Nutrition and the gut microbiome regulate many systems, including the immune, metabolic, and nervous systems. We propose that the host responds to deficiency (or sufficiency) of dietary and bacterial metabolites in a dynamic way, to optimize responses and survival. A family of G protein–coupled receptors (GPCRs) termed the metabolite-sensing GPCRs bind to various metabolites and transmit signals that are important for proper immune and metabolic functions. Members of this family include GPR43, GPR41, GPR109A, GPR120, GPR40, GPR84, GPR35, and GPR91. In addition, bile acid receptors such as GPR131 (TGR5) and proton-sensing receptors such as GPR65 show similar features. A consistent feature of this family of GPCRs is that they provide anti-inflammatory signals; many also regulate metabolism and gut homeostasis. These receptors represent one of the main mechanisms whereby the gut microbiome affects vertebrate physiology, and they also provide a link between the immune and metabolic systems. Insufficient signaling through one or more of these metabolite-sensing GPCRs likely contributes to human diseases such as asthma, food allergies, type 1 and type 2 diabetes, hepatic steatosis, cardiovascular disease, and inflammatory bowel diseases.


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Literature Cited

  1. Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF. 1.  1997. A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem. Biophys. Res. Commun. 239:543–47 [Google Scholar]
  2. Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. 2.  2014. The role of short-chain fatty acids in health and disease. Adv. Immunol. 121:91–119 [Google Scholar]
  3. Zelante T, Iannitti RG, Cunha C, De Luca A, Giovannini G. 3.  et al. 2013. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39:372–85 [Google Scholar]
  4. St-Onge MP, Jones PJ. 4.  2002. Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity. J. Nutr. 132:329–32 [Google Scholar]
  5. Niot I, Poirier H, Tran TT, Besnard P. 5.  2009. Intestinal absorption of long-chain fatty acids: evidence and uncertainties. Prog. Lipid Res. 48:101–15 [Google Scholar]
  6. Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S. 6.  et al. 2014. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5:3611 [Google Scholar]
  7. Page KA, Williamson A, Yu N, McNay EC, Dzuira J. 7.  et al. 2009. Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia. Diabetes 58:1237–44 [Google Scholar]
  8. Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F. 8.  et al. 2009. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461:1282–86 [Google Scholar]
  9. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H. 9.  et al. 2010. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142:687–98 [Google Scholar]
  10. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK. 10.  et al. 2003. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278:11303–11 [Google Scholar]
  11. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L. 11.  et al. 2003. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278:11312–19 [Google Scholar]
  12. Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V. 12.  et al. 2003. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278:25481–89 [Google Scholar]
  13. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T. 13.  et al. 2005. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11:90–94 [Google Scholar]
  14. Wang J, Wu X, Simonavicius N, Tian H, Ling L. 14.  2006. Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J. Biol. Chem. 281:34457–64 [Google Scholar]
  15. Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J. 15.  et al. 2006. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281:22021–28 [Google Scholar]
  16. Deng H, Hu H, Fang Y. 16.  2012. Multiple tyrosine metabolites are GPR35 agonists. Sci. Rep. 2:373 [Google Scholar]
  17. Lukasova M, Malaval C, Gille A, Kero J, Offermanns S. 17.  2011. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J. Clin. Investig. 121:1163–73 [Google Scholar]
  18. Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J. 18.  et al. 2008. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol. 9:1261–69 [Google Scholar]
