Bile acids and their receptors in regulation of gut health and diseases

Progress in Lipid Research - Tập 89 - Trang 101210 - 2023
Sen Lin1,2, Sutian Wang3, Peng Wang4, Cuiming Tang2, Zhenjiang Wang2, Lian Chen2, Guoqing Luo2, Hong Chen5, Yuntao Liu5, Bin Feng5, De Wu1, Douglas G. Burrin6, Zhengfeng Fang1,5
1Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
2Key Laboratory of Urban Agriculture in South China, Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou 510640, China
3State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, China
4College of Biological Engineering, Henan University of Technology, Zhengzhou 450001, China
5Key Laboratory for Food Science and Human Health, College of Food Science, Sichuan Agricultural University, Ya'an 625014, China
6USDA-ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston 77030, United States

Tài liệu tham khảo

Fiorucci, 2021, Bile acids and their receptors in metabolic disorders, Prog Lipid Res, 82, 10.1016/j.plipres.2021.101094 Makishima, 1999, Identification of a nuclear receptor for bile acids, Science, 284, 1362, 10.1126/science.284.5418.1362 Parks, 1999, Bile acids: natural ligands for an orphan nuclear receptor, Science, 284, 1365, 10.1126/science.284.5418.1365 Wang, 1999, Endogenous bile acids are ligands for the nuclear receptor FXR/BAR, Mol Cell, 3, 543, 10.1016/S1097-2765(00)80348-2 Maruyama, 2002, Identification of membrane-type receptor for bile acids (M-BAR), Biochem Bioph Res Co, 298, 714, 10.1016/S0006-291X(02)02550-0 Haslewood, 1967, Bile salt evolution, J Lipid Res, 8, 535, 10.1016/S0022-2275(20)38873-8 Hofmann, 2010, Bile salts of vertebrates: structural variation and possible evolutionary significance, J Lipid Res, 51, 226, 10.1194/jlr.R000042 Russell, 2003, The enzymes, regulation, and genetics of bile acid synthesis, Annu Rev Biochem, 72, 137, 10.1146/annurev.biochem.72.121801.161712 Babiker, 1999, Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin, J Lipid Res, 40, 1417, 10.1016/S0022-2275(20)33383-6 Orth, 1992, The adrenal cortex Russell, 2009, Fifty years of advances in bile acid synthesis and metabolism, J Lipid Res, 50, S120, 10.1194/jlr.R800026-JLR200 Long, 2017, Interactions between gut bacteria and bile in health and disease, Mol Aspects Med, 56, 54, 10.1016/j.mam.2017.06.002 Andersson, 1985, Purification from rabbit and rat liver of cytochromes P-450 involved in bile acid biosynthesis, Methods Enzymol, 111, 364, 10.1016/S0076-6879(85)11023-2 Wikvall, 1981, Purification and properties of a 3 beta-hydroxy-delta 5-C27-steroid oxidoreductase from rabbit liver microsomes, J Biol Chem, 256, 3376, 10.1016/S0021-9258(19)69618-3 Andersson, 1989, Cloning, structure, and expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme, J Biol Chem, 264, 8222, 10.1016/S0021-9258(18)83172-6 Wikvall, 1984, Hydroxylations in biosynthesis of bile acids. Isolation of a cytochrome P-450 from rabbit liver mitochondria catalyzing 26-hydroxylation of C27-steroids, J Biol Chem, 259, 3800, 10.1016/S0021-9258(17)43166-8 Thomas, 2008, Targeting bile-acid signalling for metabolic diseases, Nat Rev Drug Discov, 7, 678, 10.1038/nrd2619 Schwarz, 1998, Marked reduction in bile acid synthesis in cholesterol 7α-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia, J Lipid Res, 39, 1833, 10.1016/S0022-2275(20)32171-4 Russell, 1992, Bile acid biosynthesis, Biochemistry, 31, 4737, 10.1021/bi00135a001 Chiang, 2022, Discovery of farnesoid X receptor and its role in bile acid metabolism, Mol Cell Endocrinol, 548, 10.1016/j.mce.2022.111618 Furster, 1996, Purification of a 3β-Hydroxy-Δ5-C27-steroid dehydrogenase from pig liver microsomes active in major and alternative pathways