Towards the Understanding on the Physiological Functions of Bile Acids and Interactions with Gut Microbiota

doi:10.13560/j.cnki.biotech.bull.1985.2022-0931

Abstract

Abstract:

Bile acids（BAs）are produced from the metabolism of cholesterol. In the liver, cholesterol is converted into primary bile acids，and they are metabolized into secondary bile acids by gut microbiota when they reache the intestinal tract. Their homeostasis are maintained in the body through the enterohepatic circulation. The molecules of bile acids have both hydrophilic and lipophilic ends, which can play the role of detergent and help to dissolve and absorb dietary lipids and lipid-soluble vitamins. This also endows bile acids with certain antibacterial properties. The interaction between bile acids and gut microbiota is not only reflected in their own physiological functions of bile acids, but also in the regulations of the gut microbial composition and abundances in bile acid metabolism. Bile acids regulate glucose, lipid and energy metabolisms, and immune and inflammatory reactions by activating different receptor signal pathways. This article reviews the metabolic process of bile acids, and discusses how it regulates host physiological functions through FXR, TGR5 and other receptor signal pathways. It also provides references for maintaining animal health and promoting livestock and poultry production performance through scientifically and reasonably regulating gut microbiota and its metabolites.

Key words: bile acids, gut microbiota, physiological function, interaction

XIONG Shu-qi. Towards the Understanding on the Physiological Functions of Bile Acids and Interactions with Gut Microbiota[J]. Biotechnology Bulletin, 2023, 39(4): 187-200.

