Comprehensive Physiology Wiley Online Library

Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology

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ABSTRACT

Nutrient sensing is a mechanism for organisms to sense their environment. In larger animals, including humans, the intestinal tract is a major site of nutrient sensing for the body, not surprisingly, as this is the central location where nutrients are absorbed. In the gut, bacterial fermentation results in generation of short chain fatty acids (SCFAs), a class of nutrients, which are sensed by specific membrane bound receptors, FFA2, FFA3, GPR109a, and Olfr78. These receptors are expressed uniquely throughout the gut and signal through distinct mechanisms. To date, the emerging data suggests a role of these receptors in normal and pathological conditions. The overall function of these receptors is to regulate aspects of intestinal motility, hormone secretion, maintenance of the epithelial barrier, and immune cell function. Besides in intestinal health, a prominent role of these receptors has emerged in modulation of inflammatory and immune responses during pathological conditions. Moreover, these receptors are being revealed to interact with the gut microbiota. This review article updates the current body of knowledge on SCFA sensing receptors in the gut and their roles in intestinal health and disease as well as in whole body energy homeostasis. © 2017 American Physiological Society. Compr Physiol 8:1091‐1115, 2018.

Figure 1. Figure 1. Different G‐protein signaling pathways. Ligand (agonist) occupation of the binding pocket in the GPCR leads to conformational changes in the receptor and an altered interaction with heterotrimeric G‐proteins. The activated receptor acts as a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on the Gα subunit and induced dissociation of active Gα subunit and Gβγ dimer (activated subunits represented with orange shade). There are four main Gα subunit protein classes, Gαq, Gαs, Gαi, Gα12/13. Each GPCR can couple with one or more Gα subunits. The activated Gα subunits can bind to and regulate the activity of several downstream effector molecules generating a cascade of signaling responses that culminate into specific cellular responses. Gαq/11 family members bind to and activate phospholipase C (PLC) which hydrolyses phosphotidylinositol 4,5‐bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3) which can mobilize calcium from intracellular stores or activate downstream protein kinases and modulate cell response. Gαs subunit activates adenylyl cyclase (AC) which increases intracellular cyclic adenosine monophosphate (cAMP) levels leading to activation of protein kinase A (PKA). Gαi subunit inhibits AC and reduces intracellular cAMP concentration. Gα12/13 can activate Rho kinases. The Gβγ subunit can activate phosphoinositide 3 kinase γ (PI3Kγ), protein kinases (PKD), and phospholipases (PLC). Various short chain fatty acid receptors (highlighted in blue color) are listed based on their G‐protein‐coupling preference. FFA2/3, free fatty acid receptor 2/3; Olfr78, olfactory receptor 78; GPR109a, G‐protein‐coupled receptor 109a ().
Figure 2. Figure 2. Regulation of GPCR signaling. Binding of agonist to the GPCR initiates a series of events: exchange of GDP for GTP on Gα subunit, dissociation of activated GTP‐Gα and Gβγ dimer, stimulation of downstream effectors (depicted in Fig. 1). To prevent overstimulation and assure receptor resensitization, GPCR signaling is regulated by multiple mechanisms (few are enumerated here; see Further Reading list for detailed description). (A) Regulator of G‐protein signaling (RGS) proteins function as GTPase‐activating proteins, enhance the intrinsic GTP hydrolysis activity of the Gα subunit resulting in generation of inactive GDP‐Gα, and promoting the reassembly G‐protein heterotrimer and its reassociation with the receptor. (B) GPCR kinases (GRK) phosphorylate specific residues on the intracellular domain of agonist‐occupied receptor. Phosphorylated receptor recruits β arrestin that sterically hinders interaction of the receptor with G‐protein, thus uncoupling the G‐protein complex from the GPCR (termed as desensitization). (C) Binding to the phosphorylated GPCR activates arrestin enabling it to perform ligand regulated scaffolding functions. Activated β arrestin interacts with the endocytic machinery (clathrin and adaptor proteins) and initiates receptor internalization. (D‐F) Internalized GPCR in GPCR‐β arrestin endosome can have multiple fates. GPCR‐β arrestin complex can (D) direct the assembly of signalosome by allowing coupling of mitogen‐activated protein kinases propagating further signaling pathways, (E) be targeted for lysosomal degradation, or (F) GPCRs can be trafficked to recycling endosomes and recycled back to the plasma membrane for resensitization. (G) Ligand type can also determine course of GPCR signaling where biased agonists can specifically activate either G‐protein or β arrestin‐mediated signaling pathway. (H) Gene transcription can also affect the total membrane levels of the GPCR. Transcription can be regulated by various inflammatory mediators, which can activate transcription factors that bind directly like XBP‐1 on FFA2 promoter or indirectly affect chromatin accessibility by altering acetylation/methylation of the promoter (IFNγ for GPR109a). (I) GPCRs can form oligomers (homodimers or heterodimers) that can regulate () cell surface delivery following receptor maturation or cellular trafficking following agonist activation, and () receptor pharmacology and signaling. Short chain fatty acid receptors (highlighted in blue color font) are noted if data exist on their regulatory mechanisms. FFA2/3, free fatty acid receptor 2/3; GPR109a, G‐protein‐coupled receptor 109a ().