of bile acid biosynthesis, J Biol Chem, 271, 20903, 10.1074/jbc.271.34.20903 Norlin, 2007, Enzymes in the conversion of cholesterol into bile acids, Curr Mol Med, 7, 199, 10.2174/156652407780059168 Chiang, 2013, Bile acid metabolism and signaling, Compr Physiol, 3, 1191, 10.1002/cphy.c120023 Duane, 1999, 27-hydroxycholesterol: production rates in normal human subjects, J Lipid Res, 40, 1194, 10.1016/S0022-2275(20)33481-7 Chiang, 2019, Bile acids as metabolic regulators and nutrient sensors, Annu Rev Nutr, 39, 175, 10.1146/annurev-nutr-082018-124344 Wahlström, 2016, Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism, Cell Metab, 24, 41, 10.1016/j.cmet.2016.05.005 Li-Hawkins, 2002, Cholic acid mediates negative feedback regulation of bile acid synthesis in mice, J Clin Invest, 110, 1191, 10.1172/JCI0216309 Zheng, 2016, The brain metabolome of male rats across the lifespan, Sci Rep, 6 Wang, 2019, Targeted metabolomics analysis of maternal-placental-fetal metabolism in pregnant swine reveals links in fetal bile acid homeostasis and sulfation capacity, Am J Physiol-Gastr L, 317, G8 Hegyi, 2018, Guts and gall: bile acids in regulation of intestinal epithelial function in health and disease, Physiol Rev, 98, 1983, 10.1152/physrev.00054.2017 Lefebvre, 2009, Role of bile acids and bile acid receptors in metabolic regulation, Physiol Rev, 89, 147, 10.1152/physrev.00010.2008 Hofmann, 1999, The continuing importance of bile acids in liver and intestinal disease, Arch Intern Med, 159, 2647, 10.1001/archinte.159.22.2647 Voronova, 2020, A physiology-based model of bile acid distribution and metabolism under healthy and pathologic conditions in human beings, Cell Mol Gastroenter, 10, 149 Grandvuinet, 2012, Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions, J Pharm Pharmacol, 64, 1523, 10.1111/j.2042-7158.2012.01505.x Dawson, 2010, Getting the mOST from OST: Role of organic solute transporter, OSTalpha-OSTbeta, in bile acid and steroid metabolism, BBA-Mol Cell Biol L, 1801, 994 Fernandez-Barrena, 2012, Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice, J Hepatol, 56, 367, 10.1016/j.jhep.2011.05.031 Slijepcevic, 2017, Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice, Hepatology, 66, 1631, 10.1002/hep.29251 Campbell, 2020, Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells, Nature, 581, 475, 10.1038/s41586-020-2193-0 Sayin, 2013, Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell Metab, 17, 225, 10.1016/j.cmet.2013.01.003 Jonsson, 1995, Intestinal microbial bile acid transformation in healthy infants, J Pediatr Gastroenterol Nutr, 20, 394, 10.1097/00005176-199505000-00004 Joyce, 2016, Bile acid modifications at the microbe-host interface: potential for nutraceutical and pharmaceutical interventions in host health, Annu Rev Food Sci T, 7, 313, 10.1146/annurev-food-041715-033159 Gopalsrivastava, 1988, Purification and characterization of bile salt hydrolase from Clostridium perfringens, J Lipid Res, 29, 1079, 10.1016/S0022-2275(20)38464-9 Hae-Keun, 2008, Molecular cloning and characterization of a bile salt hydrolase from Lactobacillus acidophilus PF01, J Microbiol Biotechnol, 18, 449 Jarocki, 2013, Genetic diversity of bile salt hydrolases among human intestinal bifidobacteria, Curr Microbiol, 67, 286, 10.1007/s00284-013-0362-1 Ridlon, 2016, Consequences of bile salt biotransformations by intestinal bacteria, Gut Microbes, 7, 22, 10.1080/19490976.2015.1127483 Mallonee, 1996, Sequencing and expression of a gene encoding a bile acid transporter from Eubacterium sp strain VPI 12708, J Bacteriol, 178, 7053, 10.1128/jb.178.24.7053-7058.1996 Mallonee, 1992, The bile acid-inducible baiB gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A ligase, J Bacteriol, 174, 2065, 10.1128/jb.174.7.2065-2071.1992 Ridlon, 2012, Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7 alpha-dehydroxylating intestinal bacterium, J Lipid Res, 53, 66, 10.1194/jlr.M020313 Mallonee, 1995, Expression in escherichia-coli and characterization of a bile acid-inducible 3-alpha-hydroxysteroid dehydrogenase from eubacterium sp strain VPI-12708, Curr Microbiol, 30, 259, 10.1007/BF00295498 Dawson, 1996, Expression and characterization of a C-24 bile acid 7 alpha-dehydratase from Eubacterium sp strain VPI 12708 in Escherichia coli, J Lipid Res, 37, 1258, 10.1016/S0022-2275(20)39155-0 Ridlon, 2006, Bile salt biotransformations by human intestinal bacteria, J Lipid Res, 47, 241, 10.1194/jlr.R500013-JLR200 Kundu, 2017, Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis using in vitro and in vivo model systems, Medchemcomm, 8, 2248, 10.1039/C7MD00475C Berr, 1992, Interrelationships of bile acid and phospholipid fatty acid species with cholesterol saturation of duodenal bile in health and gallstone disease, Hepatology, 16, 71, 10.1002/hep.1840160114 Makishima, 2002, Vitamin D receptor as an intestinal bile acid sensor, Science, 296, 1313, 10.1126/science.1070477 Adachi, 2005, Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative, J Lipid Res, 46, 46, 10.1194/jlr.M400294-JLR200 Goodwin, 2003, Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor, Proc Natl Acad Sci U S A, 100, 223, 10.1073/pnas.0237082100 Staudinger, 2001, The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity, Proc Natl Acad Sci U S A, 98, 3369, 10.1073/pnas.051551698 Moore, 2002, Pregnane X receptor (PXR), constitutive androstane receptor (CAR), and benzoate X receptor (BXR) define three pharmacologically distinct classes of nuclear receptors, Mol Endocrinol, 16, 977, 10.1210/mend.16.5.0828 Zhang, 2004, The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity, J Biol Chem, 279, 49517, 10.1074/jbc.M409041200 Krasowski, 2011, Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR, Mol Cell Endocrinol, 334, 39, 10.1016/j.mce.2010.06.016 Whitfield, 2003, Cloning of a functional vitamin D receptor from the Lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth, Endocrinology, 144, 2704, 10.1210/en.2002-221101 Seol, 1995, Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors, Mol Endocrinol, 9, 72 Forman, 1995, Identification of a nuclear receptor that is activated by farnesol metabolites, Cell, 81, 687, 10.1016/0092-8674(95)90530-8 Cai, 2007, The farnesoid X receptor FXRα/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution, Am J Physiol-Reg I, 293, R1400 Otte, 2003, Identification of farnesoid X receptor β as a novel mammalian nuclear receptor sensing lanosterol, Mol Cell Biol, 23, 864, 10.1128/MCB.23.3.864-872.2003 Deng, 2006, Oxysterol 22(R)-hydroxycholesterol induces the expression of the bile salt export pump through nuclear receptor farsenoid X receptor but not liver X receptor, J Pharmacol Exp Ther, 317, 317, 10.1124/jpet.105.097758 Zhang, 2008, FXR signaling in metabolic disease, FEBS Lett, 582, 10, 10.1016/j.febslet.2007.11.015 Denson, 2001, The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp, Gastroenterology, 121, 140, 10.1053/gast.2001.25503 Goodwin, 2000, A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis, Mol Cell, 6, 517, 10.1016/S1097-2765(00)00051-4 van Mil, 2007, Functional variants of the central bile acid sensor FXR identified in intrahepatic cholestasis of pregnancy, Gastroenterology, 133, 507, 10.1053/j.gastro.2007.05.015 Gomez-Ospina, 2016, Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis, Nat Commun, 7, 10713, 10.1038/ncomms10713 Inagaki, 