandoval D, Cariou B, Percevault F, et al., 2005. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition. J Biol Chem, 280(33):29971-29979.

[15]Enright EF, Joyce SA, Gahan CG, et al., 2017. Impact of gut microbiota-mediated bile acid metabolism on the solubilization capacity of bile salt micelles and drug solubility. Mol Pharm, 14(4):1251-1263.

[16]Espinosa A, Dardalhon V, Brauner S, et al., 2009. Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med, 206(8):1661-1671.

[17]Gadaleta RM, Oldenburg B, Willemsen EC, et al., 2011. Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine. Biochim Biophys Acta, 1812(8):851-858.

[18]Giorgetti G, Brandimarte G, Fabiocchi F, et al., 2015. Interactions between innate immunity, microbiota, and probiotics. J Immunol Res, 2015:501361.

[19]Gonzalez FJ, Jiang CT, Patterson AD, 2016. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology, 151(5):845-859.

[20]Hofmann AF, 1999. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med, 159(22):2647-2658.

[21]Hofmann AF, 2004. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity. Drug Metab Rev, 36(3-4):703-722.

[22]Hunt MC, Yang YZ, Eggertsen G, et al., 2000. The peroxisome proliferator-activated receptor α (PPARα) regulates bile acid biosynthesis. J Biol Chem, 275(37):28947-28953.

[23]Inagaki T, Choi M, Moschetta A, et al., 2005. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab, 2(4):217-225.

[24]Inagaki T, Moschetta A, Lee YK, et al., 2006. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA, 103(10):3920-3925.

[25]Islam KBMS, Fukiya S, Hagio M, et al., 2011. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology, 141(5):1773-1781.

[26]Jiang CT, Xie C, Li F, et al., 2015. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest, 125(1):386-402.

[27]Jin DP, Wu SP, Zhang YG, et al., 2015. Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal microbiome. Clin Ther, 37(5):996-1009.

[28]Jin LH, Fang ZP, Fan MJ, et al., 2019. Bile-ology: from bench to bedside. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 20(5):414-427.

[29]Joyce SA, MacSharry J, Casey PG, et al., 2014. Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut. Proc Natl Acad Sci USA, 111(20):7421-7426.

[30]Kakiyama G, Pandak WM, Gillevet PM, et al., 2013. Modulation of the fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol, 58(5):949-955.

[31]Kakiyama G, Hylemon PB, Zhou HP, et al., 2014. Colonic inflammation and secondary bile acids in alcoholic cirrhosis. Am J Physiol Gastrointest Liver Physiol, 306(11):G929-G937.

[32]Katsuma S, Hirasawa A, Tsujimoto G, 2005. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1. Biochem Biophys Res Commun, 329(1):386-390.

[33]Keitel V, Donner M, Winandy S, et al., 2008. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun, 372(1):78-84.

[34]Kundu S, Kumar S, Bajaj A, 2015. Cross-talk between bile acids and gastrointestinal tract for progression and development of cancer and its therapeutic implications. IUBMB Life, 67(7):514-523.

[35]Laverdure R, Mezouari A, Carson MA, et al., 2018. A role for methanogens and methane in the regulation of GLP-1. Endocrinol Diabetes Metab, 1(1):e00006.

[36]Lee WJ, Hase K, 2014. Gut microbiota-generated metabolites in animal health and disease. Nat Chem Biol, 10(6):416-424.

[37]Lee YS, Shin S, Shigihara T, et al., 2007. Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes, 56(6):1671-1679.

[38]Li TG, Chiang JY, 2014. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev, 66(4):948-983.

[39]Li-Hawkins J, Gåfvels M, Olin M, et al., 2002. Cholic acid mediates negative feedback regulation of bile acid synthesis in mice. J Clin Invest, 110(8):1191-1200.

[40]Liu Q, Shao WT, Zhang CL, et al., 2017. Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice. Environ Pollut, 226:268-276.

[41]Lu TT, Makishima M, Repa JJ, et al., 2000. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell, 6(3):507-515.

[42]Ma YJ, Huang YX, Yan LN, et al., 2013. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res, 30(5):1447-1457.

[43]Masubuchi N, Sugihara M, Sugita T, et al., 2016. Oxidative stress markers, secondary bile acids and sulfated bile acids classify the clinical liver injury type: promising diagnostic biomarkers for cholestasis. Chem Biol Interact, 255:83-91.

[44]Matsubara T, Li F, Gonzalez FJ, 2013. FXR signaling in the enterohepatic system. Mol Cell Endocrinol, 368(1-2):17-29.

[45]Modica S, Murzilli S, Salvatore L, et al., 2008. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res, 68(23):9589-9594.

[46]Mullish BH, Pechlivanis A, Barker GF, et al., 2018. Functional microbiomics: evaluation of gut microbiota-bile acid metabolism interactions in health and disease. Methods, 149:49-58.

[47]Neish AS, 2009. Microbes in gastrointestinal health and disease. Gastroenterology, 136(1):65-80.

[48]Nie YF, Jun HU, Yan XH, 2015. Cross-talk between bile acids and intestinal microbiota in host metabolism and health. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 16(6):436-446.

[49]Out C, Patankar JV, Doktorova M, et al., 2015. Gut microbiota inhibit Asbt-dependent intestinal bile acid reabsorption via Gata4. J Hepatol, 63(3):697-704.

[50]Pabst O, 2012. New concepts in the generation and functions of IgA. Nat Rev Immunol, 12(12):821-832.

[51]Pathak P, Xie C, Nichols RG, et al., 2018. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology, 68(4):1574-1588.