Figures/Tables 4

References 97

[1]	Wu JY, Wang K, Wang XM, et al. The role of the gut microbiome and its metabolites in metabolic diseases[J]. Protein Cell, 2021, 12(5): 360-373. doi: 10.1007/s13238-020-00814-7
[2]	Chiang JYL. Bile acid metabolism and signaling[J]. Compr Physiol, 2013, 3(3): 1191-1212. doi: 10.1002/cphy.c120023 pmid: 23897684
[3]	Zheng XJ, Chen TL, Jiang RQ, et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism[J]. Cell Metab, 2021, 33(4): 791-803.e7. doi: 10.1016/j.cmet.2020.11.017 pmid: 33338411
[4]	Jia W, Xie GX, Jia WP. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(2): 111-128. doi: 10.1038/nrgastro.2017.119 pmid: 29018272
[5]	Fuchs CD, Trauner M. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology[J]. Nat Rev Gastroenterol Hepatol, 2022, 19(7): 432-450. doi: 10.1038/s41575-021-00566-7 pmid: 35165436
[6]	Alrefai WA, Gill RK. Bile acid transporters: structure, function, regulation and pathophysiological implications[J]. Pharm Res, 2007, 24(10): 1803-1823. doi: 10.1007/s11095-007-9289-1 URL
[7]	Wahlström A, Sayin SI, Marschall HU, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism[J]. Cell Metab, 2016, 24(1): 41-50. doi: 10.1016/j.cmet.2016.05.005 pmid: 27320064
[8]	Swann JR, Want EJ, Geier FM, et al. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments[J]. Proc Natl Acad Sci USA, 2011, 108(Suppl 1): 4523-4530. doi: 10.1073/pnas.1006734107 URL
[9]	Jones BV, Begley M, Hill C, et al. Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome[J]. Proc Natl Acad Sci USA, 2008, 105(36): 13580-13585. doi: 10.1073/pnas.0804437105 pmid: 18757757
[10]	Song ZW, Cai YY, Lao XZ, et al. Taxonomic profiling and populational patterns of bacterial bile salt hydrolase(BSH)genes based on worldwide human gut microbiome[J]. Microbiome, 2019, 7(1): 9. doi: 10.1186/s40168-019-0628-3
[11]	White BA, Lipsky RL, Fricke RJ, et al. Bile acid induction specificity of 7 alpha-dehydroxylase activity in an intestinal Eubacterium species[J]. Steroids, 1980, 35(1): 103-109. pmid: 7376208
[12]	Funabashi M, Grove TL, Wang M, et al. A metabolic pathway for bile acid dehydroxylation by the gut microbiome[J]. Nature, 2020, 582(7813): 566-570. doi: 10.1038/s41586-020-2396-4
[13]	Eyssen H, de Pauw G, Stragier J, et al. Cooperative formation of Omega-muricholic acid by intestinal microorganisms[J]. Appl Environ Microbiol, 1983, 45(1): 141-147. doi: 10.1128/aem.45.1.141-147.1983 URL
[14]	Sacquet EC, Raibaud PM, Mejean C, et al. Bacterial formation of Omega-muricholic acid in rats[J]. Appl Environ Microbiol, 1979, 37(6): 1127-1131. doi: 10.1128/aem.37.6.1127-1131.1979 URL
[15]	Paik D, Yao LN, Zhang YC, et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites[J]. Nature, 2022, 603(7903): 907-912. doi: 10.1038/s41586-022-04480-z
[16]	Li W, Hang SY, Fang Y, et al. A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1[J]. Cell Host Microbe, 2021, 29(9): 1366-1377.e9. doi: 10.1016/j.chom.2021.07.013 URL
[17]	Noh DO, Gilliland SE. Influence of bile on cellular integrity and β-galactosidase activity of Lactobacillus acidophilus[J]. J Dairy Sci, 1993, 76(5): 1253-1259. pmid: 8505417
[18]	Kandell RL, Bernstein C. Bile salt/acid induction of DNA damage in bacterial and mammalian cells: implications for colon cancer[J]. Nutr Cancer, 1991, 16(3/4): 227-238. doi: 10.1080/01635589109514161 URL
[19]	Bernstein H, Payne CM, Bernstein C, et al. Activation of the promoters of genes associated with DNA damage, oxidative stress, ER stress and protein malfolding by the bile salt, deoxycholate[J]. Toxicol Lett, 1999, 108(1): 37-46. doi: 10.1016/s0378-4274(99)00113-7 pmid: 10472808
[20]	Sorg JA, Sonenshein AL. Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid[J]. J Bacteriol, 2010, 192(19): 4983-4990. doi: 10.1128/JB.00610-10 URL
[21]	Weingarden AR, Chen C, Bobr A, et al. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection[J]. Am J Physiol Gastrointest Liver Physiol, 2014, 306(4): G310-G319. doi: 10.1152/ajpgi.00282.2013 URL
[22]	Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor[J]. Proc Natl Acad Sci USA, 2006, 103(10): 3920-3925. doi: 10.1073/pnas.0509592103 pmid: 16473946
[23]	D'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, et al. Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium[J]. Gastroenterology, 2009, 136(4): 1435-1443. doi: 10.1053/j.gastro.2008.12.040 pmid: 19245866
[24]	Nie YF, Hu J, Yan XH. Cross-talk between bile acids and intestinal microbiota in host metabolism and health[J]. J Zhejiang Univ Sci B, 2015, 16(6): 436-446. doi: 10.1631/jzus.B1400327 URL
[25]	Ticho AL, Malhotra P, Dudeja PK, et al. Bile acid receptors and gastrointestinal functions[J]. Liver Res, 2019, 3(1): 31-39. doi: 10.1016/j.livres.2019.01.001 pmid: 32368358
[26]	Teodoro JS, Rolo AP, Palmeira CM. Hepatic FXR: key regulator of whole-body energy metabolism[J]. Trends Endocrinol Metab, 2011, 22(11): 458-466. doi: 10.1016/j.tem.2011.07.002 URL
[27]	Xu GR, Pan LX, Erickson SK, et al. Removal of the bile acid pool upregulates cholesterol 7alpha-hydroxylase by deactivating FXR in rabbits[J]. J Lipid Res, 2002, 43(1): 45-50. pmid: 11792721
[28]	Lu TT, Makishima M, Repa JJ, et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors[J]. Mol Cell, 2000, 6(3): 507-515. doi: 10.1016/s1097-2765(00)00050-2 pmid: 11030331
[29]	Goodwin B, Jones SA, Price RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis[J]. Mol Cell, 2000, 6(3): 517-526. doi: 10.1016/s1097-2765(00)00051-4 pmid: 11030332
[30]	Kerr TA, Saeki S, Schneider M, et al. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis[J]. Dev Cell, 2002, 2(6): 713-720. pmid: 12062084
[31]	Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis[J]. Cell Metab, 2005, 2(4): 217-225. doi: 10.1016/j.cmet.2005.09.001 pmid: 16213224
[32]	Chiang JYL. Bile acid regulation of gene expression: roles of nuclear hormone receptors[J]. Endocr Rev, 2002, 23(4): 443-463. doi: 10.1210/er.2000-0035 pmid: 12202460