2005, Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis, Cell Metab, 2, 217, 10.1016/j.cmet.2005.09.001 Xie, 1999, FGF-19, a novel fibroblast growth factor with unique specificity for FGFR4, Cytokine, 11, 729, 10.1006/cyto.1999.0485 Hughes, 1997, Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues, J Histochem Cytochem, 45, 1005, 10.1177/002215549704500710 Kong, 2012, Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice, Hepatology, 56, 1034, 10.1002/hep.25740 Sinal, 2000, Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis, Cell, 102, 731, 10.1016/S0092-8674(00)00062-3 Chen, 2003, Liver receptor homologue-1 mediates species- and cell line-specific bile acid-dependent negative feedback regulation of the apical sodium-dependent bile acid transporter, J Biol Chem, 278, 19909, 10.1074/jbc.M207903200 Attinkara, 2012, Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease, BMC Res Notes, 5, 461, 10.1186/1756-0500-5-461 Torres, 2013, Farnesoid X receptor expression is decreased in colonic mucosa of patients with primary sclerosing cholangitis and colitis-associated neoplasia, Inflamm Bowel Dis, 19, 275, 10.1097/MIB.0b013e318286ff2e Nijmeijer, 2011, Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease, PLoS One, 6, 10.1371/journal.pone.0023745 Studer, 2012, Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes, Hepatology, 55, 267, 10.1002/hep.24681 Alemi, 2013, The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice, Gastroenterology, 144, 145, 10.1053/j.gastro.2012.09.055 Sorrentino, 2020, Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration, Gastroenterology, 159, 956, 10.1053/j.gastro.2020.05.067 Nagahashi, 2015, Conjugated bile acid–activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression, Hepatology, 61, 1216, 10.1002/hep.27592 Chen, 2017, Sphingosine-1 phosphate promotes intestinal epithelial cell proliferation via S1PR2, Front Biosci-Landmrk, 22, 596, 10.2741/4505 Keitel, 2019, Bile acid-activated receptors: GPBAR1 (TGR5) and other G protein-coupled receptors, 19 Copple, 2016, Pharmacology of bile acid receptors: evolution of bile acids from simple detergents to complex signaling molecules, Pharmacol Res, 104, 9, 10.1016/j.phrs.2015.12.007 Liu, 2015, Taurocholate induces cyclooxygenase-2 expression via the sphingosine 1-phosphate receptor 2 in a human cholangiocarcinoma cell line, J Biol Chem, 290, 30988, 10.1074/jbc.M115.668277 Petti, 2020, Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer, J Exp Clin Cancer Res, 39, 253, 10.1186/s13046-020-01740-6 Poole, 2010, Expression and function of the bile acid receptor GpBAR1 (TGR5) in the murine enteric nervous system, Neurogastroenterol Motil, 22, 10.1111/j.1365-2982.2010.01487.x Keitel, 2009, The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders, Hepatology, 50, 861, 10.1002/hep.23032 Keitel, 2010, The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain, Glia, 58, 1794, 10.1002/glia.21049 Keitel, 2008, Expression and function of the bile acid receptor TGR5 in Kupffer cells, Biochem Bioph Res Co, 372, 78, 10.1016/j.bbrc.2008.04.171 Kawamata, 2003, A G protein-coupled receptor responsive to bile acids, J Biol Chem, 278, 9435, 10.1074/jbc.M209706200 Sato, 2007, Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea, Biochem Bioph Res Co, 362, 793, 10.1016/j.bbrc.2007.06.130 Lin, 2019, Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model, Am J Physiol-Gastr L, 316, G641 Watanabe, 2006, Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation, Nature, 439, 484, 10.1038/nature04330 Pols, 2011, The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation, J Hepatol, 54, 1263, 10.1016/j.jhep.2010.12.004 Katsuma, 