  19. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R. 19.  et al. 2014. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:128–39 [Google Scholar]
  20. Venkataraman C, Kuo F. 20.  2005. The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking. Immunol. Lett. 101:144–53 [Google Scholar]
  21. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA. 21.  et al. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–73 [Google Scholar]
  22. Nøhr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS. 22.  et al. 2013. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells versus FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154:3552–64 [Google Scholar]
  23. Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H. 23.  et al. 2006. Short-chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res 324:353–60 [Google Scholar]
  24. Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L. 24.  et al. 2009. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E2 and cytokines. World J. Gastroenterol. 15:5549–57 [Google Scholar]
  25. Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K. 25.  et al. 2008. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J. Mol. Histol. 39:135–42 [Google Scholar]
  26. Senga T, Iwamoto S, Yoshida T, Yokota T, Adachi K. 26.  et al. 2003. LSSIG is a novel murine leukocyte-specific GPCR that is induced by the activation of STAT3. Blood 101:1185–87 [Google Scholar]
  27. Mamontov P, Neiman E, Cao T, Perrigoue J, Friedman J. 27.  et al. 2015. Effects of short chain fatty acids and GPR43 stimulation on human Treg function (IRC5P.631). J. Immunol. 194:58.14 [Google Scholar]
  28. Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K. 28.  et al. 2011. SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLOS ONE 6e21205 [Google Scholar]
  29. Macia L, Tan J, Vieira AT, Leach K, Stanley D. 29.  et al. 2015. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat. Commun. 6:6734 [Google Scholar]
  30. Kim M, Kang SG, Park JH, Yanagisawa M, Kim CH. 30.  2014. The commensal bacteria metabolites short chain fatty acids positively regulate epithelial innate immune responses in the gut (MUC4P.847). J. Immunol. 192:133.23 [Google Scholar]
  31. Mariño E, Richards JL, McLeod KH, Stanley D, Yap YA. 30a.  et al. 2017. Gut microbial metabolites limit autoimmune T cell frequencies and protect against type 1 diabetes. Nat. Immunol. In press [Google Scholar]
  32. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K. 31.  et al. 2013. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat. Commun. 4:1829 [Google Scholar]
  33. McNelis JC, Lee YS, Mayoral R, van der Kant R, Johnson AM. 32.  et al. 2015. GPR43 potentiates beta-cell function in obesity. Diabetes 64:3203–17 [Google Scholar]
  34. Bahar Halpern K, Veprik A, Rubins N, Naaman O, Walker MD. 33.  2012. GPR41 gene expression is mediated by internal ribosome entry site (IRES)-dependent translation of bicistronic mRNA encoding GPR40 and GPR41 proteins. J. Biol. Chem. 287:20154–63 [Google Scholar]
  35. Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T. 34.  et al. 2004. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. PNAS 101:1045–50 [Google Scholar]
  36. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C. 35.  et al. 2014. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 156:84–96 [Google Scholar]
  37. Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N. 36.  et al. 2014. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20:159–66 [Google Scholar]
  38. Puhl HL 3rd, Won YJ, Lu VB, Ikeda SR. 37.  2015. Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed. Sci. Rep. 5:12880 [Google Scholar]
  39. Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP. 38.  et al. 2009. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res 69:2826–32 [Google Scholar]
  40. Digby JE, Martinez F, Jefferson A, Ruparelia N, Chai J. 39.  et al. 2012. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler. Thromb. Vasc. Biol. 32:669–76 [Google Scholar]
  41. Zandi-Nejad K, Takakura A, Jurewicz M, Chandraker AK, Offermanns S. 40.  et al. 2013. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J 27:4366–74 [Google Scholar]