[33]	Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model[J]. Nat Med, 2004, 10(12): 1352-1358. doi: 10.1038/nm1138 pmid: 15558057
[34]	Debose-Boyd RA, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond[J]. Trends Biochem Sci, 2018, 43(5): 358-368. doi: 10.1016/j.tibs.2018.01.005 URL
[35]	Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c[J]. J Clin Invest, 2004, 113(10): 1408-1418. doi: 10.1172/JCI21025 pmid: 15146238
[36]	Duran-Sandoval D, Cariou B, Percevault F, et al. The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition[J]. J Biol Chem, 2005, 280(33): 29971-29979. doi: 10.1074/jbc.M501931200 pmid: 15899888
[37]	Li TG, Chiang JYL. Regulation of bile acid and cholesterol metabolism by PPARs[J]. PPAR Res, 2009, 2009: 501739.
[38]	Lambert G, Amar MJA, Guo G, et al. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis[J]. J Biol Chem, 2003, 278(4): 2563-2570. doi: 10.1074/jbc.M209525200 pmid: 12421815
[39]	Zhang YQ, Yin LY, Anderson J, et al. Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia[J]. J Biol Chem, 2010, 285(5): 3035-3043. doi: 10.1074/jbc.M109.083899 pmid: 19996107
[40]	Kast HR, Nguyen CM, Sinal CJ, et al. Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids[J]. Mol Endocrinol, 2001, 15(10): 1720-1728. pmid: 11579204
[41]	Jiang XC, Jin WJ, Hussain MM. The impact of phospholipid transfer protein(PLTP)on lipoprotein metabolism[J]. Nutr Metab(Lond), 2012, 9(1): 75.
[42]	Ma K, Saha PK, Chan L, et al. Farnesoid X receptor is essential for normal glucose homeostasis[J]. J Clin Invest, 2006, 116(4): 1102-1109. doi: 10.1172/JCI25604 pmid: 16557297
[43]	Shapiro H, Kolodziejczyk AA, Halstuch D, et al. Bile acids in glucose metabolism in health and disease[J]. J Exp Med, 2018, 215(2): 383-396. doi: 10.1084/jem.20171965 URL
[44]	Yamagata K, Daitoku H, Shimamoto Y, et al. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1[J]. J Biol Chem, 2004, 279(22): 23158-23165. doi: 10.1074/jbc.M314322200 pmid: 15047713
[45]	Zhang YQ, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice[J]. Proc Natl Acad Sci USA, 2006, 103(4): 1006-1011. doi: 10.1073/pnas.0506982103 pmid: 16410358
[46]	Fu L, John LM, Adams SH, et al. Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes[J]. Endocrinology, 2004, 145(6): 2594-2603. doi: 10.1210/en.2003-1671 pmid: 14976145
[47]	Kir S, Beddow SA, Samuel VT, et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis[J]. Science, 2011, 331(6024): 1621-1624. doi: 10.1126/science.1198363 pmid: 21436455
[48]	Trabelsi MS, Daoudi M, Prawitt J, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells[J]. Nat Commun, 2015, 6: 7629. doi: 10.1038/ncomms8629
[49]	Biagioli M, Carino A. Signaling from intestine to the host: how bile acids regulate intestinal and liver immunity[J]. Handb Exp Pharmacol, 2019, 256: 95-108. doi: 10.1007/164_2019_225 pmid: 31119464
[50]	Vavassori P, Mencarelli A, Renga B, et al. The bile acid receptor FXR is a modulator of intestinal innate immunity[J]. J Immunol, 2009, 183(10): 6251-6261. doi: 10.4049/jimmunol.0803978 pmid: 19864602
[51]	Gadaleta RM, van Erpecum KJ, Oldenburg B, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease[J]. Gut, 2011, 60(4): 463-472. doi: 10.1136/gut.2010.212159 pmid: 21242261
[52]	Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids(M-BAR)[J]. Biochem Biophys Res Commun, 2002, 298(5): 714-719. doi: 10.1016/S0006-291X(02)02550-0 URL
[53]	Xia XF, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes[J]. World J Gastroenterol, 2006, 12(22): 3553-3563. doi: 10.3748/wjg.v12.i22.3553 URL
[54]	Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation[J]. Nature, 2006, 439(7075): 484-489. doi: 10.1038/nature04330
[55]	Li MC, Wang SL, Li YT, et al. Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice[J]. Nat Commun, 2022, 13(1): 2060. doi: 10.1038/s41467-022-29589-7 pmid: 35440584
[56]	Hodge RJ, Nunez DJ. Therapeutic potential of takeda-G-protein-receptor-5(TGR5)agonists. hope or hype?[J]. Diabetes Obes Metab, 2016, 18(5): 439-443. doi: 10.1111/dom.12636 pmid: 26818602
[57]	Thomas C, Gioiello A, Noriega L, et al. TGR5-mediated bile acid sensing controls glucose homeostasis[J]. Cell Metab, 2009, 10(3): 167-177. doi: 10.1016/j.cmet.2009.08.001 pmid: 19723493
[58]	Yanguas-Casás N, Barreda-Manso MA, Nieto-Sampedro M, et al. TUDCA: an agonist of the bile acid receptor GPBAR1/TGR5 with anti-inflammatory effects in microglial cells[J]. J Cell Physiol, 2017, 232(8): 2231-2245. doi: 10.1002/jcp.25742 pmid: 27987324
[59]	Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids[J]. J Biol Chem, 2003, 278(11): 9435-9440. doi: 10.1074/jbc.M209706200 pmid: 12524422
[60]	Keitel V, Donner M, Winandy S, et al. Expression and function of the bile acid receptor TGR5 in Kupffer cells[J]. Biochem Biophys Res Commun, 2008, 372(1): 78-84. doi: 10.1016/j.bbrc.2008.04.171 URL
[61]	Pols TWH, Nomura M, Harach T, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading[J]. Cell Metab, 2011, 14(6): 747-757. doi: 10.1016/j.cmet.2011.11.006 pmid: 22152303
[62]	Cook J, Hagemann T. Tumour-associated macrophages and cancer[J]. Curr Opin Pharmacol, 2013, 13(4): 595-601. doi: 10.1016/j.coph.2013.05.017 pmid: 23773801
[63]	Priyanka S, Medhamurthy R. Characterization of cAMP/PKA/CREB signaling cascade in the bonnet monkey corpus luteum: expressions of inhibin-alpha and StAR during different functional status[J]. Mol Hum Reprod, 2007, 13(6): 381-390. pmid: 17430983
[64]	Sorrentino G, Perino A, Yildiz E, et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration[J]. Gastroenterology, 2020, 159(3): 956-968.e8. doi: S0016-5085(20)34739-9 pmid: 32485177
[65]	Borgstroem B. Influence of bile salt, ph, and time on the action of pancreatic lipase; physiological implications[J]. J Lipid Res, 1964, 5: 522-531. pmid: 14221095