2005, Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1, Biochem Bioph Res Co, 329, 386, 10.1016/j.bbrc.2005.01.139 Thomas, 2009, TGR5-mediated bile acid sensing controls glucose homeostasis, Cell Metab, 10, 167, 10.1016/j.cmet.2009.08.001 Lund, 2020, L-cell differentiation is induced by bile acids through GPBAR1 and paracrine GLP-1 and serotonin signaling, Diabetes, 69, 614, 10.2337/db19-0764 Kumar, 2012, Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells, Biochem Bioph Res Co, 427, 600, 10.1016/j.bbrc.2012.09.104 Schirra, 1996, Gastric emptying and release of incretin hormones after glucose ingestion in humans, J Clin Invest, 97, 92, 10.1172/JCI118411 Ahren, 1998, Glucagon-like peptide-1 (GLP-1): a gut hormone of potential interest in the treatment of diabetes, Bioessays, 20, 642, 10.1002/(SICI)1521-1878(199808)20:8<642::AID-BIES7>3.0.CO;2-K Kumar, 2016, Activation of transmembrane bile acid receptor TGR5 modulates pancreatic islet α cells to promote glucose homeostasis, J Biol Chem, 291, 6626, 10.1074/jbc.M115.699504 Ferrell, 2019, Understanding bile acid signaling in diabetes: from pathophysiology to therapeutic targets, Diabetes Metab J, 43, 257, 10.4093/dmj.2019.0043 Broeders, 2015, The bile acid chenodeoxycholic acid increases human brown adipose tissue activity, Cell Metab, 22, 418, 10.1016/j.cmet.2015.07.002 Huang, 2019, TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice, Metabolism, 99, 45, 10.1016/j.metabol.2019.07.003 Sasaki, 2021, Muscle-specific TGR5 overexpression improves glucose clearance in glucose-intolerant mice, J Biol Chem, 296, 10.1074/jbc.RA120.016203 Hov, 2010, Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis, PLoS One, 5, 10.1371/journal.pone.0012403 McMahan, 2013, Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease, J Biol Chem, 288, 11761, 10.1074/jbc.M112.446575 Yan-Dong, 2011, The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor κ light-chain enhancer of activated B cells (NF-κB) in mice, Hepatology, 54, 1421, 10.1002/hep.24525 Pols, 2011, TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading, Cell Metab, 14, 747, 10.1016/j.cmet.2011.11.006 Perino, 2014, TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation, J Clin Invest, 124, 5424, 10.1172/JCI76289 Wammers, 2018, Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids, Sci Rep, 8, 255, 10.1038/s41598-017-18305-x Ichikawa, 2012, Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway, Immunology, 136, 153, 10.1111/j.1365-2567.2012.03554.x Delgado, 2016, Cell death at the intestinal epithelial front line, FEBS J, 283, 2701, 10.1111/febs.13575 Williams, 2015, Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip, Vet Pathol, 52, 445, 10.1177/0300985814559404 Barrasa, 2013, Bile acids in the colon, from healthy to cytotoxic molecules, Toxicol In Vitro, 27, 964, 10.1016/j.tiv.2012.12.020 Stenman, 2013, A novel mechanism for gut barrier dysfunction by dietary fat: epithelial disruption by hydrophobic bile acids, Am J Physiol-Gastr L, 304, G227 Merchant, 2005, Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells, Surgery, 138, 415, 10.1016/j.surg.2005.06.030 Cheng, 2005, Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors, Biochem Pharmacol, 70, 1035, 10.1016/j.bcp.2005.07.023 Katona, 2009, Characterization of enantiomeric bile acid-induced apoptosis in colon cancer cell lines, J Biol Chem, 284, 3354, 10.1074/jbc.M805804200 Lin, 2019, Undernutrition shapes the gut microbiota and bile acid profile in association with altered gut-liver FXR signaling in weaning pigs, J Agric Food Chem, 67, 3691, 10.1021/acs.jafc.9b01332 Lin, 2020, Dietary supplementation with Lactobacillus plantarum modified gut microbiota, bile