J Rheum Dis.  2017 Oct;24(5):253-260. 10.4078/jrd.2017.24.5.253.

The Role of Bile Acid Receptors in Chronic Inflammatory Diseases

• Park R
• Ji JD

• KMID: 2394340
• DOI: http://doi.org/10.4078/jrd.2017.24.5.253

Abstract

With recent developments, biologic therapies has shown superior efficacy for rheumatic diseases compared with preexisting pharmacologic therapies, which are associated with high costs, non-response in certain patient groups, and severe adverse effects such as infections limiting their wide-spread use and revealing a need for the development of novel treatments. Since discovering the role of bile acid receptors in regulating inflammation, clinical trials evaluating the use of bile acid receptor agonists as a means to potentially treat various inflammatory disorders, such as alcoholic hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis have been ongoing. This review summarizes the results of studies on the anti-inflammatory effects and mechanisms of bile acid receptors and the results of previous to date looking at the use of bile acid receptor agonists in animal models of inflammatory disorders and clinical trials. Furthermore, we present the potentials of the bile acid receptor agonists in the treatment of inflammatory rheumatic diseases, including rheumatoid arthritis.

Keyword

Inflammation; Rheumatoid arthritis; Bile acid receptor

MeSH Terms

Arthritis, Rheumatoid
Bile*
Biological Therapy
Cholangitis, Sclerosing
Fatty Liver
Hepatitis, Alcoholic
Humans
Inflammation
Liver Cirrhosis, Biliary
Models, Animal
Rheumatic Diseases

Figure

• 

  Figure 1 Therapeutic applications of bile acid receptors in chronic inflammatory diseases. TGR5: Takeda G-protein-coupled receptor 5, FXR: farnesoid X receptor, NF-κB: nuclear factor- κB.

• 

  Figure 2 Regulatory mechanisms of inflammation and immune response by bile acid receptors. TLRs: toll-like receptors, NF-κB: nuclear factor-κB, AC: adenylyl cyclase, cAMP: cyclic adenosine 3',5'-monophosphate, PKA: protein kinase A, mTOR: mammalian target of rapamycin, C/EBPβ: CCAAT/enhancer-binding protein β, LIP: liver-enriched inhibitor protein, LAP: liver-enriched activator protein, NLRP3: Nod-like receptor pyrin domain containing 3, CREB: cAMP response element binding protein, CBP: CREB binding protein, NcoR: nuclear receptor corepressor, FXR: farnesoid X receptor, SUMO: small ubiquitin-like modifier.

Reference

1. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003; 423:356–361.

2. Caporali R, Pallavicini FB, Filippini M, Gorla R, Marchesoni A, Favalli EG, et al. Treatment of rheumatoid arthritis with anti-TNF-alpha agents: a reappraisal. Autoimmun Rev. 2009; 8:274–280.

3. Still GF. On a form of chronic joint disease in children. Med Chir Trans. 1897; 80:47–60.

4. Hench PS. Effect of jaundice on rheumatoid arthritis. Br Med J. 1938; 2:394–398.

5. Crocker I, Lawson N, Fletcher J. Effect of pregnancy and obstructive jaundice on inflammatory diseases: the work of P S Hench revisited. Ann Rheum Dis. 2002; 61:307–310.

6. Bruusgaard A, Andersen RB. Chenodeoxycholic-acid treatments of rheumatoid arthritis. Lancet. 1976; 1:700.

7. Bruusgaard A, Andersen RB. Effect of an intravenously administered bile acid (chenodeoxycholic acid) on rheumatoid arthritis. Scand J Rheumatol. 1975; 4:169–173.

8. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008; 7:678–693.

9. 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.

10. Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen EC, Renooij W, Murzilli S, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut. 2011; 60:463–472.

11. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016; 45:802–816.

12. Ho PP, Steinman L. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2016; 113:1600–1605.

13. Haselow K, Bode JG, Wammers M, Ehlting C, Keitel V, Kleinebrecht L, 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.

14. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011; 14:747–757.

15. 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 κ light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology. 2011; 54:1421–1432.

16. Lewis ND, Patnaude LA, Pelletier J, Souza DJ, Lukas SM, King FJ, et al. A GPBAR1 (TGR5) small molecule agonist shows specific inhibitory effects on myeloid cell activation in vitro and reduces experimental autoimmune encephalitis (EAE) in vivo. PLoS One. 2014; 9:e100883.