[66]	Gottlieb A, Bechmann L, Canbay A. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids[J]. Ann Hepatol, 2018, 17(3): 340-341. doi: 10.5604/01.3001.0011.7378 pmid: 29735794
[67]	Schreuder TCMA, Marsman HA, Lenicek M, et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance[J]. Am J Physiol Gastrointest Liver Physiol, 2010, 298(3): G440-G445. doi: 10.1152/ajpgi.00322.2009 URL
[68]	Beuers U, Trauner M, Jansen P, et al. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond[J]. J Hepatol, 2015, 62(1 Suppl): S25-S37. doi: 10.1016/j.jhep.2015.02.023 URL
[69]	Solá S, Amaral JD, Aranha MM, et al. Modulation of hepatocyte apoptosis: cross-talk between bile acids and nuclear steroid receptors[J]. Curr Med Chem, 2006, 13(25): 3039-3051. pmid: 17073645
[70]	Ratziu V, de Ledinghen V, Oberti F, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis[J]. J Hepatol, 2011, 54(5): 1011-1019. doi: 10.1016/j.jhep.2010.08.030 pmid: 21145828
[71]	Wagner M, Zollner G, Trauner M. Nuclear receptors in liver disease[J]. Hepatology, 2011, 53(3): 1023-1034. doi: 10.1002/hep.24148 pmid: 21319202
[72]	Degirolamo C, Modica S, Vacca M, et al. Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation[J]. Hepatology, 2015, 61(1): 161-170. doi: 10.1002/hep.27274 pmid: 24954587
[73]	Mertens KL, Kalsbeek A, Soeters MR, et al. Bile acid signaling pathways from the enterohepatic circulation to the central nervous system[J]. Front Neurosci, 2017, 11: 617. doi: 10.3389/fnins.2017.00617 URL
[74]	McMillin M, DeMorrow S. Effects of bile acids on neurological function and disease[J]. FASEB J, 2016, 30(11): 3658-3668. pmid: 27468758
[75]	McMillin M, Frampton G, Tobin R, et al. TGR5 signaling reduces neuroinflammation during hepatic encephalopathy[J]. J Neurochem, 2015, 135(3): 565-576. doi: 10.1111/jnc.13243 pmid: 26179031
[76]	Huang F, Wang TT, Lan YY, et al. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior[J]. Front Behav Neurosci, 2015, 9: 70. doi: 10.3389/fnbeh.2015.00070 pmid: 25870546
[77]	Xie MH, Holcomb I, Deuel B, et al. FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4[J]. Cytokine, 1999, 11(10): 729-735. doi: 10.1006/cyto.1999.0485 pmid: 10525310
[78]	Marcelin G, Jo YH, Li XS, et al. Central action of FGF19 reduces hypothalamic AGRP/NPY neuron activity and improves glucose metabolism[J]. Mol Metab, 2013, 3(1): 19-28. doi: 10.1016/j.molmet.2013.10.002 URL
[79]	Morton GJ, Matsen ME, Bracy DP, et al. FGF19 action in the brain induces insulin-independent glucose lowering[J]. J Clin Invest, 2013, 123(11): 4799-4808. doi: 10.1172/JCI70710 URL
[80]	Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells[J]. Nature, 2013, 504(7480): 446-450. doi: 10.1038/nature12721
[81]	Arpaia N, Campbell C, Fan XY, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation[J]. Nature, 2013, 504(7480): 451-455. doi: 10.1038/nature12726
[82]	Sefik E, Geva-Zatorsky N, Oh S, et al. MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of RORγ⁺ regulatory T cells[J]. Science, 2015, 349(6251): 993-997. doi: 10.1126/science.aaa9420 pmid: 26272906
[83]	Song XY, Sun XM, Oh SF, et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis[J]. Nature, 2020, 577(7790): 410-415. doi: 10.1038/s41586-019-1865-0
[84]	Makishima M, Lu TT, Xie W, et al. Vitamin D receptor as an intestinal bile acid sensor[J]. Science, 2002, 296(5571): 1313-1316. doi: 10.1126/science.1070477 pmid: 12016314
[85]	Adachi R, Honma Y, Masuno H, et al. Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative[J]. J Lipid Res, 2005, 46(1): 46-57. doi: 10.1194/jlr.M400294-JLR200 pmid: 15489543
[86]	Ishizawa M, Matsunawa M, Adachi R, et al. Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia[J]. J Lipid Res, 2008, 49(4): 763-772. doi: 10.1194/jlr.M700293-JLR200 pmid: 18180267
[87]	Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity[J]. Proc Natl Acad Sci USA, 2001, 98(6): 3369-3374. doi: 10.1073/pnas.051551698 pmid: 11248085
[88]	Shah YM, Ma XC, Morimura K, et al. Pregnane X receptor activation ameliorates DSS-induced inflammatory bowel disease via inhibition of NF-kappaB target gene expression[J]. Am J Physiol Gastrointest Liver Physiol, 2007, 292(4): G1114-G1122. doi: 10.1152/ajpgi.00528.2006 URL
[89]	Campbell C, McKenney PT, Konstantinovsky D, et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells[J]. Nature, 2020, 581(7809): 475-479. doi: 10.1038/s41586-020-2193-0
[90]	Hang SY, Paik D, Yao LN, et al. Bile acid metabolites control TH17 and Treg cell differentiation[J]. Nature, 2019, 576(7785): 143-148. doi: 10.1038/s41586-019-1785-z
[91]	Floreani A, Mangini C. Primary biliary cholangitis: old and novel therapy[J]. Eur J Intern Med, 2018, 47: 1-5. doi: S0953-6205(17)30264-9 pmid: 28669591
[92]	Trauner M, Nevens F, Shiffman ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study[J]. Lancet Gastroenterol Hepatol, 2019, 4(6): 445-453. doi: 10.1016/S2468-1253(19)30094-9 URL
[93]	Pearson T, Caporaso JG, Yellowhair M, et al. Effects of ursodeoxycholic acid on the gut microbiome and colorectal adenoma development[J]. Cancer Med, 2019, 8(2): 617-628. doi: 10.1002/cam4.2019.8.issue-2 URL
[94]	Ge XK, Wang AA, Ying ZX, et al. Effects of diets with different energy and bile acids levels on growth performance and lipid metabolism in broilers[J]. Poult Sci, 2019, 98(2): 887-895. doi: 10.3382/ps/pey434 URL
[95]	Udomprasert P, Rukkwamsuk T. Effect of an exogenous emulsifier on growth performance in weanling pigs[J]. Kasetsart Journal, 2006, 40(3): p.652-656.
[96]	Jain AK, Stoll B, Burrin DG, et al. Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs[J]. Am J Physiol Gastrointest Liver Physiol, 2012, 302(2): G218-G224. doi: 10.1152/ajpgi.00280.2011 URL
[97]	Wu XY, Yin SN, Cheng CS, et al. Inclusion of soluble fiber during gestation regulates gut microbiota, improves bile acid homeostasis, and enhances the reproductive performance of sows[J]. Front Vet Sci, 2021, 8: 756910. doi: 10.3389/fvets.2021.756910 URL