acid profile and glucose homoeostasis in weaning piglets, Brit J Nutr, 124, 797, 10.1017/S0007114520001774 Maran, 2009, Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development, J Pharmacol Exp Ther, 328, 469, 10.1124/jpet.108.145409 Stenman, 2012, High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids, World J Gastroenterol, 18, 923, 10.3748/wjg.v18.i9.923 Raimondi, 2008, Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation, Am J Physiol-Gastr L, 294, G906 Liu, 2018, Deoxycholic acid disrupts the intestinal mucosal barrier and promotes intestinal tumorigenesis, Food Funct, 9, 5588, 10.1039/C8FO01143E Wang, 2020, (-)-Epicatechin and NADPH oxidase inhibitors prevent bile acid-induced Caco-2 monolayer permeabilization through ERK1/2 modulation, Redox Biol, 28, 10.1016/j.redox.2019.101360 Wang, 2018, Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non-alcoholic fatty liver disease, Brit J Pharmacol, 175, 469, 10.1111/bph.14095 Gadaleta, 2011, Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease, Gut, 60, 463, 10.1136/gut.2010.212159 Cipriani, 2011, The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis, PLoS One, 6, 10.1371/journal.pone.0025637 Song, 2019, Chenodeoxycholic acid (CDCA) protects against the lipopolysaccharide-induced impairment of the intestinal epithelial barrier function via the FXR-MLCK pathway, J Agric Food Chem, 67, 8868, 10.1021/acs.jafc.9b03173 Chen, 2019, Emerging roles of bile acids in mucosal immunity and inflammation, Mucosal Immunol, 12, 851, 10.1038/s41385-019-0162-4 Cao, 2017, The xenobiotic transporter Mdr1 enforces T cell homeostasis in the presence of intestinal bile acids, Immunity, 47, 1182, 10.1016/j.immuni.2017.11.012 Chen, 2021, CAR directs T cell adaptation to bile acids in the small intestine, Nature, 593, 147, 10.1038/s41586-021-03421-6 Song, 2020, Microbial bile acid metabolites modulate gut ROR gamma(+) regulatory T cell homeostasis, Nature, 577, 410, 10.1038/s41586-019-1865-0 Josefowicz, 2012, Extrathymically generated regulatory T cells control mucosal TH2 inflammation, Nature, 482, 395, 10.1038/nature10772 Biagioli, 2017, The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis, J Immunol, 199, 718, 10.4049/jimmunol.1700183 Vavassori, 2009, The bile acid receptor FXR is a modulator of intestinal innate immunity, J Immunol, 183, 6251, 10.4049/jimmunol.0803978 Wang, 2011, The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor κ light-chain enhancer of activated B cells (NF-κB) in mice, Hepatology, 54, 1421, 10.1002/hep.24525 Guo, 2016, Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome, Immunity, 45, 802, 10.1016/j.immuni.2016.09.008 Renga, 2013, The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation, PLoS One, 8, 10.1371/journal.pone.0054472 Verbeke, 2014, Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats, Hepatology, 59, 2286, 10.1002/hep.26939 Verbeke, 2015, The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats, Am J Pathol, 185, 409, 10.1016/j.ajpath.2014.10.009 Ceulemans, 2017, Farnesoid X receptor activation attenuates intestinal ischemia reperfusion injury in rats, PLoS One, 12, 10.1371/journal.pone.0169331 Gadaleta, 2011, Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-kappa B signaling in the intestine, BBA-Mol Basis Dis, 1812, 851, 10.1016/j.bbadis.2011.04.005 Fiorucci, 2018, Bile acids activated receptors regulate innate immunity, Front Immunol, 9, 1853, 10.3389/fimmu.2018.01853 Vantrappen, 1977, Bile acid studies in uncomplicated Crohn’s disease, Gut, 18, 730, 10.1136/gut.18.9.730 Duboc, 2013, Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases, Gut, 62, 531, 10.1136/gutjnl-2012-302578 Sinha, 