Interactions between bile salts, gut microbiota, and hepatic innate immunity

Immunological Reviews

Volumn 279, Issue 1, 2017, Pages 23-35

  Schubert, Kristin ^a   Olde Damink, Steven W M ^b,c   von Bergen, Martin ^a,d   Schaap, Frank G ^b,c  

^a HELMHOLTZ CENTRE FOR ENVIRONMENTAL RESEARCH UFZ   (Germany)

^b MAASTRICHT UNIVERSITY   (Netherlands)

^c UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^d UNIVERSITY OF LEIPZIG   (Germany)

Author keywords

bile salt metabolism; bile salt signaling; bile salt toxicity; FXR; innate immunity; microbiota:host interaction

Indexed keywords

BILE SALT; CELL NUCLEUS RECEPTOR; BILE ACID; CELL RECEPTOR; FARNESOID X-ACTIVATED RECEPTOR; G PROTEIN COUPLED RECEPTOR; GPBAR1 PROTEIN, HUMAN;

CELL MEMBRANE; ECOLOGY; ENTEROHEPATIC CIRCULATION; HUMAN; IMMUNOCOMPETENT CELL; INNATE IMMUNITY; INTESTINE FLORA; LIVER FUNCTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; ANIMAL; HOMEOSTASIS; HOST PATHOGEN INTERACTION; IMMUNOLOGY; LIVER; METABOLISM; MICROBIOLOGY;

ANIMALS; BILE ACIDS AND SALTS; GASTROINTESTINAL MICROBIOME; HOMEOSTASIS; HOST-PATHOGEN INTERACTIONS; HUMANS; IMMUNITY, INNATE; LIVER; RECEPTORS, CYTOPLASMIC AND NUCLEAR; RECEPTORS, G-PROTEIN-COUPLED;

EID: 85028567221     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12579     Document Type: Review

References (121)

1. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med. 1999;159:2647-2658.
2. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137-174.
3. Hofmann AF. The enterohepatic circulation of bile acids in mammals: form and functions. Front Biosci. 2009;14:2584-2598.
4. Boyer JL. Bile formation and secretion. Compr Physiol. 2013;3:1035-1078.
5. Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res. 2015;56:1085-1099.
6. Doring B, Lutteke T, Geyer J, Petzinger E. The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr. 2012;70:105-168.
7. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241-259.
8. Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11:55-67.
9. Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell Mol Life Sci. 2008;65:2461-2483.
10. Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362-1365.
11. Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365-1368.
12. Studer E, Zhou X, Zhao R, et al. Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes. Hepatology. 2012;55:267-276.
13. Holt JA, Luo G, Billin AN, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003;17:1581-1591.
14. Gohlke H, Schmitz B, Sommerfeld A, Reinehr R, Haussinger D. alpha5 beta1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes. Hepatology. 2013;57:1117-1129.
15. Sayin SI, Wahlstrom A, Felin J, 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;17:225-235.
16. Wahlstrom A, Kovatcheva-Datchary P, Stahlman M, Backhed F, Marschall HU. Crosstalk between bile acids and gut microbiota and its impact on farnesoid X receptor signalling. Dig Dis. 2017;35:246-250.
17. Downes M, Verdecia MA, Roecker AJ, et al. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell. 2003;11:1079-1092.
18. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956-965.
19. Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631-643.
20. Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003;278:9435-9440.
21. Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002;298:714-719.
22. Reich M, Klindt C, Deutschmann K, Spomer L, Haussinger D, Keitel V. Role of the G protein-coupled bile acid receptor TGR5 in liver damage. Dig Dis. 2017;35:235-240.
23. Werneburg NW, Yoon JH, Higuchi H, Gores GJ. Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol Gastrointest Liver Physiol. 2003;285:G31-G36.
24. Gonzalez-Sanchez E, Firrincieli D, Housset C, Chignard N. Expression patterns of nuclear receptors in parenchymal and non-parenchymal mouse liver cells and their modulation in cholestasis. Biochim Biophys Acta 2017;1863:1699-1708.
25. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the big bang. Cell. 2014;157:255-266.
26. Inagaki T, Moschetta A, Lee YK, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A. 2006;103:3920-3925.
27. Candela M, Biagi E, Turroni S, Maccaferri S, Figini P, Brigidi P. Dynamic efficiency of the human intestinal microbiota. Crit Rev Microbiol. 2015;41:165-171.
28. Hollman DA, Milona A, van Erpecum KJ, van Mil SW. Anti-inflammatory and metabolic actions of FXR: insights into molecular mechanisms. Biochim Biophys Acta. 2012;1821:1443-1452.
29. Keitel V, Haussinger D. Perspective: TGR5 (Gpbar-1) in liver physiology and disease. Clin Res Hepatol Gastroenterol. 2012;36:412-419.
30. Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap–bile acids in metabolic control. Nat Rev Endocrinol. 2014;10:488-498.
31. Perino A, Schoonjans K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci. 2015;36:847-857.
32. Wang YD, Chen WD, Moore DD, Huang W. FXR: a metabolic regulator and cell protector. Cell Res. 2008;18:1087-1095.
33. Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3:543-553.
34. Begley M, Gahan CG, Hill C. The interaction between bacteria and bile. FEMS Microbiol Rev. 2005;29:625-651.
35. Islam KB, Fukiya S, Hagio M, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology. 2011;141:1773-1781.
36. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7:22-39.
37. Stork A, Fabian E, Sponarova J. Bile salts and lipolysis. Enzymol Biol Clin. 1968;9:137-142.
38. Hofmann AF. The function of bile salts in fat absorption. The solvent properties of dilute micellar solutions of conjugated bile salts. Biochem J. 1963;89:57-68.
39. Maldonado-Valderrama J, Wilde P, Macierzanka A, Mackie A. The role of bile salts in digestion. Adv Colloid Interface Sci. 2011;165:36-46.
40. Westergaard H, Dietschy JM. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Invest. 1976;58:97-108.
41. Roda A, Hofmann AF, Mysels KJ. The influence of bile salt structure on self-association in aqueous solutions. J Biol Chem. 1983;258:6362-6370.
42. Attili AF, Angelico M, Cantafora A, Alvaro D, Capocaccia L. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses. 1986;19:57-69.
43. Heuman DM. Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J Lipid Res. 1989;30:719-730.
44. Kurdi P, Tanaka H, Van Veen HW, Asano K, Tomita F, Yokota A. Cholic acid accumulation and its diminution by short-chain fatty acids in bifidobacteria. Microbiology. 2003;149:2031-2037.
45. Kurdi P, van Veen HW, Tanaka H, et al. Cholic acid is accumulated spontaneously, driven by membrane deltapH, in many lactobacilli. J Bacteriol. 2000;182:6525-6528.
46. Kurdi P, Kawanishi K, Mizutani K, Yokota A. Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria. J Bacteriol. 2006;188:1979-1986.
47. Ridlon JM, Wolf PG, Gaskins HR. Taurocholic acid metabolism by gut microbes and colon cancer. Gut Microbes. 2016;7:201-215.