  42. Digby JE, McNeill E, Dyar OJ, Lam V, Greaves DR, Choudhury RP. 41.  2010. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin. Atherosclerosis 209:89–95 [Google Scholar]
  43. Gambhir D, Ananth S, Veeranan-Karmegam R, Elangovan S, Hester S. 42.  et al. 2012. GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Investig. Ophthalmol. Vis. Sci. 53:2208–17 [Google Scholar]
  44. Tang Y, Chen Y, Jiang H, Robbins GT, Nie D. 43.  2011. G-protein-coupled receptor for short-chain fatty acids suppresses colon cancer. Int. J. Cancer 128:847–56 [Google Scholar]
  45. Irukayama-Tomobe Y, Tanaka H, Yokomizo T, Hashidate-Yoshida T, Yanagisawa M, Sakurai T. 44.  2009. Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor, GPR109B. PNAS 106:3930–34 [Google Scholar]
  46. Ahmed K, Tunaru S, Langhans CD, Hanson J, Michalski CW. 45.  et al. 2009. Deorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis. J. Biol. Chem. 284:21928–33 [Google Scholar]
  47. Suzuki M, Takaishi S, Nagasaki M, Onozawa Y, Iino I. 46.  et al. 2013. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J. Biol. Chem. 288:10684–91 [Google Scholar]
  48. Nagasaki H, Kondo T, Fuchigami M, Hashimoto H, Sugimura Y. 47.  et al. 2012. Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes. FEBS Lett 586:368–72 [Google Scholar]
  49. Bouchard C, Page J, Bedard A, Tremblay P, Vallieres L. 48.  2007. G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions. Glia 55:790–800 [Google Scholar]
  50. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R. 49.  et al. 2003. Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422:173–76 [Google Scholar]
  51. Li M, Meng X, Xu J, Huang X, Li H. 50.  et al. 2016. GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway. Sci. Rep. 6:25237 [Google Scholar]
  52. Fujita T, Matsuoka T, Honda T, Kabashima K, Hirata T, Narumiya S. 51.  2011. A GPR40 agonist GW9508 suppresses CCL5, CCL17, and CXCL10 induction in keratinocytes and attenuates cutaneous immune inflammation. J. Invest. Dermatol. 131:1660–67 [Google Scholar]
  53. Mobraten K, Haug TM, Kleiveland CR, Lea T. 52.  2013. Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids Health Dis 12:101 [Google Scholar]
  54. Calder PC. 53.  2005. Polyunsaturated fatty acids and inflammation. Biochem. Soc. Trans. 33:423–27 [Google Scholar]
  55. Simopoulos AP. 54.  2002. Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr. 21:495–505 [Google Scholar]
  56. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D. 55.  et al. 2013. Primary prevention of cardiovascular disease with a Mediterranean diet. N. Engl. J. Med. 368:1279–90 [Google Scholar]
  57. Iwasaki K, Harada N, Sasaki K, Yamane S, Iida K. 56.  et al. 2015. Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K cells of the upper small intestine and has a critical role in GIP secretion after fat ingestion. Endocrinology 156:837–46 [Google Scholar]
  58. Konno Y, Ueki S, Takeda M, Kobayashi Y, Tamaki M. 57.  et al. 2015. Functional analysis of free fatty acid receptor GPR120 in human eosinophils: implications in metabolic homeostasis. PLOS ONE 10:e0120386 [Google Scholar]
  59. Anbazhagan AN, Priyamvada S, Gujral T, Bhattacharyya S, Alrefai WA. 58.  et al. 2016. A novel anti-inflammatory role of GPR120 in intestinal epithelial cells. Am. J. Physiol. Cell Physiol. 310:C612–21 [Google Scholar]
  60. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP. 59.  et al. 2012. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–24 [Google Scholar]
  61. Hubbard TD, Murray IA, Perdew GH. 60.  2015. Indole and tryptophan metabolism: endogenous and dietary routes to Ah receptor activation. Drug Metab. Dispos. 43:1522–35 [Google Scholar]
  62. Maravillas-Montero JL, Burkhardt AM, Hevezi PA, Carnevale CD, Smit MJ, Zlotnik A. 61.  2015. Cutting edge: GPR35/CXCR8 is the receptor of the mucosal chemokine CXCL17. J. Immunol. 194:29–33 [Google Scholar]
  63. He W, Miao FJ, Lin DC, Schwandner RT, Wang Z. 62.  et al. 2004. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429:188–93 [Google Scholar]