2020, Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation, Cell Host Microbe, 27, 659, 10.1016/j.chom.2020.01.021 Inagaki, 2006, Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor, Proc Natl Acad Sci U S A, 103, 3920, 10.1073/pnas.0509592103 Gadaleta, 2020, Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor, EBioMedicine, 54, 10.1016/j.ebiom.2020.102719 Massafra, 2016, Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis, BBA-Mol Basis Dis, 1862, 166, 10.1016/j.bbadis.2015.11.001 Downes, 2003, A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR, Mol Cell, 11, 1079, 10.1016/S1097-2765(03)00104-7 Xu, 2021, Modulation of the gut microbiota-farnesoid X receptor axis improves deoxycholic acid-induced intestinal inflammation in mice, J Crohns Colitis, 15, 1197, 10.1093/ecco-jcc/jjab003 Biagioli, 2020, Identification of cysteinyl-leukotriene-receptor 1 antagonists as ligands for the bile acid receptor GPBAR1, Biochem Pharmacol, 177, 10.1016/j.bcp.2020.113987 Yoneno, 2013, TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease, Immunology, 139, 19, 10.1111/imm.12045 Bain, 2014, The monocyte-macrophage axis in the intestine, Cell Immunol, 291, 41, 10.1016/j.cellimm.2014.03.012 Cerovic, 2014, Intestinal macrophages and dendritic cells: what’s the difference?, Trends Immunol, 35, 270, 10.1016/j.it.2014.04.003 Biagioli, 2021, Bile acids activated receptors in inflammatory bowel disease, Cells-Basel, 10, 1281, 10.3390/cells10061281 Arnold, 2017, Global patterns and trends in colorectal cancer incidence and mortality, Gut, 66, 683, 10.1136/gutjnl-2015-310912 Aries, 1969, Bacteria and aetiology of cancer of large bowel, Gut, 10, 334, 10.1136/gut.10.5.334 Reddy, 1973, Large-bowel carcinogenesis: fecal constituents of populations with diverse incidence rates of colon cancer, JNCI-J Natl Cancer I, 50, 1437, 10.1093/jnci/50.6.1437 Lax, 2012, Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis, Int J Cancer, 130, 2232, 10.1002/ijc.26293 De Gottardi, 2004, The bile acid nuclear receptor FXR and the bile acid binding protein IBABP are differently expressed in colon cancer, Dig Dis Sci, 49, 982, 10.1023/B:DDAS.0000034558.78747.98 Modica, 2008, Nuclear bile acid receptor FXR protects against intestinal tumorigenesis, Cancer Res, 68, 9589, 10.1158/0008-5472.CAN-08-1791 Epifano, 2012, Nelumal A, the active principle from Ligularia nelumbifolia, is a novel farnesoid X receptor agonist, Bioorg Med Chem Lett, 22, 3130, 10.1016/j.bmcl.2012.03.057 Miyazaki, 2021, Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis, Sci Rep, 11, 492, 10.1038/s41598-020-79916-5 Peng, 2012, Src-mediated cross-talk between farnesoid X and epidermal growth factor receptors inhibits human intestinal cell proliferation and tumorigenesis, PLoS One, 7, 11, 10.1371/journal.pone.0048461 Qiao, 2018, Farnesoid X receptor inhibits proliferation of human colorectal cancer cells via the miR-135A1/CCNG2 signaling pathway, Oncol Rep, 40, 2067 Yu, 2020, Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis, Cell Death Dis, 11, 640, 10.1038/s41419-020-02819-w Ferlay, 2015, Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012, Int J Cancer, 136, E359, 10.1002/ijc.29210 Bass, 2014, Comprehensive molecular characterization of gastric adenocarcinoma, Nature, 513, 202, 10.1038/nature13480 Selmin, 2015, Inactivation of adenomatous polyposis coli reduces bile acid/farnesoid x receptor expression through fxr gene cpg methylation in mouse colon tumors and human colon cancer cells, J Nutr, 146, 236, 10.3945/jn.115.216580 Wang, 2019, Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis, Mol Carcinog, 58, 1155, 10.1002/mc.22999 O’Keefe, 2016, Diet, microorganisms and their