Figure 3. Figure 3. Short chain fatty acid levels and expression of cognate receptors in select tissues. Short chain fatty acid concentrations in contents along the intestine (left upper panel) and systemic and portal blood in human subjects (left lower panel) [adapted, from Cummings et al. ()]. Right‐hand panel, human short chain fatty acid receptor expression in select tissues presented as plot of mean transcripts per million from HPA (human protein atlas) except for expression in human islets that was obtained by qRT‐PCR and presented relative to GAPDH (Brian T Layden, unpublished data).
Figure 4. Figure 4. Signaling pathways downstream of FFA2, FFA3, and GPR109a activation and corresponding effects. Apart from G‐proteins, FFA2 can signal via arrestin exerting anti‐inflammatory effects. Niacin at GPR109a shows biased agonism, arrestin signaling preferentially over G‐protein signaling causing flushing.
Figure 5. Figure 5. Short chain fatty acid receptors in gut immune homeostasis. Short chain fatty acids produced by fermentative activity of gut microbiota bind and activate receptors on intestinal epithelial cells and immune cells like macrophages, neutrophils, and dendritic cells. Production of cytoprotective IL‐18 (from FFA2/GPR109a‐dependent activation of inflammasome), anti‐inflammatory IgA (from FFA2‐dependent activation of B cells), anti‐inflammatory IL‐10 (from FFA2 activation and GPR109a‐dependent activation of macrophages and dendritic cells), and (FFA2‐ and GPR109a‐dependent) differentiation and proliferation of Tregs protect against conditions leading to colitis and colitis associated cancer. Taken together, these processes influence epithelial barrier integrity, adequate neutrophil migration, balanced proinflammatory (Th1 and Th17), and immunosuppressive (Treg) responses under conditions of inflammatory insult. CD, cluster of differentiation; IgA, immunoglobulin A; Th, T helper cells; Treg, regulatory T cells; short chain fatty acids are represented by , ; FFA2 and GPR109a, respectively, on immune cells are represented by , ; red upward arrow signifies increase; blue downward arrow signifies decrease ().
Figure 6. Figure 6. Customizing our approach for resolution of the roles of short chain fatty acid receptors. Evidence connects short chain fatty acid receptors to gut inflammatory responses. For reasons like shared endogenous ligands, differences in ligand efficacy for species orthologs (and others, enumerated in the text) there are hurdles in assigning selective physiological roles to these receptors. Their actual therapeutic potential thus remains unappreciated. These blocks can be overcome by customized approaches like, development of selective and potent agonists and antagonists for these receptors and their use in in vitro and ex vivo models (A and D); use of designer receptors with modified ligand binging sites, allowing activation of a particular member from the family which also contains a fluorescent tag (if attached to the receptor) (B); minimizing discrepancies by determining receptor expression along the course of cell/tissue differentiation (C); several different mouse models can be used to ascertain specific physiological effects of these receptors (E), including use of mice lacking two or more members of the family (multiple receptor KO), tissue specific KO or mice with gene of a human receptor replacing the mouse ortholog (tissue specific human receptor knock‐in). These mouse models can then be used in combination with gut microbiota knockdown approaches (germ free), colonized with human microbiota, or fed SCFAs alone or in combination to determine the interrelationship of these receptors with gut microbiota ().
Figure 7. Figure 7. Interplay of diet, gut microbiota, and short chain fatty acid receptors. Gut microbiota converts fiber in the diet to SCFAs. Activity of SCFAs at their receptors on gut cells promotes epithelial integrity and immune homeostasis. High‐fiber diet also shapes and selects for beneficial gut microbiota, and this selection is dependent on the genotype of the host. The combinatorial effect of these processes is resistance against inflammatory states like colitis and colitis associated cancer ().