  64. Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J. 63.  et al. 2016. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J. Exp. Med. 213:1655–62 [Google Scholar]
  65. Ishii S, Kihara Y, Shimizu T. 64.  2005. Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein-coupled receptor. J. Biol. Chem. 280:9083–87 [Google Scholar]
  66. Im D-S, Heise CE, Nguyen T, O'Dowd BF, Lynch KR. 65.  2001. Identification of a molecular target of psychosine and its role in globoid cell formation. J. Cell Biol. 153:429–34 [Google Scholar]
  67. Kyaw H, Zeng Z, Su K, Fan P, Shell BK. 66.  et al. 1998. Cloning, characterization, and mapping of human homolog of mouse T-cell death-associated gene. DNA Cell Biol 17:493–500 [Google Scholar]
  68. Kottyan LC, Collier AR, Cao KH, Niese KA, Hedgebeth M. 67.  et al. 2009. Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner. Blood 114:2774–82 [Google Scholar]
  69. Zhu X, Mose E, Hogan SP, Zimmermann N. 68.  2014. Differential eosinophil and mast cell regulation: Mast cell viability and accumulation in inflammatory tissue are independent of proton-sensing receptor GPR65. Am. J. Physiol. Gastrointest. Liver Physiol. 306:G974–82 [Google Scholar]
  70. Choi JW, Lee SY, Choi Y. 69.  1996. Identification of a putative G protein-coupled receptor induced during activation-induced apoptosis of T cells. Cell Immunol 168:78–84 [Google Scholar]
  71. Tosa N, Murakami M, Jia WY, Yokoyama M, Masunaga T. 70.  et al. 2003. Critical function of T cell death-associated gene 8 in glucocorticoid-induced thymocyte apoptosis. Int. Immunol. 15:741–49 [Google Scholar]
  72. Ryder C, McColl K, Zhong F, Distelhorst CW. 71.  2012. Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor GPR65 signaling to MEK/ERK. J. Biol. Chem. 287:27863–75 [Google Scholar]
  73. Rosko AE, McColl KS, Zhong F, Ryder CB, Chang MJ. 72.  et al. 2014. Acidosis sensing receptor GPR65 correlates with anti-apoptotic Bcl-2 family member expression in CLL cells: potential implications for the CLL microenvironment. J. Leuk. 2:160 [Google Scholar]
  74. Franke A, McGovern DPB, Barrett JC, Wang K, Radford-Smith GL. 73.  et al. 2010. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat. Genet. 42:1118–25 [Google Scholar]
  75. Ke X. 74.  2012. Presence of multiple independent effects in risk loci of common complex human diseases. Am. J. Hum. Genet. 91:185–92 [Google Scholar]
  76. Ballester V, Guo X, Vendrell R, Haritunians T, Klomhaus AM. 75.  et al. 2014. Association of NOD2 and IL23R with inflammatory bowel disease in Puerto Rico. PLOS ONE 9:e108204 [Google Scholar]
  77. Lassen KG, McKenzie CI, Mari M, Murano T, Begun J. 76.  et al. 2016. Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity 44:1392–1405 [Google Scholar]
  78. Brestoff JR, Artis D. 77.  2013. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol. 14:676–84 [Google Scholar]
  79. Ding L, Yang L, Wang Z, Huang W. 78.  2015. Bile acid nuclear receptor FXR and digestive system diseases. Acta Pharm. Sin. B 5:135–44 [Google Scholar]
  80. Wahlström A, Sayin SI, Marschall H-U, Bäckhed F. 79.  2016. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 24:41–50 [Google Scholar]
  81. Duboc H, Tache Y, Hofmann AF. 80.  2014. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig. Liver. Dis. 46:302–12 [Google Scholar]
  82. Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B. 81.  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 [Google Scholar]
  83. Perino A, Pols TW, Nomura M, Stein S, Pellicciari R, Schoonjans K. 82.  2014. TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J. Clin. Investig. 124:5424–36 [Google Scholar]
  84. Guo C, Xie S, Chi Z, Zhang J, Liu Y. 83.  et al. 2016. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity 45:944 [Google Scholar]
  85. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID. 84.  et al. 2011. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. PNAS 108:Suppl. 14523–30 [Google Scholar]
  86. Liu C, Wu J, Zhu J, Kuei C, Yu J. 85.  et al. 2009. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284:2811–22 [Google Scholar]
  87. Ljungh A, Wadstrom T. 86.  2006. Lactic acid bacteria as probiotics. Curr. Issues Intest. Microbiol. 7:73–89 [Google Scholar]