metabolites, and colon cancer, Nat Rev Gastroenterol Hepatol, 13, 691, 10.1038/nrgastro.2016.165 Sagar, 2017 Kurien, 2011, Bile acid malabsorption: an under-investigated differential diagnosis in patients presenting with diarrhea predominant irritable bowel syndrome type symptoms, Scand J Gastroenterol, 46, 818, 10.3109/00365521.2011.574728 Smith, 2000, Bile acid malabsorption in persistent diarrhoea, J Roy Coll Phys Lond, 34, 448 Pattni, 2013, Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention, Aliment Pharm Ther, 38, 967, 10.1111/apt.12466 Vijayvargiya, 2020, Combined fasting serum C4 and primary bile acids from a single stool sample to diagnose bile acid diarrhea, Gastroenterology, 159, 1952, 10.1053/j.gastro.2020.07.001 Walters, 2009, A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis, Clin Gastroenterol H, 7, 1189, 10.1016/j.cgh.2009.04.024 Hofmann, 1967, The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy, Gastroenterology, 52, 752, 10.1016/S0016-5085(67)80140-9 Thaysen, 1976, Idiopathic bile acid catharsis, Gut, 17, 965, 10.1136/gut.17.12.965 Fromm, 1986, Bile acid-induced diarrhoea, Clin Gastroenterol, 15, 567, 10.1016/S0300-5089(21)00739-2 Lee, 2018, Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants, J Lipid Res, 59, 429, 10.1194/jlr.M078279 Bajor, 2015, Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS, Gut, 64, 84, 10.1136/gutjnl-2013-305965 Oelkers, 1997, Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2), J Clin Invest, 99, 1880, 10.1172/JCI119355 Johnston, 2013, 271 a new therapy for chronic diarrhea? A proof of concept study of the fxr agonist obeticholic acid in patients with primary bile acid diarrhea, Gastroenterology, 144, 10.1016/S0016-5085(13)60217-6 Mroz, 2014, Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo, Gut, 63, 808, 10.1136/gutjnl-2013-305088 Camilleri, 2020, Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea, Aliment Pharm Ther, 52, 808, 10.1111/apt.15967 Boyer, 2006, Upregulation of a basolateral FXR-dependent bile acid efflux transporter OSTalpha-OSTbeta in cholestasis in humans and rodents, Am J Physiol-Gastr L, 290, G1124 Zheng, 2021, Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism, Cell Metab, 33, 791, 10.1016/j.cmet.2020.11.017 Liu, 2014, Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2, Hepatology, 60, 908, 10.1002/hep.27085 Li, 2005, Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription, Am J Physiol-Gastr L, 288, G74 Han, 2010, A novel bile acid-activated vitamin D receptor signaling in human hepatocytes, Mol Endocrinol, 24, 1151, 10.1210/me.2009-0482 Kim, 2013, Implication of intestinal VDR deficiency in inflammatory bowel disease, BBA-Gen Subjects, 1830, 2118, 10.1016/j.bbagen.2012.09.020 Goyal, 2015, Effect of chenodeoxycholic acid and sodium hydrogen sulfide in dinitro benzene sulfonic acid (DNBS) – induced ulcerative colitis in rats, Pharmacol Rep, 67, 616, 10.1016/j.pharep.2014.12.018 Zhao, 2016, Deoxycholic acid triggers NLRP3 inflammasome activation and aggravates DSS-induced colitis in mice, Front Immunol, 7, 536, 10.3389/fimmu.2016.00536 Shant, 2009, Akt-dependent NF-κB activation is required for bile acids to rescue colon cancer cells from stress-induced apoptosis, Exp Cell Res, 315, 432, 10.1016/j.yexcr.2008.11.003 Crowley-Weber, 2002, Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate, Carcinogenesis, 23, 2063, 10.1093/carcin/23.12.2063 Walters, 2015, The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid, Aliment Pharm Ther, 41, 54, 10.1111/apt.12999 Camilleri, 2014, Genetic variation in GPBAR1 predisposes to quantitative changes in colonic transit and bile acid excretion, Am J Physiol-Gastr L, 307, G508