Figure 1. Different G‐protein signaling pathways. Ligand (agonist) occupation of the binding pocket in the GPCR leads to conformational changes in the receptor and an altered interaction with heterotrimeric G‐proteins. The activated receptor acts as a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on the Gα subunit and induced dissociation of active Gα subunit and Gβγ dimer (activated subunits represented with orange shade). There are four main Gα subunit protein classes, Gαq, Gαs, Gαi, Gα12/13. Each GPCR can couple with one or more Gα subunits. The activated Gα subunits can bind to and regulate the activity of several downstream effector molecules generating a cascade of signaling responses that culminate into specific cellular responses. Gαq/11 family members bind to and activate phospholipase C (PLC) which hydrolyses phosphotidylinositol 4,5‐bisphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3) which can mobilize calcium from intracellular stores or activate downstream protein kinases and modulate cell response. Gαs subunit activates adenylyl cyclase (AC) which increases intracellular cyclic adenosine monophosphate (cAMP) levels leading to activation of protein kinase A (PKA). Gαi subunit inhibits AC and reduces intracellular cAMP concentration. Gα12/13 can activate Rho kinases. The Gβγ subunit can activate phosphoinositide 3 kinase γ (PI3Kγ), protein kinases (PKD), and phospholipases (PLC). Various short chain fatty acid receptors (highlighted in blue color) are listed based on their G‐protein‐coupling preference. FFA2/3, free fatty acid receptor 2/3; Olfr78, olfactory receptor 78; GPR109a, G‐protein‐coupled receptor 109a ().


Figure 2. Regulation of GPCR signaling. Binding of agonist to the GPCR initiates a series of events: exchange of GDP for GTP on Gα subunit, dissociation of activated GTP‐Gα and Gβγ dimer, stimulation of downstream effectors (depicted in Fig. 1). To prevent overstimulation and assure receptor resensitization, GPCR signaling is regulated by multiple mechanisms (few are enumerated here; see Further Reading list for detailed description). (A) Regulator of G‐protein signaling (RGS) proteins function as GTPase‐activating proteins, enhance the intrinsic GTP hydrolysis activity of the Gα subunit resulting in generation of inactive GDP‐Gα, and promoting the reassembly G‐protein heterotrimer and its reassociation with the receptor. (B) GPCR kinases (GRK) phosphorylate specific residues on the intracellular domain of agonist‐occupied receptor. Phosphorylated receptor recruits β arrestin that sterically hinders interaction of the receptor with G‐protein, thus uncoupling the G‐protein complex from the GPCR (termed as desensitization). (C) Binding to the phosphorylated GPCR activates arrestin enabling it to perform ligand regulated scaffolding functions. Activated β arrestin interacts with the endocytic machinery (clathrin and adaptor proteins) and initiates receptor internalization. (D‐F) Internalized GPCR in GPCR‐β arrestin endosome can have multiple fates. GPCR‐β arrestin complex can (D) direct the assembly of signalosome by allowing coupling of mitogen‐activated protein kinases propagating further signaling pathways, (E) be targeted for lysosomal degradation, or (F) GPCRs can be trafficked to recycling endosomes and recycled back to the plasma membrane for resensitization. (G) Ligand type can also determine course of GPCR signaling where biased agonists can specifically activate either G‐protein or β arrestin‐mediated signaling pathway. (H) Gene transcription can also affect the total membrane levels of the GPCR. Transcription can be regulated by various inflammatory mediators, which can activate transcription factors that bind directly like XBP‐1 on FFA2 promoter or indirectly affect chromatin accessibility by altering acetylation/methylation of the promoter (IFNγ for GPR109a). (I) GPCRs can form oligomers (homodimers or heterodimers) that can regulate () cell surface delivery following receptor maturation or cellular trafficking following agonist activation, and () receptor pharmacology and signaling. Short chain fatty acid receptors (highlighted in blue color font) are noted if data exist on their regulatory mechanisms. FFA2/3, free fatty acid receptor 2/3; GPR109a, G‐protein‐coupled receptor 109a ().


Figure 3. Short chain fatty acid levels and expression of cognate receptors in select tissues. Short chain fatty acid concentrations in contents along the intestine (left upper panel) and systemic and portal blood in human subjects (left lower panel) [adapted, from Cummings et al. ()]. Right‐hand panel, human short chain fatty acid receptor expression in select tissues presented as plot of mean transcripts per million from HPA (human protein atlas) except for expression in human islets that was obtained by qRT‐PCR and presented relative to GAPDH (Brian T Layden, unpublished data).