  88. Khor B, Gardet A, Xavier RJ. 87.  2011. Genetics and pathogenesis of inflammatory bowel disease. Nature 474:307–17 [Google Scholar]
  89. de Valliere C, Wang Y, Eloranta JJ, Vidal S, Clay I. 88.  et al. 2015. G protein-coupled pH-sensing receptor OGR1 is a regulator of intestinal inflammation. Inflamm. Bowel Dis. 21:1269–81 [Google Scholar]
  90. Cohen LJ, Kang HS, Chu J, Huang YH, Gordon EA. 89.  et al. 2015. Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist. PNAS 112:E4825–34 [Google Scholar]
  91. Obinata H, Hattori T, Nakane S, Tatei K, Izumi T. 90.  2005. Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. J. Biol. Chem. 280:40676–83 [Google Scholar]
  92. Guo Y, Zhang W, Giroux C, Cai Y, Ekambaram P. 91.  et al. 2011. Identification of the orphan G protein-coupled receptor GPR31 as a receptor for 12-(S)-hydroxyeicosatetraenoic acid. J. Biol. Chem. 286:33832–40 [Google Scholar]
  93. Hosoi T, Koguchi Y, Sugikawa E, Chikada A, Ogawa K. 92.  et al. 2002. Identification of a novel human eicosanoid receptor coupled to Gi/o. J. Biol. Chem. 277:31459–65 [Google Scholar]
  94. Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH. 93.  et al. 2010. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. PNAS 107:1660–65 [Google Scholar]
  95. Schmid M, Gemperle C, Rimann N, Hersberger M. 94.  2016. Resolvin D1 polarizes primary human macrophages toward a proresolution phenotype through GPR32. J. Immunol. 196:3429–37 [Google Scholar]
  96. Godlewski G, Offertaler L, Wagner JA, Kunos G. 95.  2009. Receptors for acylethanolamides—GPR55 and GPR119. Prostaglandins Other Lipid Mediat 89:105–11 [Google Scholar]
  97. Henstridge CM, Balenga NA, Ford LA, Ross RA, Waldhoer M, Irving AJ. 96.  2009. The GPR55 ligand L-α-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB J 23:183–93 [Google Scholar]
  98. Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW. 97.  et al. 2013. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340:1456–59 [Google Scholar]
  99. Gardner J, Wu S, Ling L, Danao J, Li Y. 98.  et al. 2012. G-protein-coupled receptor GPR21 knockout mice display improved glucose tolerance and increased insulin response. Biochem. Biophys. Res. Commun. 418:1–5 [Google Scholar]
  100. Osborn O, Oh DY, McNelis J, Sanchez-Alavez M, Talukdar S. 99.  et al. 2012. G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice. J. Clin. Investig. 122:2444–53 [Google Scholar]
  101. Isberg V, Andersen KB, Bisig C, Dietz GP, Brauner-Osborne H, Gloriam DE. 100.  2014. Computer-aided discovery of aromatic L-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139. J. Chem. Inf. Model. 54:1553–57 [Google Scholar]
  102. Gao H, Sun Y, Wu Y, Luan B, Wang Y. 101.  et al. 2004. Identification of β-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-κB pathways. Mol. Cell 14:303–17 [Google Scholar]
  103. Lee SU, In HJ, Kwon MS, Park BO, Jo M. 102.  et al. 2013. β-Arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor-κB. Biol. Pharm. Bull. 36:1754–59 [Google Scholar]
  104. Chai JT, Digby JE, Choudhury RP. 103.  2013. GPR109A and vascular inflammation. Curr. Atheroscler. Rep. 15:325 [Google Scholar]
  105. Violin JD, Lefkowitz RJ. 104.  2007. β-Arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28:416–22 [Google Scholar]
  106. Kim HY, Jadhav VB, Jeong DY, Park WK, Song JH. 105.  et al. 2015. Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor. Arch. Pharm. Res. 38:1019–32 [Google Scholar]
  107. Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM. 106.  et al. 2009. β-Arrestin1 mediates nicotinic acid-induced flushing, but not its antilipolytic effect, in mice. J. Clin. Investig. 119:1312–21 [Google Scholar]
  108. Tedelind S, Westberg F, Kjerrulf M, Vidal A. 107.  2007. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J. Gastroenterol. 13:2826–32 [Google Scholar]
  109. Place RF, Noonan EJ, Giardina C. 108.  2005. HDAC inhibition prevents NF-κB activation by suppressing proteasome activity: Down-regulation of proteasome subunit expression stabilizes Iκβα. Biochem. Pharmacol. 70:394–406 [Google Scholar]
  110. Xu X, Ye L, Araki K, Ahmed R. 109.  2012. mTOR, linking metabolism and immunity. Semin. Immunol. 24:429–35 [Google Scholar]
