New Role for Fatty Acid Receptor Regulation of Immune Cells to Control Intestinal Inflammation

See “GPR120 inhibits colitis through regulation of CD4+T cell interleukin 10 production” by Yang W, Liu H, Xu L, et al, on page 150.The mechanisms through which diet influences susceptibility to or modifies inflammatory bowel disease (IBD) are poorly understood. The <50% penetrance of IBD in identical twins of affected individuals and the rapid increase in its incidence during the 21st century are only explained by strong environmental influences on disease development.1Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321.e2Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Diets rich in fish or their abundant fat long-chain omega-3 (ω3) polyunsaturated fatty acids (PUFAs) are associated with a reduced risk of IBD, in particular ulcerative colitis (UC).2Mozaffari H. Daneshzad E. Larijani B. et al.Dietary intake of fish, n-3 polyunsaturated fatty acids, and risk of inflammatory bowel disease: a systematic review and meta-analysis of observational studies.Europ J Nutr. 2020; 59: 1-17Crossref PubMed Scopus (58) Google Scholar,3Ananthakrishnan A.N. Khalili H. Konijeti G.G. et al.Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.Gut. 2014; 63: 776Crossref PubMed Scopus (279) Google Scholar Clinical trials of ω3 PUFAs for the treatment of IBD have produced mixed results. Some showed positive results for induction of remission in UC and maintenance of remission in Crohn’s disease (CD); others have not demonstrated an effect on disease course.4Mullin G.E. Limketkai B.N. Parian A.M. Fish oil for inflammatory bowel disease panacea or placebo?.Gastroenterol Clin North Am. 2021; 50: 169-182Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholarω3 PUFAs exert anti-inflammatory effects through several established mechanisms (Figure 1).4Mullin G.E. Limketkai B.N. Parian A.M. Fish oil for inflammatory bowel disease panacea or placebo?.Gastroenterol Clin North Am. 2021; 50: 169-182Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar,5Li X. Bi X. Wang S. et al.Therapeutic potential of ω-3 polyunsaturated fatty acids in human autoimmune diseases.Front Immunol. 2019; 10: 2241Crossref PubMed Scopus (62) Google Scholar They inhibit the conversion of arachidonic acid to proinflammatory prostaglandins and leukotrienes and are directly metabolized to anti-inflammatory resolvins. Free fatty acids are also ligands for cell surface receptors, and the G-protein-coupled receptor (GPCR) GPR120 is the receptor for long-chain ω3 PUFAs.6Oh D.Y. Talukdar S. Bae E.J. et al.GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.Cell. 2010; 142: 687-698Abstract Full Text Full Text PDF PubMed Scopus (1714) Google Scholar ω3 PUFAs regulate obesity and lipid metabolism by signaling through GPR120 on macrophages to down-regulate nuclear factor kappa B activation and production of proinflammatory cytokines.6Oh D.Y. Talukdar S. Bae E.J. et al.GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.Cell. 2010; 142: 687-698Abstract Full Text Full Text PDF PubMed Scopus (1714) Google Scholar,7Oh D.Y. Walenta E. Akiyama T.E. et al.A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.Nat Med. 2014; 20: 942-947Crossref PubMed Scopus (259) Google Scholar In this issue of Gastroenterology, Yang et al8Yang W. Liu H. Xu L. et al.GPR120 inhibits colitis through regulation of CD4+ T cell interleukin 10 production.Gastroenterology. 2022; 162: 150-165Abstract Full Text Full Text PDF Scopus (3) Google Scholar demonstrate the importance of signaling through GPR120 in another immune cell type, CD4+ T helper cells, for inducing the regulatory cytokine interleukin (IL) 10 and controlling intestinal inflammation.Based on the observation of high GPR120 expression in CD4+ T helper cells compared with other immune cell types, the authors tested the role of GPR120 expressed specifically in CD4+ T cells for regulating intestinal homeostasis. They applied parallel experimental approaches, including inducing colitis through epithelial injury or infection in mice deficient for GPR120 only in CD4+ T cells, and by transferring CD4+ T cells deficient for GPR120 or treated with a GPR120 selective agonist into immunodeficient mice. Collectively, these complementary experiments supported a role for GPR120 signaling ameliorating colitis in association with increased IL10 production by CD4+ T cells. Interestingly, GPR120 signaling did not induce forkhead box P3-expressing T regulatory cells, the classical cellular source of IL10. Colitis was not mitigated by GPR120 agonist-treatment of T cells deficient for IL10, confirming the requirement of IL10 for colitis protection. The importance of IL10 as a critical regulatory cytokine for preventing chronic IBD in humans is well established. Rare biallelic genetic mutations in the IL10 receptor cause severe very early–onset IBD and common genetic variation in IL10 is associated with IBD.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3153) Google Scholar,10Glocker E.