Figure 4. Signaling pathways downstream of FFA2, FFA3, and GPR109a activation and corresponding effects. Apart from G‐proteins, FFA2 can signal via arrestin exerting anti‐inflammatory effects. Niacin at GPR109a shows biased agonism, arrestin signaling preferentially over G‐protein signaling causing flushing.


Figure 5. Short chain fatty acid receptors in gut immune homeostasis. Short chain fatty acids produced by fermentative activity of gut microbiota bind and activate receptors on intestinal epithelial cells and immune cells like macrophages, neutrophils, and dendritic cells. Production of cytoprotective IL‐18 (from FFA2/GPR109a‐dependent activation of inflammasome), anti‐inflammatory IgA (from FFA2‐dependent activation of B cells), anti‐inflammatory IL‐10 (from FFA2 activation and GPR109a‐dependent activation of macrophages and dendritic cells), and (FFA2‐ and GPR109a‐dependent) differentiation and proliferation of Tregs protect against conditions leading to colitis and colitis associated cancer. Taken together, these processes influence epithelial barrier integrity, adequate neutrophil migration, balanced proinflammatory (Th1 and Th17), and immunosuppressive (Treg) responses under conditions of inflammatory insult. CD, cluster of differentiation; IgA, immunoglobulin A; Th, T helper cells; Treg, regulatory T cells; short chain fatty acids are represented by , ; FFA2 and GPR109a, respectively, on immune cells are represented by , ; red upward arrow signifies increase; blue downward arrow signifies decrease ().


Figure 6. Customizing our approach for resolution of the roles of short chain fatty acid receptors. Evidence connects short chain fatty acid receptors to gut inflammatory responses. For reasons like shared endogenous ligands, differences in ligand efficacy for species orthologs (and others, enumerated in the text) there are hurdles in assigning selective physiological roles to these receptors. Their actual therapeutic potential thus remains unappreciated. These blocks can be overcome by customized approaches like, development of selective and potent agonists and antagonists for these receptors and their use in in vitro and ex vivo models (A and D); use of designer receptors with modified ligand binging sites, allowing activation of a particular member from the family which also contains a fluorescent tag (if attached to the receptor) (B); minimizing discrepancies by determining receptor expression along the course of cell/tissue differentiation (C); several different mouse models can be used to ascertain specific physiological effects of these receptors (E), including use of mice lacking two or more members of the family (multiple receptor KO), tissue specific KO or mice with gene of a human receptor replacing the mouse ortholog (tissue specific human receptor knock‐in). These mouse models can then be used in combination with gut microbiota knockdown approaches (germ free), colonized with human microbiota, or fed SCFAs alone or in combination to determine the interrelationship of these receptors with gut microbiota ().


Figure 7. Interplay of diet, gut microbiota, and short chain fatty acid receptors. Gut microbiota converts fiber in the diet to SCFAs. Activity of SCFAs at their receptors on gut cells promotes epithelial integrity and immune homeostasis. High‐fiber diet also shapes and selects for beneficial gut microbiota, and this selection is dependent on the genotype of the host. The combinatorial effect of these processes is resistance against inflammatory states like colitis and colitis associated cancer ().
References
 1.Agus A, Denizot J, Thevenot J, Martinez‐Medina M, Massier S, Sauvanet P, Bernalier‐Donadille A, Denis S, Hofman P, Bonnet R, Billard E, Barnich N. Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent‐Invasive E. coli infection and intestinal inflammation. Sci Rep 6: 19032, 2016.
 2.Alhopuro P, Sammalkorpi H, Niittymaki I, Bistrom M, Raitila A, Saharinen J, Nousiainen K, Lehtonen HJ, Heliovaara E, Puhakka J, Tuupanen S, Sousa S, Seruca R, Ferreira AM, Hofstra RM, Mecklin JP, Jarvinen H, Ristimaki A, Orntoft TF, Hautaniemi S, Arango D, Karhu A, Aaltonen LA. Candidate driver genes in microsatellite‐unstable colorectal cancer. Int J Cancer 130: 1558‐1566, 2012.
 3.Alvarez‐Curto E, Milligan G. Metabolism meets immunity: The role of free fatty acid receptors in the immune system. Biochem Pharmacol 114: 3‐13, 2016.
 4.Anabazhagan AN, Chatterjee I, Priyamvada S, Kumar A, Tyagi S, Saksena S, Alrefai WA, Dudeja PK, Gill RK. Methods to study epithelial transport protein function and expression in native intestine and Caco‐2 cells grown in 3D. J Vis Exp 2017(121): e55304.