48. Hardison WG. Hepatic taurine concentration and dietary taurine as regulators of bile acid conjugation with taurine. Gastroenterology. 1978;75:71-75.
49. Sjovall J. Dietary glycine and taurine on bile acid conjugation in man; bile acids and steroids 75. Proc Soc Exp Biol Med. 1959;100:676-678.
50. De Smet I, Van Hoorde L, Vande Woestyne M, Christiaens H, Verstraete W. Significance of bile salt hydrolytic activities of lactobacilli. J Appl Bacteriol. 1995;79:292-301.
51. Wijaya A, Hermann A, Abriouel H, et al. Cloning of the bile salt hydrolase (bsh) gene from Enterococcus faecium FAIR-E 345 and chromosomal location of bsh genes in food enterococci. J Food Prot. 2004;67:2772-2778.
52. Masuda N. Deconjugation of bile salts by Bacteroids and Clostridium. Microbiol Immunol. 1981;25:1-11.
53. Jarocki P, Targonski Z. Genetic diversity of bile salt hydrolases among human intestinal bifidobacteria. Curr Microbiol. 2013;67:286-292.
54. Jarocki P, Podlesny M, Glibowski P, Targonski Z. A new insight into the physiological role of bile salt hydrolase among intestinal bacteria from the genus Bifidobacterium. PLoS ONE. 2014;9:e114379.
55. Narushima S, Itoha K, Miyamoto Y, et al. Deoxycholic acid formation in gnotobiotic mice associated with human intestinal bacteria. Lipids. 2006;41:835-843.
56. Laue H, Friedrich M, Ruff J, Cook AM. Dissimilatory sulfite reductase (desulfoviridin) of the taurine-degrading, non-sulfate-reducing bacterium Bilophila wadsworthia RZATAU contains a fused DsrB-DsrD subunit. J Bacteriol. 2001;183:1727-1733.
57. Nava GM, Carbonero F, Croix JA, Greenberg E, Gaskins HR. Abundance and diversity of mucosa-associated hydrogenotrophic microbes in the healthy human colon. ISME J. 2012;6:57-70.
58. Parey K, Warkentin E, Kroneck PM, Ermler U. Reaction cycle of the dissimilatory sulfite reductase from Archaeoglobus fulgidus. Biochemistry. 2010;49:8912-8921.
59. Ijssennagger N, van der Meer R, van Mil SW. Sulfide as a mucus barrier-breaker in inflammatory bowel disease? Trends Mol Med. 2016;22:190-199.
60. O'Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015;350:1214-1215.
61. ElRakaiby M, Dutilh BE, Rizkallah MR, Boleij A, Cole JN, Aziz RK. Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics. OMICS. 2014;18:402-414.
62. Kayama H, Nishimura J, Takeda K. Regulation of intestinal homeostasis by innate immune cells. Immune Netw. 2013;13:227-234.
63. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5:e177.
64. De AngelisM, Garruti G, Minervini F, Bonfrate L, Portincasac P, Gobbetti M. The food-gut human axis: the effects of diet on gut microbiota and metabolome. Curr Med Chem 2017. https://doi.org/10.2174/0929867324666170428103848. [Epub ahead of print].
65. Quercia S, Candela M, Giuliani C, et al. From lifetime to evolution: timescales of human gut microbiota adaptation. Front Microbiol. 2014;5:587.
66. Thaiss CA, Levy M, Suez J, Elinav E. The interplay between the innate immune system and the microbiota. Curr Opin Immunol. 2014;26:41-48.
67. Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med. 2013;5:1465-1483.
68. Parseus A, Sommer N, Sommer F, et al. Microbiota-induced obesity requires farnesoid X receptor. Gut. 2017;66:429-437.
69. Sutherland DB, Suzuki K, Fagarasan S. Fostering of advanced mutualism with gut microbiota by immunoglobulin A. Immunol Rev. 2016;270:20-31.
70. Colmer JA, Fralick JA, Hamood AN. Isolation and characterization of a putative multidrug resistance pump from Vibrio cholerae. Mol Microbiol. 1998;27:63-72.
71. Lacroix FJ, Cloeckaert A, Grepinet O, et al. Salmonella typhimurium acrB-like gene: identification and role in resistance to biliary salts and detergents and in murine infection. FEMS Microbiol Lett. 1996;135:161-167.
72. Thanassi DG, Cheng LW, Nikaido H. Active efflux of bile salts by Escherichia coli. J Bacteriol. 1997;179:2512-2518.
73. Van Eldere J, Celis P, De Pauw G, Lesaffre E, Eyssen H. Tauroconjugation of cholic acid stimulates 7 alpha-dehydroxylation by fecal bacteria. Appl Environ Microbiol. 1996;62:656-661.
74. Peschel A, Jack RW, Otto M, et al. Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with l-lysine. J Exp Med. 2001;193:1067-1076.
75. Wilson CL, Ouellette AJ, Satchell DP, et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science. 1999;286:113-117.
76. Chateau N, Castellanos I, Deschamps AM. Distribution of pathogen inhibition in the Lactobacillus isolates of a commercial probiotic consortium. J Appl Bacteriol. 1993;74:36-40.
77. Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S. Cellular and molecular mechanisms of liver tolerance. Immunol Rev. 2006;213:101-118.
78. Doherty DG, O'Farrelly C. Innate and adaptive lymphoid cells in the human liver. Immunol Rev. 2000;174:5-20.
79. Robinson MW, Harmon C, O'Farrelly C. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016;13:267-276.
80. Adams DH, Eksteen B, Curbishley SM. Immunology of the gut and liver: a love/hate relationship. Gut. 2008;57:838-848.
81. Tang X-Z, Jo J, Tan AT, et al. IL-7 licenses activation of human liver intrasinusoidal mucosal-associated invariant T cells. J Immunol. 2013;190:3142-3152.
82. Treiner E, Duban L, Bahram S, Radosavljevic M, Wanner V, Tilloy F. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 2003;422:164-169.
83. Rahimpour A, Koay H-F, Enders A, et al. Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers. J Exp Med. 2015;212:1095-1108.
