Abstract
Primary bile acids (BAs) are generated in the liver as the end products of cholesterol catabolism; they are then conjugated and accumulated in the gallbladder. After a meal ingestion, BAs are reversed into the duodenum to facilitate the lipid absorption. At the intestinal level, the 95% of BAs are reabsorbed and redirected into enterohepatic circulation; indeed only a small amount of them are then subjected to chemical modifications by the intestinal microbiota, which plays a very important role in the generation of secondary bile acids and in regulating host’s metabolism and activity of the immune system. Behind their role in nutrients absorption, bile acids act as signaling molecules, activating several receptors, known as bile acid-activated receptors (BARs), including the farnesoid-X-receptor (FXR) and the G protein-coupled bile acid receptor 1 (GPBAR1 or Takeda G-protein receptor 5). Both receptors appear to contribute to maintain the tolerogenic state of the liver and intestine immunity. In particular, FXR and GPBAR1 are highly expressed in cells of innate immunity including intestinal and liver macrophages, dendritic cells, and natural killer T cells. In this chapter, we provide an overview on mechanisms through which FXR and GPBAR1 modulate the signaling between microbiota and intestinal and liver innate immune system. This overview could help to explain beneficial effects exerted by GPBAR1 and FXR agonists in the treatment of metabolic and immuno-mediated diseases.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Biagioli M, Carino A, Cipriani S, Francisci D, MarchianĂ² S, Scarpelli P et al (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 199:718–733. https://doi.org/10.4049/jimmunol.1700183
Carino A, Cipriani S, MarchianĂ² S, Biagioli M, Scarpelli P, Zampella A et al (2017a) Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice. Sci Rep 7:13689. https://doi.org/10.1038/s41598-017-13102-y
Carino A, Cipriani S, MarchianĂ² S, Biagioli M, Santorelli C, Donini A et al (2017b) BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep 7:42801. https://doi.org/10.1038/srep42801
Carino A, MarchianĂ² S, Biagioli M, Bucci M, Vellecco V, Brancaleone V et al (2018) Agonism for the bile acid receptor GPBAR1 reverses liver and vascular damage in a mouse model of steatohepatitis. FASEB J 10:2809. https://doi.org/10.1096/fj.201801373RR
Chanda D, Park JH, Choi HS (2008) Molecular basis of endocrine regulation by orphan nuclear receptor small heterodimer partner. Endocr J 55:253–268. https://doi.org/10.1507/endocrj.K07E-103
Chiang JY (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966. https://doi.org/10.1194/jlr.R900010-JLR200
Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G et al (2011) The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One 6:e25637. https://doi.org/10.1371/journal.pone.0025637
Crispe IN (2009) The liver as a lymphoid organ. Annu Rev Immunol 27:147–163. https://doi.org/10.1146/annurev.immunol.021908.132629
Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S (2006) Cellular and molecular mechanisms of liver tolerance. Immunol Rev 213:101–118
Ding JW, Andersson R, Soltesz V, Willén R, Bengmark S (1993) The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur Surg Res 25:11–19
Donkers JM, Roscam Abbing RLP, van de Graaf SFJ (2018) Developments in bile salt based therapies: a critical overview. Biochem Pharmacol 161:1–13. https://doi.org/10.1016/j.bcp.2018.12.018
Falany CN, Johnson MR, Barnes S, Diasio RB (1994) Glycine and taurine conjugation of bile acids by a single enzyme. Molecular cloning and expression of human liver bile acid CoA: amino acid N-acyltransferase. J Biol Chem 269:19375–19379
Festa C, Renga B, D’Amore C, Sepe V, Finamore C, de Marino S et al (2014) Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands. J Med Chem 57:8477–8495. https://doi.org/10.1021/jm501273r
Fiorucci S, Distrutti E (2015) Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med 21:702–714. https://doi.org/10.1016/j.molmed.2015.09.001
Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–1512
Fiorucci S, Cipriani S, Mencarelli A, Renga B, Distrutti E, Baldelli F (2010) Counter-regulatory role of bile acid activated receptors in immunity and inflammation. Curr Mol Med 10:579–595