-O. Kotlarz D. Boztug K. et al.Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.N Engl J Med. 2009; 361: 2033-2045Crossref PubMed Scopus (1047) Google ScholarThe investigators used in vitro approaches to isolate the effect of GPR120 signaling directly on CD4+ T cells and to determine the underlying intracellular mechanisms. Treatment with a GPR120 agonist induced IL10 production in naïve CD4+ T cells and interferon-γ–producing Th1 cells, but not Th17 or T regulatory cells. Importantly, they demonstrated that a natural dietary ligand for GPR120, the ω3 PUFA docosahexaenoic acid, also increased IL10 production by Th1 cells. Using differential gene expression analysis, T-cell-specific genetic deletion, and chemical inhibitor experiments, they showed that GPR120 induces a mechanistic target of rapamycin (mTOR)–signal transducer and activator of transcription 3 intracellular signaling pathway to increase expression of the transcription factor B lymphocyte–induced maturation protein-1 (BLIMP-1), which, in turn, promotes IL10 production. Interestingly, rare missense mutations in the gene encoding BLIMP-1 that impair its expression have been associated with CD.11Ellinghaus D. Zhang H. Zeissig S. et al.Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies.Gastroenterology. 2013; 145: 339-347Abstract Full Text Full Text PDF PubMed Scopus (115) Google ScholarDifferential CD4+ T-cell gene expression after GPR120 activation also suggested effects on cellular metabolism. There is increased recognition that cellular metabolism is as important as intracellular signaling for regulating T-cell fate and function.12Bantug G.R. Galluzzi L. Kroemer G. et al.The spectrum of T cell metabolism in health and disease.Nat Rev Immunol. 2018; 18: 19-34Crossref PubMed Scopus (219) Google Scholar Using extracellular flux analysis to metabolically profile cells, the investigators found that GPR120 stimulation enhanced both oxidative phosphorylation and glycolysis in CD4+ T cells. Additional experiments revealed that GPR120 activation increases glycolysis through mTOR signaling, leading to induction of hypoxia-inducible factor 1α, which also stimulates IL10 production.To determine relevance of these observations to human disease, the authors analyzed tissue gene expression from a publicly available UC data set and locally collected IBD tissues. They found GPR120 expression was increased in UC and generally correlated with IL10 expression. Future experiments associating GPR120 expression with phenotypic characterization and cytokine production from live CD4+ T cells from patients with IBD or testing the effect of GPR120 activation on such cells will be needed to strengthen the case for human relevance.There is strong precedent for GPCRs as drug targets. In fact, GPCRs account for the therapeutic effect of one third of small molecule drugs.13Santos R. Ursu O. Gaulton A. et al.A comprehensive map of molecular drug targets.Nat Rev Drug Discov. 2017; 16: 19-34Crossref PubMed Scopus (1067) Google Scholar Perhaps this better understanding of how the natural ligand ω3 PUFA may mitigate risk for IBD through GPR120 could lead to new IBD drug development. Indeed, the investigators established proof of this principle by demonstrating oral administration of a GPR120 agonist improved colitis induced by naïve T-cell transfer into immunodeficient mice when administered prior (prevention) and after (treatment) colitis onset. Importantly, the effect required expression of GPR120 on CD4+ cells. It should be noted that this T-cell–driven model of colitis may be particularly amenable to such a T-cell–directed treatment compared with other models or human disease with a more complex immunopathogenesis. One drug with GPR120 agonist activity has been studied in a small phase 2 trial to examine effects on insulin resistance in obese adults. Notably, treatment was generally well-tolerated and associated with a reduction in plasma tumor necrosis factor levels.14Kern P.A. Finlin B.S. Ross D. et al.Effects of KDT501 on metabolic parameters in insulin-resistant prediabetic humans.J Endocr Soc. 2017; 1: 650-659Crossref PubMed Scopus (19) Google Scholar Past clinical trials of IL10 therapy have not been able to establish efficacy for IBD treatment, but may have been hampered by the short half-life of IL10 or limited mucosal penetration.15Wang X. Wong K. Ouyang W. et al.Targeting IL-10 family cytokines for the treatment of human diseases.Cold Spring Harb Perspect Biol. 2019; 11: a028548Crossref PubMed Scopus (85) Google Scholar This work draws a nutrient receptor into the spotlight as a potential drug target for biochemically reprograming our own T cells to produce more IL10 in the hopes of restoring or maintaining intestinal mucosal homeostasis. See “GPR120 inhibits colitis through regulation of CD4+T cell interleukin 10 production” by Yang W, Liu H, Xu L, et al, on page 150. See “GPR120 inhibits colitis through regulation of CD4+T cell interleukin 10 production” by Yang W, Liu H, Xu L, et al, on page 150. See “GPR120 inhibits colitis through regulation of CD4+T cell interleukin 10 production” by Yang W, Liu H, Xu L, et al, on page 150. The mechanisms through which diet influences susceptibility to or modifies inflammatory bowel disease (IBD) are poorly understood. The <50% penetrance of IBD in identical twins of affected individuals and the rapid increase in its incidence during the 21st century are only explained by strong environmental influences on disease development.1Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2017; 152: 313-321.e2Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Diets rich in fish or their abundant fat long-chain omega-3 (ω3) polyunsaturated fatty acids (PUFAs) are associated with a reduced risk of IBD, in particular ulcerative colitis (UC).2Mozaffari H. Daneshzad E. Larijani B. et al.Dietary intake of fish, n-3 polyunsaturated fatty acids, and risk of inflammatory bowel disease: a systematic review and meta-analysis of observational studies.Europ J Nutr. 2020; 59: 1-17Crossref PubMed Scopus (58) Google Scholar,3Ananthakrishnan A.N. Khalili H. Konijeti G.G. et al.Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.Gut. 2014; 63: 776Crossref PubMed Scopus (279) Google Scholar Clinical trials of ω3 PUFAs for the treatment of IBD have produced mixed results. Some showed positive results for induction of remission in UC and maintenance of remission in Crohn’s disease (CD); others have not demonstrated an effect on disease course.4Mullin G.E. Limketkai B.N. Parian A.M. Fish oil for inflammatory bowel disease panacea or placebo?.Gastroenterol Clin North Am. 2021; 50: 169-182Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar ω3 PUFAs exert anti-inflammatory effects through several established mechanisms (Figure 1).4Mullin G.E. Limketkai B.N. Parian A.M. Fish oil for inflammatory bowel disease panacea or placebo?.Gastroenterol Clin North Am. 2021; 50: 169-182Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar,5Li X. Bi X. Wang S. et al.Therapeutic potential of ω-3 polyunsaturated fatty acids in human autoimmune diseases.Front Immunol. 2019; 10: 2241Crossref PubMed Scopus (62) Google Scholar They inhibit the conversion of arachidonic acid to proinflammatory prostaglandins and leukotrienes and are directly metabolized to anti-inflammatory resolvins. Free fatty acids are also ligands for cell surface receptors, and the G-protein-coupled receptor (GPCR) GPR120 is the receptor for long-chain ω3 PUFAs.6Oh D.Y. Talukdar S. Bae E.J. et al.GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.Cell. 2010; 142: 687-698Abstract Full Text Full Text PDF PubMed Scopus (1714) Google Scholar ω3 PUFAs regulate obesity and lipid metabolism by signaling through GPR120 on macrophages to down-regulate nuclear factor kappa B activation and production of proinflammatory cytokines.6Oh D.Y. Talukdar S. Bae E.J. et al.GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.Cell. 2010; 142: 687-698Abstract Full Text Full Text PDF PubMed Scopus (1714) Google Scholar,7Oh D.Y. Walenta E. Akiyama T.E. et al.A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.Nat Med. 2014; 20: 942-947Crossref PubMed Scopus (259) Google Scholar In this issue of Gastroenterology, Yang et al8Yang W. Liu H. Xu L. et al.GPR120 inhibits colitis through regulation of CD4+ T cell interleukin 10 production.Gastroenterology. 2022; 162: 150-165Abstract Full Text Full Text PDF Scopus (3) Google Scholar demonstrate the importance of signaling through GPR120 in another immune cell type, CD4+ T helper cells, for inducing the regulatory cytokine interleukin (IL) 10 and controlling intestinal inflammation. Based on the observation of high GPR120 expression in CD4+ T helper cells compared with other immune cell types, the authors tested the role of GPR120 expressed specifically in CD4+ T cells for regulating intestinal homeostasis. They applied parallel experimental approaches, including inducing colitis through epithelial injury or infection in mice deficient for GPR120 only in CD4+ T cells, and by transferring CD4+ T cells deficient for GPR120 or treated with a GPR120 selective agonist into immunodeficient mice. Collectively, these complementary experiments supported a role for GPR120 signaling ameliorating colitis in association with increased IL10 production by CD4+ T cells. Interestingly, GPR120 signaling did not induce forkhead box P3-expressing T regulatory cells, the classical cellular source of IL10. Colitis was not mitigated by GPR120 agonist-treatment of T cells deficient for IL10, confirming the requirement of IL10 for colitis protection. The importance of IL10 as a critical regulatory cytokine for preventing chronic IBD in humans is well established. Rare biallelic genetic mutations in the IL10 receptor cause severe very early–onset IBD and common genetic variation in IL10 is associated with IBD.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3153) Google Scholar,10Glocker E.-O. Kotlarz D. Boztug K. et al.Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.N Engl J Med. 2009; 361: 2033-2045Crossref PubMed Scopus (1047) Google Scholar The investigators used in vitro approaches to isolate the effect of GPR120 signaling directly on CD4+ T cells and to determine the underlying intracellular mechanisms. Treatment with a GPR120 agonist induced IL10 production in naïve CD4+ T cells and interferon-γ–producing Th1 cells, but not Th17 or T regulatory cells. Importantly, they demonstrated that a natural dietary ligand for GPR120, the ω3 PUFA docosahexaenoic acid, also increased IL10 production by Th1 cells. Using differential gene expression analysis, T-cell-specific genetic deletion, and chemical inhibitor experiments, they showed that GPR120 induces a mechanistic target of rapamycin (mTOR)–signal transducer and activator of transcription 3 intracellular signaling pathway to increase expression of the transcription factor B lymphocyte–induced maturation protein-1 (BLIMP-1), which, in turn, promotes IL10 production. Interestingly, rare missense mutations in the gene encoding BLIMP-1 that impair its expression have been associated with CD.11Ellinghaus D. Zhang H. Zeissig S. et al.Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies.Gastroenterology. 2013; 145: 339-347Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Differential CD4+ T-cell gene expression after GPR120 activation also suggested effects on cellular metabolism. There is increased recognition that cellular metabolism is as important as intracellular signaling for regulating T-cell fate and function.12Bantug G.R. Galluzzi L. Kroemer G. et al.The spectrum of T cell metabolism in health and disease.Nat Rev Immunol. 2018; 18: 19-34Crossref PubMed Scopus (219) Google Scholar Using extracellular flux analysis to metabolically profile cells, the investigators found that GPR120 stimulation enhanced both oxidative phosphorylation and glycolysis in CD4+ T cells. Additional experiments revealed that GPR120 activation increases glycolysis through mTOR signaling, leading to induction of hypoxia-inducible factor 1α, which also stimulates IL10 production. To determine relevance of these observations to human disease, the authors analyzed tissue gene expression from a publicly available UC data set and locally collected IBD tissues. They found GPR120 expression was increased in UC and generally correlated with IL10 expression. Future experiments associating GPR120 expression with phenotypic characterization and cytokine production from live CD4+ T cells from patients with IBD or testing the effect of GPR120 activation on such cells will be needed to strengthen the case for human relevance. There is strong precedent for GPCRs as drug targets. In fact, GPCRs account for the therapeutic effect of one third of small molecule drugs.13Santos R. Ursu O. Gaulton A. et al.A comprehensive map of molecular drug targets.Nat Rev Drug Discov. 2017; 16: 19-34Crossref PubMed Scopus (1067) Google Scholar Perhaps this better understanding of how the natural ligand ω3 PUFA may mitigate risk for IBD through GPR120 could lead to new IBD drug development. Indeed, the investigators established proof of this principle by demonstrating oral administration of a GPR120 agonist improved colitis induced by naïve T-cell transfer into immunodeficient mice when administered prior (prevention) and after (treatment) colitis onset. Importantly, the effect required expression of GPR120 on CD4+ cells. It should be noted that this T-cell–driven model of colitis may be particularly amenable to such a T-cell–directed treatment compared with other models or human disease with a more complex immunopathogenesis. One drug with GPR120 agonist activity has been studied in a small phase 2 trial to examine effects on insulin resistance in obese adults. Notably, treatment was generally well-tolerated and associated with a reduction in plasma tumor necrosis factor levels.14Kern P.A. Finlin B.S. Ross D. et al.Effects of KDT501 on metabolic parameters in insulin-resistant prediabetic humans.J Endocr Soc. 2017; 1: 650-659Crossref PubMed Scopus (19) Google Scholar Past clinical trials of IL10 therapy have not been able to establish efficacy for IBD treatment, but may have been hampered by the short half-life of IL10 or limited mucosal penetration.15Wang X. Wong K. Ouyang W. et al.Targeting IL-10 family cytokines for the treatment of human diseases.Cold Spring Harb Perspect Biol. 2019; 11: a028548Crossref PubMed Scopus (85) Google Scholar This work draws a nutrient receptor into the spotlight as a potential drug target for biochemically reprograming our own T cells to produce more IL10 in the hopes of restoring or maintaining intestinal mucosal homeostasis. GPR120 Inhibits Colitis Through Regulation of CD4+ T Cell Interleukin 10 ProductionGastroenterologyVol. 162Issue 1PreviewLong-chain fatty acid receptor G protein–coupled receptor 120 induces interleukin 10 production in CD4+ T cells to inhibit colitis development through up-regulation of B lymphocyte–induced maturation protein 1 and enhancing glycolysis. Full-Text PDF