17. Shaik FB, Prasad DV, Narala VR. Role of farnesoid X receptor in inflammation and resolution. Inflamm Res. 2015; 64:9–20.

18. Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014; 11:55–67.

19. Zhu C, Fuchs CD, Halilbasic E, Trauner M. Bile acids in regulation of inflammation and immunity: friend or foe? Clin Exp Rheumatol. 2016; 34:4 Suppl 98. 25–31.

20. Ma H, Patti ME. Bile acids, obesity, and the metabolic syndrome. Best Pract Res Clin Gastroenterol. 2014; 28:573–583.

21. Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis. 2014; 46:302–312.

22. Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT, et al. TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. Immunology. 2013; 139:19–29.

23. Cho SW, An JH, Park H, Yang JY, Choi HJ, Kim SW, et al. Positive regulation of osteogenesis by bile acid through FXR. J Bone Miner Res. 2013; 28:2109–2121.

24. Perino A, Schoonjans K. TGR5 and immunometabolism: insights from physiology and pharmacology. Trends Pharmacol Sci. 2015; 36:847–857.

25. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein-coupled receptor responsive to bile acids. J Biol Chem. 2003; 278:9435–9440.

26. Renga B, Mencarelli A, Cipriani S, D'Amore C, Carino A, Bruno A, et al. The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation. PLoS One. 2013; 8:e54472.

27. Kim MS, Shigenaga J, Moser A, Feingold K, Grunfeld C. Repression of farnesoid X receptor during the acute phase response. J Biol Chem. 2003; 278:8988–8995.

28. Renga B, Migliorati M, Mencarelli A, Fiorucci S. Reciprocal regulation of the bile acid-activated receptor FXR and the interferon-gamma-STAT-1 pathway in macrophages. Biochim Biophys Acta. 2009; 1792:564–573.

29. 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.

30. McMahan RH, Wang XX, Cheng LL, Krisko T, Smith M, El Kasmi K, et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem. 2013; 288:11761–11770.

31. Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H, et al. Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway. Immunology. 2012; 136:153–162.

32. Kida T, Tsubosaka Y, Hori M, Ozaki H, Murata T. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2013; 33:1663–1669.

33. Duboc H, Aelion H, Rainteau D, Rajca S, Sokol H, Humbert L, et al. Crosstalk between the hepatologist and the cardiologist: a future place for the lithocholic acid as a coronary atheroma risk factor? Hepatology. 2012; 56:2426.

34. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One. 2011; 6:e25637.

35. Hov JR, Keitel V, Laerdahl JK, Spomer L, Ellinghaus E, ElSharawy A, et al. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One. 2010; 5:e12403.

36. Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology. 2008; 48:1632–1643.

37. Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol. 2009; 51:380–388.

38. Zhang S, Liu Q, Wang J, Harnish DC. Suppression of interleukin-6-induced C-reactive protein expression by FXR agonists. Biochem Biophys Res Commun. 2009; 379:476–479.

39. Mencarelli A, Renga B, Migliorati M, Cipriani S, Distrutti E, Santucci L, 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.

40. Mencarelli A, Renga B, Distrutti E, Fiorucci S. Antiatherosclerotic effect of farnesoid X receptor. Am J Physiol Heart Circ Physiol. 2009; 296:H272–H281.

41. Bishop-Bailey D, Walsh DT, Warner TD. Expression and activation of the farnesoid X receptor in the vasculature. Proc Natl Acad Sci U S A. 2004; 101:3668–3673.

42. Li YT, Swales KE, Thomas GJ, Warner TD, Bishop-Bailey D. Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol. 2007; 27:2606–2611.

43. Miyazaki-Anzai S, Masuda M, Levi M, Keenan AL, Miyazaki M. Dual activation of the bile acid nuclear receptor FXR and G-protein-coupled receptor TGR5 protects mice against atherosclerosis. PLoS One. 2014; 9:e108270.

44. Zhang L, Li T, Yu D, Forman BM, Huang W. FXR protects lung from lipopolysaccharide-induced acute injury. Mol Endocrinol. 2012; 26:27–36.

45. Shaik FB, Panati K, Narasimha VR, Narala VR. Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the T(H)2 cytokines. Biochem Biophys Res Commun. 2015; 463:600–605.

46. Perino A, Pols TW, 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.

47. Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med. 2015; 3:5.

48. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, 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.

49. Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCOXMLLink_XYZ3 output. Hepatology. 2011; 54:1303–1312.