Fiorucci S, Biagioli M, Zampella A, Distrutti E (2018a) Bile acids activated receptors regulate innate immunity. Front Immunol 9:1853. https://doi.org/10.3389/fimmu.2018.01853
Fiorucci S, Biagioli M, Distrutti E (2018b) Future trends in the treatment of non-alcoholic steatohepatitis. Pharmacol Res 134:289–298. https://doi.org/10.1016/j.phrs.2018.07.014
Fryer RM, Ng KJ, Nodop Mazurek SJ, Patnaude L, Skow DJ, Muthukumarana A et al (2014) G protein-coupled bile acid receptor 1 stimulation mediates arterial vasodilation through a K(Ca)1.1 (BK(Ca))-dependent mechanism. J Pharmacol Exp Ther 348:421–431. https://doi.org/10.1124/jpet.113.210005
Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S et al (2011) Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 60:463–472. https://doi.org/10.1136/gut.2010.212159
Grober J, Zaghini I, Fujii H, Jones SA, Kliewer SA, Willson TM et al (1999) Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem 274:29749–29754
Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L et al (2013) Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. J Leukoc Biol 94:1253–1264. https://doi.org/10.1189/jlb.0812396
Högenauer K, Arista L, Schmiedeberg N, Werner G, Jaksche H, Bouhelal R et al (2014) 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 57:10343–10354. https://doi.org/10.1021/jm501052c
Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H et al (2012) Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology 136:153–162
Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M et al (2006) Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 103:3920–3925
Iracheta-Vellve A, Calenda CD, Petrasek J, Ambade A, Kodys K, Adorini L et al (2018) FXR and TGR5 agonists ameliorate liver injury, steatosis, and inflammation after binge or prolonged alcohol feeding in mice. Hepatol Commun 2:1379–1391. https://doi.org/10.1002/hep4.1256
Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T et al (2011) Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 141:1773–1781. https://doi.org/10.1053/j.gastro.2011.07.046
Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M et al (2003) A G protein-coupled receptor responsive to bile acids. J Biol Chem 278:9435–9440
Keane RM, Gadacz TR, Munster AM, Birmingham W, Winchurch RA (1984) Impairment of human lymphocyte function by bile salts. Surgery 95:439–443
Kida T, Omori K, Hori M, Ozaki H, Murata T (2014) Stimulation of G protein-coupled bile acid receptor enhances vascular endothelial barrier function via activation of protein kinase A and Rac1. J Pharmacol Exp Ther 348:125–130. https://doi.org/10.1124/jpet.113.209288
Kim I, Ahn SH, Inagaki T, Choi M, Ito S, Guo GL et al (2007) Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 48:2664–2672
Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M et al (2018) Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360. pii: eaan5931. https://doi.org/10.1126/science.aan5931
Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365
Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E et al (2002) Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun 298:714–719. https://doi.org/10.1016/S0006-291X(02)02550-0
Massafra V, Ijssennagger N, Plantinga M, Milona A, Ramos Pittol JM, Boes M et al (2016) Splenic dendritic cell involvement in FXR-mediated amelioration of DSS colitis. Biochim Biophys Acta 1862:166–173. https://doi.org/10.1016/j.bbadis.2015.11.001
Massafra V, Pellicciari R, Gioiello A, van Mil SWC (2018) Progress and challenges of selective Farnesoid X Receptor modulation. Pharmacol Ther 191:162–177. https://doi.org/10.1016/j.pharmthera.2018.06.009
McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K et al (2013) Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 288:11761–11770. https://doi.org/10.1074/jbc.M112.446575
Mencarelli A, Renga B, Migliorati M, Cipriani S, Distrutti E, Santucci L et al (2009) The bile acid sensor farnesoid X receptor is a modulator of liver immunity in a rodent model of acute hepatitis. J Immunol 183:6657–6666. https://doi.org/10.4049/jimmunol.0901347
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, van Natta ML, Abdelmalek MF et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965. https://doi.org/10.1016/S0140-6736(14)61933-4
Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P et al (2016) A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 375:631–643. https://doi.org/10.1056/NEJMoa1509840