  111. Park J, Kim M, Kang SG, Jannasch AH, Cooper B. 110.  et al. 2015. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol 8:80–93 [Google Scholar]
  112. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA. 111.  et al. 2011. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145:745–57 [Google Scholar]
  113. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R. 112.  et al. 2012. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492:123–27 [Google Scholar]
  114. Murakami T, Ockinger J, Yu J, Byles V, McColl A. 113.  et al. 2012. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. PNAS 109:11282–87 [Google Scholar]
  115. Kahlenberg JM, Dubyak GR. 114.  2004. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am. J. Physiol. Cell Physiol. 286:C1100–8 [Google Scholar]
  116. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. 115.  2013. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142–53 [Google Scholar]
  117. Vieira AT, Macia L, Galvao I, Martins FS, Canesso MC. 116.  et al. 2015. A role for gut microbiota and the metabolite-sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol 67:1646–56 [Google Scholar]
  118. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J. 117.  et al. 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:451–55 [Google Scholar]
  119. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G. 118.  et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–50 [Google Scholar]
  120. Tan J, McKenzie C, Vuillermin PJ, Goverse G, Vinuesa CG. 119.  et al. 2016. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep 15:2809–24 [Google Scholar]
  121. Kamp ME, Shim R, Nicholls AJ, Oliverira AC, Mason LJ. 120.  et al. 2016. G protein-coupled receptor 43 modulates neutrophil recruitment during acute inflammation. PLOS ONE 11:9e0163750 [Google Scholar]
  122. Barth MC, Ahluwalia N, Anderson TJ, Hardy GJ, Sinha S. 121.  et al. 2009. Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. J. Biol. Chem. 284:19189–95 [Google Scholar]
  123. Li J, Wang Y, Tang L, de Villiers WJ, Cohen D. 122.  et al. 2013. Dietary medium-chain triglycerides promote oral allergic sensitization and orally induced anaphylaxis to peanut protein in mice. J. Allergy Clin. Immunol. 131:442–50 [Google Scholar]
  124. Perez CJ, Dumas A, Vallieres L, Guenet JL, Benavides F. 123.  2013. Several classical mouse inbred strains, including DBA/2, NOD/Lt, FVB/N, and SJL/J, carry a putative loss-of-function allele of Gpr84. J. Hered. 104:565–71 [Google Scholar]
  125. Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS. 124.  et al. 2008. The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat. Med. 14:1067–76 [Google Scholar]
  126. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF. 125.  et al. 2013. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496:238–42 [Google Scholar]
  127. Harig JM, Soergel KH, Komorowski RA, Wood CM. 126.  1989. Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 320:23–8 [Google Scholar]
  128. Steinhart AH, Brzezinski A, Baker JP. 127.  1994. Treatment of refractory ulcerative proctosigmoiditis with butyrate enemas. Am. J. Gastroenterol. 89:179–83 [Google Scholar]
  129. Scheppach W, Sommer H, Kirchner T, Paganelli GM, Bartram P. 128.  et al. 1992. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 103:51–6 [Google Scholar]
  130. Butzner JD, Parmar R, Bell CJ, Dalal V. 129.  1996. Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. Gut 38:568–73 [Google Scholar]
  131. Huda-Faujan N, Abdulamir AS, Fatimah AB, Anas OM, Shuhaimi M. 130.  et al. 2010. The impact of the level of the intestinal short chain fatty acids in inflammatory bowel disease patients versus healthy subjects. Open Biochem. J. 4:53–58 [Google Scholar]
  132. Segain JP, Raingeard de la Bletiere D, Bourreille A, Leray V, Gervois N. 131.  et al. 2000. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn's disease. Gut 47:397–403 [Google Scholar]
  133. Luhrs H, Gerke T, Boxberger F, Backhaus K, Melcher R. 132.  et al. 2001. Butyrate inhibits interleukin-1-mediated nuclear factor-kappa B activation in human epithelial cells. Dig. Dis. Sci. 46:1968–73 [Google Scholar]