物种Species	初级胆汁酸Primary bile acids		次级胆汁酸Secondary bile acids
物种Species	游离型Free	结合型Conjugated	游离型Free	结合型Conjugated
人	胆酸、鹅脱氧胆酸	甘氨胆酸、甘氨鹅脱氧胆酸	石胆酸、脱氧胆酸	甘氨石胆酸、甘氨脱氧胆酸
啮齿动物（鼠）	α-鼠胆酸、β-鼠胆酸、胆酸	牛磺α/β-鼠胆酸、牛磺胆酸	ω-鼠胆酸、熊脱氧胆酸、石胆酸	牛磺ω-鼠胆酸、牛磺熊脱氧胆酸、牛磺石胆酸
猪	猪胆酸	甘氨/牛磺猪胆酸	猪脱氧胆酸	甘氨/牛磺猪脱氧胆酸

物种Species	初级胆汁酸Primary bile acids		次级胆汁酸Secondary bile acids
物种Species	游离型Free	结合型Conjugated	游离型Free	结合型Conjugated
人	胆酸、鹅脱氧胆酸	甘氨胆酸、甘氨鹅脱氧胆酸	石胆酸、脱氧胆酸	甘氨石胆酸、甘氨脱氧胆酸
啮齿动物（鼠）	α-鼠胆酸、β-鼠胆酸、胆酸	牛磺α/β-鼠胆酸、牛磺胆酸	ω-鼠胆酸、熊脱氧胆酸、石胆酸	牛磺ω-鼠胆酸、牛磺熊脱氧胆酸、牛磺石胆酸
猪	猪胆酸	甘氨/牛磺猪胆酸	猪脱氧胆酸	甘氨/牛磺猪脱氧胆酸