[52]Peng L, Piekos S, Guo GL, et al., 2016. Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver. Acta Pharm Sin B, 6(5):453-459.

[53]Pols TWH, Nomura M, Harach T, et al., 2011. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab, 14(6):747-757.

[54]Reijnders D, Goossens GH, Hermes GDA, et al., 2016. Effects of gut microbiota manipulation by antibiotics on host metabolism in obese humans: a randomized double-blind placebo-controlled trial. Cell Metab, 24(1):63-74.

[55]Ridlon JM, Kang DJ, Hylemon PB, 2006. Bile salt biotransformations by human intestinal bacteria. J Lipid Res, 47(2):241-259.

[56]Russell DW, 2003. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem, 72:137-174.

[57]Sayin SI, Wahlström A, Felin J, et al., 2013. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab, 17(2):225-235.

[58]Shehata MG, el Sohaimy SA, El-Sahn MA, et al., 2016. Screening of isolated potential probiotic lactic acid bacteria for cholesterol lowering property and bile salt hydrolase activity. Ann Agric Sci, 61(1):65-75.

[59]Sinclair P, Brennan DJ, le Roux CW, 2018. Gut adaptation after metabolic surgery and its influences on the brain, liver and cancer. Nat Rev Gastroenterol Hepatol, 15(10):606-624.

[60]Sonnenburg JL, Bäckhed F, 2016. Diet-microbiota interactions as moderators of human metabolism. Nature, 535(7610):56-64.

[61]Sun J, 2016. VDR/vitamin D receptor regulates autophagic activity through ATG16L1. Autophagy, 12(6):1057-1058.

[62]Sun J, 2017. The role of vitamin D and vitamin D receptors in colon cancer. Clin Transl Gastroenterol, 8(6):e103.

[63]Sung J, Kim S, Cabatbat JJT, et al., 2017. Global metabolic interaction network of the human gut microbiota for context-specific community-scale analysis. Nat Commun, 8:15393.

[64]Swann JR, Want EJ, Geier FM, et al., 2011. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci USA, 108(Suppl 1):4523-4530.

[65]Thaiss CA, Zmora N, Levy M, et al., 2016. The microbiome and innate immunity. Nature, 535(7610):65-74.

[66]Theriot CM, Bowman AA, Young VB, 2016. Antibiotic-induced alterations of the gut microbiota alter secondary bile acid production and allow for Clostridium difficile spore germination and outgrowth in the large intestine. mSphere, 1(1):e00045-15.

[67]Tremaroli V, Bäckhed F, 2012. Functional interactions between the gut microbiota and host metabolism. Nature, 489(7415):242-249.

[68]Vijayvargiya P, Camilleri M, Carlson P, et al., 2017. Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea. Aliment Pharmacol Ther, 46(6):581-588.

[69]Vítek L, Haluzík M, 2016. The role of bile acids in metabolic regulation. J Endocrinol, 228(3):R85-R96.

[70]Vogtmann E, Goedert JJ, 2016. Epidemiologic studies of the human microbiome and cancer. Br J Cancer, 114(3):237-242.

[71]Vrieze A, van Nood E, Holleman F, et al., 2012. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology, 143(4):913-916.

[72]Vrieze A, Out C, Fuentes S, et al., 2014. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol, 60(4):824-831.

[73]Wada K, Tanaka H, Maeda K, et al., 2009. Vitamin D receptor expression is associated with colon cancer in ulcerative colitis. Oncol Rep, 22(5):1021-1025.

[74]Wang J, Thingholm LB, Skiecevičienė J, et al., 2016. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet, 48(11):1396-1406.

[75]Wang YD, Chen WD, Wang MH, et al., 2008. Farnesoid X receptor antagonizes nuclear factor κB in hepatic inflammatory response. Hepatology, 48(5):1632-1643.

[76]Wang YD, Chen WD, Yu D, et al., 2011. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology, 54(4):1421-1432.

[77]Watanabe M, Houten SM, Mataki C, et al., 2006. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature, 439(7075):484-489.

[78]Wolfe A, Thomas A, Edwards G, et al., 2011. Increased activation of the Wnt/β-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther, 338(1):12-21.

[79]Woodhouse CA, Patel VC, Singanayagam A, et al., 2018. Review article: the gut microbiome as a therapeutic target in the pathogenesis and treatment of chronic liver disease. Aliment Pharmacol Ther, 47(2):192-202.

[80]Wu SP, Liao AP, Xia YL, et al., 2010. Vitamin D receptor negatively regulates bacterial-stimulated NF-κB activity in intestine. Am J Pathol, 177(2):686-697.

[81]Xie C, Jiang CT, Shi JM, et al., 2017. An intestinal farnesoid X receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes, 66(3):613-626.

[82]Yamada S, Takashina Y, Watanabe M, et al., 2018. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget, 9(11):9925-9939.

[83]https://doi.org/10.18632/oncotarget.24066

[84]Yamagata K, Daitoku H, Shimamoto Y, et al., 2004. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1. J Biol Chem, 279(22):23158-23165.

[85]Yang T, Owen JL, Lightfoot YL, et al., 2013. Microbiota impact on the epigenetic regulation of colorectal cancer. Trends Mol Med, 19(12):714-725.

[86]Zhang YQ, Lee FY, Barrera G, et al., 2006. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci USA, 103(4):1006-1011.

[87]Zimmer J, Lange B, Frick JS, et al., 2012. A vegan or vegetarian diet substantially alters the human colonic faecal microbiota. Eur J Clin Nutr, 66(1):53-60.