  134. Yin L, Laevsky G, Giardina C. 133.  2001. Butyrate suppression of colonocyte NF-κB activation and cellular proteasome activity. J. Biol. Chem. 276:44641–46 [Google Scholar]
  135. Fukuda S, Toh H, Hase K, Oshima K, Nakanishi Y. 134.  et al. 2011. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469:543–47 [Google Scholar]
  136. Olszak T, An D, Zeissig S, Vera MP, Richter J. 135.  et al. 2012. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336:489–93 [Google Scholar]
  137. Herbst T, Sichelstiel A, Schar C, Yadava K, Burki K. 136.  et al. 2011. Dysregulation of allergic airway inflammation in the absence of microbial colonization. Am. J. Respir. Crit. Care Med. 184:198–205 [Google Scholar]
  138. Perry RJ, Peng L, Barry NA, Cline GW, Zhang D. 137.  et al. 2016. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 534:213–17 [Google Scholar]
  139. Tang C, Ahmed K, Gille A, Lu S, Grone HJ. 138.  et al. 2015. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat. Med. 21:173–77 [Google Scholar]
  140. Thorburn AN, McKenzie CI, Shen S, Stanley D, Macia L. 139.  et al. 2015. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat. Commun. 6:7320 [Google Scholar]
  141. Stefka AT, Feehley T, Tripathi P, Qiu J, McCoy K. 140.  et al. 2014. Commensal bacteria protect against food allergen sensitization. PNAS 111:13145–50 [Google Scholar]
  142. Hinterleitner R, Jabri B. 141.  2016. A dendritic cell subset designed for oral tolerance. Nat. Immunol. 17:474–76 [Google Scholar]
  143. Park Y, Subar AF, Hollenbeck A, Schatzkin A. 142.  2011. Dietary fiber intake and mortality in the NIH-AARP diet and health study. Arch. Intern. Med. 171:1061–68 [Google Scholar]
  144. Marques FZ, Nelson EM, Chu P-Y, Horlock D, Fiedler A. 142a.  et al. 2011. High fibre diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in DOCA-salt hypertensive mice. Circulation. In press. https://doi.org/10.1161/CIRCULATIONAHA.116.024545 [Google Scholar]
  145. Ignarro LJ, Balestrieri ML, Napoli C. 143.  2007. Nutrition, physical activity, and cardiovascular disease: an update. Cardiovasc. Res. 73:326–40 [Google Scholar]
  146. Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M. 144.  et al. 2013. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am. J. Clin. Nutr. 98:111–20 [Google Scholar]
  147. Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM. 145.  et al. 2012. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br. J. Cancer 107:1337–44 [Google Scholar]
  148. Wu Q, Wang H, Zhao X, Shi Y, Jin M. 146.  et al. 2013. Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma. Oncogene 32:5541–50 [Google Scholar]
  149. Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L. 147.  et al. 2008. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455:1109–13 [Google Scholar]
  150. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM. 148.  et al. 2013. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–88 [Google Scholar]
  151. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J. 149.  et al. 2013. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309:2473–79 [Google Scholar]
  152. McKenzie CI, Mackay CR, Macia L. 150.  2015. GPR43—a prototypic metabolite sensor linking metabolic and inflammatory diseases. Trends Endocrinol. Metab. 26:511–12 [Google Scholar]
  153. Maslowski KM, Mackay CR. 151.  2011. Diet, gut microbiota and immune responses. Nat. Immunol. 12:5–9 [Google Scholar]
  154. Kamanna VS, Ganji SH, Kashyap ML. 152.  2009. The mechanism and mitigation of niacin-induced flushing. Int. J. Clin. Pract. 63:1369–77 [Google Scholar]
  155. Thorburn AN, Macia L, Mackay CR. 153.  2014. Diet, metabolites, and “western-lifestyle” inflammatory diseases. Immunity 40:833–42 [Google Scholar]
  156. Oka S, Ota R, Shima M, Yamashita A, Sugiura T. 154.  2010. GPR35 is a novel lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 395:232–37 [Google Scholar]
  157. Hakak Y, Lehmann-Bruinsma K, Phillips S, Le T, Liaw C. 155.  et al. 2009. The role of the GPR91 ligand succinate in hematopoiesis. J. Leukoc. Biol. 85:837–43 [Google Scholar]

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