受体Receptor	胆汁酸配体Ligand bile acids		表达组织 Expressive tissues	作用途径Functional pathways
受体Receptor	激活剂 Activators	拮抗剂Antagonists	表达组织 Expressive tissues	作用途径Functional pathways
FXR	CDCA、CA、T（G）CDCA、T（G）CA、LCA、DCA、HCAs	TαMC、TβMCA UDCA、isoDCA	肝脏	胆汁酸代谢	FXR—SHP-1—LRH-1—抑制CYP7A1
				胆汁酸代谢	FXR—IR-1—激活胆汁酸转运载体蛋白
				脂代谢	FXR—SHP—SREBP-1c—抑制脂肪酸合成酶
					FXR—PPARα—促进脂肪酸氧化代谢
					FXR—ApoCII—LPL—促进甘油三酯水解
					FXR—p-JNK—HNF4α—SRB1—促进HDL-C清除
				糖代谢	FXR—SHP—抑制糖异生基因
				糖代谢	FXR—LPK—抑制糖酵解
			肠道	胆汁酸代谢	FXR—FGF19/15—结合肝脏FGFR4/βKlotho—激活JNK途径—抑制CYP7A1
				糖代谢	FXR—FGF19/15—结合肝脏FGFR4/βKlotho—抑制肝脏糖异生基因
				糖代谢	FXR—抑制GLP-1分泌
			免疫细胞	炎症反应	FXR—抑制促炎细胞因子的分泌
TGR5	T（G）LCA、LCA、T（G）DCA、DCA、CDCA、T（G）CDCA、TCA、CA、UDCA、HCAs		棕色脂肪组织	能量代谢	TGR5—cAMP—Dio2—增强能量消耗
			骨骼肌	能量代谢	TGR5—cAMP—Dio2—增强能量消耗
			免疫细胞	免疫反应	TGR5—cAMP—抑制NF-kB信号通路—抑制促炎细胞因子
			肠道	糖代谢	TGR5—cAMP—促进GLP-1分泌
			肠道	肠上皮稳态	调控肠道干细胞自我更新、增殖和分化