Perino A, Pols TW, Nomura M, Stein S, Pellicciari R, Schoonjans K (2014) TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J Clin Invest 124:5424–5436. https://doi.org/10.1172/JCI76289
Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C et al (2011) TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab 14:747–757. https://doi.org/10.1016/j.cmet.2011.11.006
RamĂrez-PĂ©rez O, Cruz-RamĂ³n V, Chinchilla-LĂ³pez P, MĂ©ndez-SĂ¡nchez N (2017) The role of the gut microbiota in bile acid metabolism. Ann Hepatol 16:s15–s20. https://doi.org/10.5604/01.3001.0010.5494
Renga B, Mencarelli A, Cipriani S, D’Amore C, Carino A, Bruno A et al (2013) The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation. PLoS One 8:e54472. https://doi.org/10.1371/journal.pone.0054472
Ridlon JM, Kang DJ, Hylemon PB (2006) Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47:241–259
Robinson MW, Harmon C, O’Farrelly C (2016) Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol 13:267–276. https://doi.org/10.1038/cmi.2016.3
Sakanaka T, Inoue T, Yorifuji N, Iguchi M, Fujiwara K, Narabayashi K et al (2015) The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice. J Gastroenterol Hepatol 30:60–65. https://doi.org/10.1111/jgh.12740
Schubert K, Olde Damink SWM, von Bergen M, Schaap FG (2017) Interactions between bile salts, gut microbiota, and hepatic innate immunity. Immunol Rev 279:23–35. https://doi.org/10.1111/imr.12579
Song Y, Liu C, Liu X, Trottier J, Beaudoin M, Zhang L et al (2017) H19 promotes cholestatic liver fibrosis by preventing ZEB1-mediated inhibition of epithelial cell adhesion molecule. Hepatology 66:1183–1196. https://doi.org/10.1002/hep.29209
Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE et al (2011) Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A 1:4523–4530. https://doi.org/10.1073/pnas.1006734107
U.S. Food and Drug Administration (FDA) (2018) FDA adds Boxed Warning to highlight correct dosing of Ocaliva (obeticholic acid) for patients with a rare chronic liver disease. U.S. Food and Drug Administration (FDA), Silver Spring. https://www.fda.gov/Drugs/DrugSafety/ucm594941.html
Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S (2009) The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 183:6251–6261. https://doi.org/10.4049/jimmunol.0803978
Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS et al (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 2:721–731
Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643. https://doi.org/10.1002/hep.22519
Wang YD, Chen WD, Yu D, Forman BM, Huang W (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 54:1421–1432. https://doi.org/10.1002/hep.24525
Wildenberg ME, van den Brink GR (2011) FXR activation inhibits inflammation and preserves the intestinal barrier in IBD. Gut 60:432–433. https://doi.org/10.1136/gut.2010.233304
Yang F, Huang X, Yi T, Yen Y, Moore DD, Huang W (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67:863–867
Yang Z, Koehler AN, Wang L (2016) A novel small molecule activator of nuclear receptor SHP inhibits HCC cell migration via suppressing Ccl2. Mol Cancer Ther 15:2294–2301. https://doi.org/10.1158/1535-7163.MCT-16-0153
Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT et al (2013) TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. Immunology 139:19–29. https://doi.org/10.1111/imm.12045
Zhang Y, Liu C, Barbier O, Smalling R, Tsuchiya H, Lee S et al (2016) Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci Rep 6:20559. https://doi.org/10.1038/srep20559
Zundler S, Neurath MF (2017) Novel insights into the mechanisms of gut homing and antiadhesion therapies in inflammatory bowel diseases. Inflamm Bowel Dis 23:617–627. https://doi.org/10.1097/MIB.000000000000106
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Biagioli, M., Carino, A. (2019). Signaling from Intestine to the Host: How Bile Acids Regulate Intestinal and Liver Immunity. In: Fiorucci, S., Distrutti, E. (eds) Bile Acids and Their Receptors. Handbook of Experimental Pharmacology, vol 256. Springer, Cham. https://doi.org/10.1007/164_2019_225
Download citation
DOI: https://doi.org/10.1007/164_2019_225
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-22004-4
Online ISBN: 978-3-030-22005-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)