84. Tilloy F, Treiner E, Park S-H, et al. An invariant T cell receptor α chain defines a novel TAP-independent major histocompatibility complex class Ib–restricted α/β T cell subpopulation in mammals. J Exp Med. 1999;189:1907-1921.
85. Martin E, Treiner E, Duban L, et al. Stepwise development of MAIT cells in mouse and human. PLoS Biol. 2009;7:e1000054.
86. Huang S, Gilfillan S, Kim S, et al. MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. J Exp Med. 2008;205:1201-1211.
87. Kjer-Nielsen L, Patel O, Corbett AJ, et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature. 2012;491:717-723.
88. Ussher JE, Bilton M, Attwod E, et al. CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner. Eur J Immunol. 2014;44:195-203.
89. Chua W-J, Truscott SM, Eickhoff CS, Blazevic A, Hoft DF, Hansen TH. Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect Immun. 2012;80:3256-3267.
90. Tomura M, Maruo S, Mu J, et al. Differential capacities of CD4+, CD8+, and CD4-CD8- T cell subsets to express IL-18 receptor and produce IFN-gamma in response to IL-18. J Immunol. 1998;160:3759-3765.
91. Gold MC, Cerri S, Smyk-Pearson S, et al. Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 2010;8:e1000407.
92. Le Bourhis L, Martin E, Péguillet I, et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol. 2010;11:701-708.
93. Gold MC, Eid T, Smyk-Pearson S, et al. Human thymic MR1-restricted MAIT cells are innate pathogen-reactive effectors that adapt following thymic egress. Mucosal Immunol. 2013;6:35-44.
94. Cosgrove C, Ussher JE, Rauch A, Gärtner K, Kurioka A, Hühn MH. Early and nonreversible decrease of CD161++/MAIT cells in HIV infection. Blood 2013;121:951-961.
95. Hengst J, Strunz B, Deterding K, et al. Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy. Eur J Immunol. 2016;46:2204-2210.
96. Kurioka A, Walker LJ, Klenerman P, Willberg CB. MAIT cells: new guardians of the liver. Clin Trans Immunol. 2016;5:e98.
97. Leeansyah E, Ganesh A, Quigley MF, Sönnerborg A, Andersson J, Hunt PW. Activation, exhaustion, and persistent decline of the antimicrobial MR1-restricted MAIT-cell population in chronic HIV-1 infection. Blood. 2013;121:1124-1135.
98. van Wilgenburg B, Scherwitzl I, Hutchinson EC, et al. MAIT cells are activated during human viral infections. Nat Commun. 2016;7:11653.
99. Oo YH, Banz V, Kavanagh D, et al. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J Hepatol. 2012;57:1044-1051.
100. Jeffery HC, van Wilgenburg B, Kurioka A, et al. Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1. J Hepatol. 2016;64:1118-1127.
101. Levy M, Kolodziejczyk AA, Thaiss CA, Elinav E. Dysbiosis and the immune system. Nat Rev Immunol. 2017;17:219-232.
102. Högenauer K, Arista L, Schmiedeberg N, et al. G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype. J Med Chem. 2014;57:10343-10354.
103. Schote AB, Turner JD, Schiltz J, Muller CP. Nuclear receptors in human immune cells: expression and correlations. Mol Immunol. 2007;44:1436-1445.
104. Haselow K, Bode JG, Wammers M, et al. Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. J Leukoc Biol. 2013;94:1253-1264.
105. Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008;372:78-84.
106. Perino A, Pols TWH, Nomura M, Stein S, Pellicciari R, Schoonjans K. TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J Clin Invest. 2014;124:5424-5436.
107. Wang YD, Chen WD, Yu D, Forman BM, Huang W. 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. 2011;54:1421-1432.
108. Calmus Y, Guechot J, Podevin P, Bonnefis MT, Giboudeau J, Poupon R. Differential effects of chenodeoxycholic and ursodeoxycholic acids on interleukin 1, interleukin 6 and tumor necrosis factor-alpha production by monocytes. Hepatology. 1992;16:719-723.
109. Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol. 2009;183:6251-6261.
110. Guo C, Xie S, Chi Z, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016;45:802-816.
111. Perez MJ, Briz O. Bile-acid-induced cell injury and protection. World J Gastroenterol. 2009;15:1677-1689.
112. Cai S-Y, Boyer JL. The role of inflammation in the mechanisms of bile acid-induced liver damage. Dig Dis. 2017;35:232-234.
113. Cai S-Y, Ouyang X, Chen Y, et al. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight. 2017;2:e90780.
114. Houten SM, Volle DH, Cummins CL, Mangelsdorf DJ, Auwerx J. In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue. Mol Endocrinol. 2007;21:1312-1323.
115. Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes. Am J Pathol. 2011;178:175-186.
116. Gujral JS, Farhood A, Bajt ML, Jaeschke H. Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct–ligated mice. Hepatology. 2003;38:355-363.
117. Gong Z, Zhou J, Zhao S, et al. Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget. 2016;7:83951-83963.
118. Hao H, Cao L, Jiang C, et al. Farnesoid X receptor regulation of the NLRP3 inflammasome underlies cholestasis-associated sepsis. Cell Metab. 2017;25:856-867.e5.
119. Mencarelli A, Renga B, Migliorati M, et al. The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol. 2009;183:6657-6666.
120. Ashkar S, Weber GF, Panoutsakopoulou V, et al. Eta-1 (osteopontin): An early component of type-1 (cell-mediated) immunity. Science. 2000;287:860-864.
121. Calmus Y, Poupon R. Shaping macrophages function and innate immunity by bile acids: mechanisms and implication in cholestatic liver diseases. Clin Res Hepatol Gastroenterol. 2014;38:550-556.