 5.Ang Z, Ding JL. GPR41 and GPR43 in obesity and inflammation—protective or causative? Front Immunol 7: 28, 2016.
 6.Ang Z, Er JZ, Ding JL. The short‐chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes. Sci Rep 5: 8134, 2015.
 7.Ang Z, Er JZ, Tan NS, Lu J, Liou YC, Grosse J, Ding JL. Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short‐chain fatty acid receptor agonists. Sci Rep 6: 34145, 2016.
 8.Ang Z, Xiong D, Wu M, Ding JL. FFAR2‐FFAR3 receptor heteromerization modulates short‐chain fatty acid sensing. FASEB J 32: 289‐303, 2018.
 9.Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T‐cell generation. Nature 504: 451‐455, 2013.
 10.Arthur JC, Perez‐Chanona E, Muhlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB, Rhodes JM, Stintzi A, Simpson KW, Hansen JJ, Keku TO, Fodor AA, Jobin C. Intestinal inflammation targets cancer‐inducing activity of the microbiota. Science 338: 120‐123, 2012.
 11.Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov, II, Umesaki Y, Itoh K, Honda K. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337‐341, 2011.
 12.Atwan A, Ingram JR, Abbott R, Kelson MJ, Pickles T, Bauer A, Piguet V. Oral fumaric acid esters for psoriasis. Cochrane Database Syst Rev. 10(8):CD010497, 2015.
 13.Bahar Halpern K, Veprik A, Rubins N, Naaman O, Walker MD. 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: 20154‐20163, 2012.
 14.Bahouth SW, Nooh MM. Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks. Cell Signal 36: 42‐55, 2017.
 15.Bardhan K, Paschall AV, Yang D, Chen MR, Simon PS, Bhutia YD, Martin PM, Thangaraju M, Browning DD, Ganapathy V, Heaton CM, Gu K, Lee JR, Liu K. IFNgamma induces DNA methylation‐silenced GPR109A expression via pSTAT1/p300 and H3K18 acetylation in colon cancer. Cancer Immunol Res 3: 795‐805, 2015.
 16.Basson A, Trotter A, Rodriguez‐Palacios A, Cominelli F. Mucosal interactions between genetics, diet, and microbiome in inflammatory bowel disease. Front Immunol 7: 290, 2016.
 17.Beglinger C, Degen L. Gastrointestinal satiety signals in humans–‐physiologic roles for GLP‐1 and PYY? Physiol Behav 89: 460‐464, 2006.
 18.Bellahcene M, O'Dowd JF, Wargent ET, Zaibi MS, Hislop DC, Ngala RA, Smith DM, Cawthorne MA, Stocker CJ, Arch JR. Male mice that lack the G‐protein‐coupled receptor GPR41 have low energy expenditure and increased body fat content. Br J Nutr 109: 1755‐1764, 2013.
 19.Benyo Z, Gille A, Kero J, Csiky M, Suchankova MC, Nusing RM, Moers A, Pfeffer K, Offermanns S. GPR109A (PUMA‐G/HM74A) mediates nicotinic acid‐induced flushing. J Clin Invest 115: 3634‐3640, 2005.
 20.Bhutia YD, Ganapathy V. Short, but smart: SCFAs train T cells in the gut to fight autoimmunity in the brain. Immunity 43: 629‐631, 2015.
 21.Bindels LB, Dewulf EM, Delzenne NM. GPR43/FFA2: Physiopathological relevance and therapeutic prospects. Trends Pharmacol Sci 34: 226‐232, 2013.
 22.Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, Scott KP, Buc Calderon P, Feron O, Muccioli GG, Sonveaux P, Cani PD, Delzenne NM. Gut microbiota‐derived propionate reduces cancer cell proliferation in the liver. Br J Cancer 107: 1337‐1344, 2012.
 23.Bjursell M, Admyre T, Goransson M, Marley AE, Smith DM, Oscarsson J, Bohlooly YM. Improved glucose control and reduced body fat mass in free fatty acid receptor 2‐deficient mice fed a high‐fat diet. Am J Physiol Endocrinol Metab 300: E211‐E220, 2011.
 24.Black JB, Premont RT, Daaka Y. Feedback regulation of G protein‐coupled receptor signaling by GRKs and arrestins. Semin Cell Dev Biol 50: 95‐104, 2016.