受体Receptor	胆汁酸配体Ligand bile acids		表达组织 Expressive tissues	作用途径Functional pathways
受体Receptor	激活剂 Activators	拮抗剂Antagonists	表达组织 Expressive tissues	作用途径Functional pathways
FXR	CDCA、CA、T（G）CDCA、T（G）CA、LCA、DCA、HCAs	TαMC、TβMCA UDCA、isoDCA	肝脏	胆汁酸代谢	FXR—SHP-1—LRH-1—抑制CYP7A1
				胆汁酸代谢	FXR—IR-1—激活胆汁酸转运载体蛋白
				脂代谢	FXR—SHP—SREBP-1c—抑制脂肪酸合成酶
					FXR—PPARα—促进脂肪酸氧化代谢
					FXR—ApoCII—LPL—促进甘油三酯水解
					FXR—p-JNK—HNF4α—SRB1—促进HDL-C清除
				糖代谢	FXR—SHP—抑制糖异生基因
				糖代谢	FXR—LPK—抑制糖酵解
			肠道	胆汁酸代谢	FXR—FGF19/15—结合肝脏FGFR4/βKlotho—激活JNK途径—抑制CYP7A1
				糖代谢	FXR—FGF19/15—结合肝脏FGFR4/βKlotho—抑制肝脏糖异生基因
				糖代谢	FXR—抑制GLP-1分泌
			免疫细胞	炎症反应	FXR—抑制促炎细胞因子的分泌
TGR5	T（G）LCA、LCA、T（G）DCA、DCA、CDCA、T（G）CDCA、TCA、CA、UDCA、HCAs		棕色脂肪组织	能量代谢	TGR5—cAMP—Dio2—增强能量消耗
			骨骼肌	能量代谢	TGR5—cAMP—Dio2—增强能量消耗
			免疫细胞	免疫反应	TGR5—cAMP—抑制NF-kB信号通路—抑制促炎细胞因子
			肠道	糖代谢	TGR5—cAMP—促进GLP-1分泌
			肠道	肠上皮稳态	调控肠道干细胞自我更新、增殖和分化