 25.Blad CC, Tang C, Offermanns S. G protein‐coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov 11: 603‐619, 2012.
 26.Boirivant M, Amendola A, Butera A, Sanchez M, Xu L, Marinaro M, Kitani A, Di Giacinto C, Strober W, Fuss IJ. A transient breach in the epithelial barrier leads to regulatory T‐cell generation and resistance to experimental colitis. Gastroenterology 135: 1612‐1623 e1615, 2008.
 27.Bolognini D, Moss CE, Nilsson K, Petersson AU, Donnelly I, Sergeev E, Konig GM, Kostenis E, Kurowska‐Stolarska M, Miller A, Dekker N, Tobin AB, Milligan G. A novel allosteric activator of free fatty acid 2 receptor displays unique Gi‐functional bias. J Biol Chem 291: 18915‐18931, 2016.
 28.Bolognini D, Tobin AB, Milligan G, Moss CE. The pharmacology and function of receptors for short‐chain fatty acids. Mol Pharmacol 89: 388‐398, 2016.
 29.Bonini JA, Anderson SM, Steiner DF. Molecular cloning and tissue expression of a novel orphan G protein‐coupled receptor from rat lung. Biochem Biophys Res Commun 234: 190‐193, 1997.
 30.Borthakur A, Priyamvada S, Kumar A, Natarajan AA, Gill RK, Alrefai WA, Dudeja PK. A novel nutrient sensing mechanism underlies substrate‐induced regulation of monocarboxylate transporter‐1. Am J Physiol Gastrointest Liver Physiol 303: G1126‐G1133, 2012.
 31.Brooks L, Viardot A, Tsakmaki A, Stolarczyk E, Howard JK, Cani PD, Everard A, Sleeth ML, Psichas A, Anastasovskaj J, Bell JD, Bell‐Anderson K, Mackay CR, Ghatei MA, Bloom SR, Frost G, Bewick GA. Fermentable carbohydrate stimulates FFAR2‐dependent colonic PYY cell expansion to increase satiety. Mol Metab 6: 48‐60, 2017.
 32.Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ. The Orphan G protein‐coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278: 11312‐11319, 2003.
 33.Canfora EE, Jocken JW, Blaak EE. Short‐chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 11: 577‐591, 2015.
 34.Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia‐induced inflammation in high‐fat diet‐induced obesity and diabetes in mice. Diabetes 57: 1470‐1481, 2008.
 35.Chang AJ, Ortega FE, Riegler J, Madison DV, Krasnow MA. Oxygen regulation of breathing through an olfactory receptor activated by lactate. Nature 527: 240‐244, 2015.
 36.Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A 111: 2247‐2252, 2014.
 37.Cox MA, Jackson J, Stanton M, Rojas‐Triana A, Bober L, Laverty M, Yang X, Zhu F, Liu J, Wang S, Monsma F, Vassileva G, Maguire M, Gustafson E, Bayne M, Chou CC, Lundell D, Jenh CH. Short‐chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol 15: 5549‐5557, 2009.
 38.Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V. Colonic gene expression in conventional and germ‐free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J Gastrointest Surg 14: 449‐461, 2010.
 39.Cummings DE, Overduin J. Gastrointestinal regulation of food intake. J Clin Invest 117: 13‐23, 2007.
 40.Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28: 1221‐1227, 1987.
 41.Daien CI, Pinget GV, Tan JK, Macia L. Detrimental impact of microbiota‐accessible carbohydrate‐deprived diet on gut and immune homeostasis: An overview. Front Immunol 8: 548, 2017.
 42.Dass NB, John AK, Bassil AK, Crumbley CW, Shehee WR, Maurio FP, Moore GB, Taylor CM, Sanger GJ. The relationship between the effects of short‐chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterol Motil 19: 66‐74, 2007.
 43.De Vadder F, Kovatcheva‐Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, Backhed F, Mithieux G. Microbiota‐generated metabolites promote metabolic benefits via gut‐brain neural circuits. Cell 156: 84‐96, 2014.
 44.Dewulf EM, Cani PD, Neyrinck AM, Possemiers S, Van Holle A, Muccioli GG, Deldicque L, Bindels LB, Pachikian BD, Sohet FM, Mignolet E, Francaux M, Larondelle Y, Delzenne NM. Inulin‐type fructans with prebiotic properties counteract GPR43 overexpression and PPARgamma‐related adipogenesis in the white adipose tissue of high‐fat diet‐fed mice. J Nutr Biochem 22: 712‐722, 2011.
 45.Dobbins RL, Shearn SP, Byerly RL, Gao FF, Mahar KM, Napolitano A, Nachbaur GJ, Le Monnier de Gouville AC. GSK256073, a selective agonist of G‐protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes Metab 15: 1013‐1021, 2013.
 46.Duranti S, Gaiani F, Mancabelli L, Milani C, Grandi A, Bolchi A, Santoni A, Lugli GA, Ferrario C, Mangifesta M, Viappiani A, Bertoni S, Vivo V, Serafini F, Barbaro MR, Fugazza A, Barbara G, Gioiosa L, Palanza P, Cantoni AM, de'Angelis GL, Barocelli E, de'Angelis N, van Sinderen D, Ventura M, Turroni F. Elucidating the gut microbiome of ulcerative colitis: Bifidobacteria as novel microbial biomarkers. FEMS Microbiol Ecol 92: fiw191, 2016.
 47.Eberle JA, Widmayer P, Breer H. Receptors for short‐chain fatty acids in brush cells at the “gastric groove.” Front Physiol 5: 152, 2014.
 48.Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Lan L, Singh N, Martin PM, Hawthorn L, Prasad PD, Ganapathy V, Thangaraju M. The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival. Cancer Res 74: 1166‐1178, 2014.
 49.Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne‐Lawrence S, Piper PK, Walker AK, Pedersen MH, Nohr MK, Pan J, Sinz CJ, Carrington PE, Akiyama TE, Jones RM, Tang C, Ahmed K, Offermanns S, Egerod KL, Zigman JM, Schwartz TW. Seven transmembrane G protein‐coupled receptor repertoire of gastric ghrelin cells. Mol Metab 2: 376‐392, 2013.
 50.Farran B. An update on the physiological and therapeutic relevance of GPCR oligomers. Pharmacol Res 117: 303‐327, 2017.
 51.Fleischer J, Bumbalo R, Bautze V, Strotmann J, Breer H. Expression of odorant receptor Olfr78 in enteroendocrine cells of the colon. Cell Tissue Res 361: 697‐710, 2015.
 52.Forbes S, Stafford S, Coope G, Heffron H, Real K, Newman R, Davenport R, Barnes M, Grosse J, Cox H. Selective FFA2 agonism appears to act via intestinal PYY to reduce transit and food intake but does not improve glucose tolerance in mouse models. Diabetes 64: 3763‐3771, 2015.
 53.Fournier BM, Parkos CA. The role of neutrophils during intestinal inflammation. Mucosal Immunol 5: 354‐366, 2012.
 54.Fu SP, Liu BR, Wang JF, Xue WJ, Liu HM, Zeng YL, Huang BX, Li SN, Lv QK, Wang W, Liu JX. beta‐Hydroxybutyric acid inhibits growth hormone‐releasing hormone synthesis and secretion through the GPR109A/extracellular signal‐regulated 1/2 signalling pathway in the hypothalamus. J Neuroendocrinol 27: 212‐222, 2015.
 55.Fu SP, Wang JF, Xue WJ, Liu HM, Liu BR, Zeng YL, Li SN, Huang BX, Lv QK, Wang W, Liu JX. Anti‐inflammatory effects of BHBA in both in vivo and in vitro Parkinson's disease models are mediated by GPR109A‐dependent mechanisms. J Neuroinflammation 12: 9, 2015.
 56.Fuller M, Priyadarshini M, Gibbons SM, Angueira AR, Brodsky M, Hayes MG, Kovatcheva‐Datchary P, Backhed F, Gilbert JA, Lowe WL, Jr., Layden BT. The short‐chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis. Am J Physiol Endocrinol Metab 309: E840‐E851, 2015.
 57.Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe‐derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504: 446‐450, 2013.
 58.Gambhir D, Ananth S, Veeranan‐Karmegam R, Elangovan S, Hester S, Jennings E, Offermanns S, Nussbaum JJ, Smith SB, Thangaraju M, Ganapathy V, Martin PM. GPR109A as an anti‐inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Invest Ophthalmol Vis Sci 53: 2208‐2217, 2012.
 59.Garrett WS, Smith PM. Modulation of regulatory t cells via g‐coupled protein receptor 43. Google Patents, US Patent 1, (2017 11 30): 59 Pages, 2014.
 60.Gelis L, Jovancevic N, Veitinger S, Mandal B, Arndt HD, Neuhaus EM, Hatt H. Functional characterization of the odorant receptor 51E2 in human melanocytes. J Biol Chem 291: 17772‐17786, 2016.
 61.Gribble FM, Diakogiannaki E, Reimann F. Gut hormone regulation and secretion via FFA1 and FFA4. Handb Exp Pharmacol 236: 181‐203, 2017.
 62.Grundmann M, Tikhonova IG, Hudson BD, Smith NJ, Mohr K, Ulven T, Milligan G, Kenakin T, Kostenis E. A molecular mechanism for sequential activation of a G protein‐coupled receptor. Cell Chem Biol 23: 392‐403, 2016.
 63.Haghikia A, Jorg S, Duscha A, Berg J, Manzel A, Waschbisch A, Hammer A, Lee DH, May C, Wilck N, Balogh A, Ostermann AI, Schebb NH, Akkad DA, Grohme DA, Kleinewietfeld M, Kempa S, Thone J, Demir S, Muller DN, Gold R, Linker RA. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43: 817‐829, 2015.
 64.Han JH, Kim IS, Jung SH, Lee SG, Son HY, Myung CS. The effects of propionate and valerate on insulin responsiveness for glucose uptake in 3T3‐L1 adipocytes and C2C12 myotubes via G protein‐coupled receptor 41. PLoS One 9: e95268, 2014.
 65.Han M, Song P, Huang C, Rezaei A, Farrar S, Brown MA, Ma X. Dietary grape seed proanthocyanidins (GSPs) improve weaned intestinal microbiota and mucosal barrier using a piglet model. Oncotarget 7: 80313‐80326, 2016.
 66.Harig JM, Soergel KH, Komorowski RA, Wood CM. Treatment of diversion colitis with short‐chain‐fatty acid irrigation. N Engl J Med 320: 23‐28, 1989.
 67.Hatanaka H, Tsukui M, Takada S, Kurashina K, Choi YL, Soda M, Yamashita Y, Haruta H, Hamada T, Ueno T, Tamada K, Hosoya Y, Sata N, Yasuda Y, Nagai H, Sugano K, Mano H. Identification of transforming activity of free fatty acid receptor 2 by retroviral expression screening. Cancer Sci 101: 54‐59, 2010.
 68.Hong YH, Nishimura Y, Hishikawa D, Tsuzuki H, Miyahara H, Gotoh C, Choi KC, Feng DD, Chen C, Lee HG, Katoh K, Roh SG, Sasaki S. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology 146: 5092‐5099, 2005.
 69.Hoverstad T, Midtvedt T. Short‐chain fatty acids in germfree mice and rats. J Nutr 116: 1772‐1776, 1986.
 70.Hu J, Kyrou I, Tan BK, Dimitriadis GK, Ramanjaneya M, Tripathi G, Patel V, James S, Kawan M, Chen J, Randeva HS. Short‐chain fatty acid acetate stimulates adipogenesis and mitochondrial biogenesis via GPR43 in brown adipocytes. Endocrinology 157: 1881‐1894, 2016.
 71.Hu Y, Le Leu RK, Christophersen CT, Somashekar R, Conlon MA, Meng XQ, Winter JM, Woodman RJ, McKinnon R, Young GP. Manipulation of the gut microbiota using resistant starch is associated with protection against colitis‐associated colorectal cancer in rats. Carcinogenesis 37: 366‐375, 2016.
 72.Hudson BD, Christiansen E, Murdoch H, Jenkins L, Hansen AH, Madsen O, Ulven T, Milligan G. Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands. Mol Pharmacol 86: 200‐210, 2014.
 73.Hudson BD, Christiansen E, Tikhonova IG, Grundmann M, Kostenis E, Adams DR, Ulven T, Milligan G. Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs. FASEB J 26: 4951‐4965, 2012.
 74.Hudson BD, Due‐Hansen ME, Christiansen E, Hansen AM, Mackenzie AE, Murdoch H, Pandey SK, Ward RJ, Marquez R, Tikhonova IG, Ulven T, Milligan G. Defining the molecular basis for the first potent and selective orthosteric agonists of the FFA2 free fatty acid receptor. J Biol Chem 288: 17296‐17312, 2013.
 75.Hudson BD, Smith NJ, Milligan G. Experimental challenges to targeting poorly characterized GPCRs: Uncovering the therapeutic potential for free fatty acid receptors. Adv Pharmacol 62: 175‐218, 2011.
 76.Hudson BD, Tikhonova IG, Pandey SK, Ulven T, Milligan G. Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3. J Biol Chem 287: 41195‐41209, 2012.
 77.Hughes‐Large JM, Pang DK, Robson DL, Chan P, Toma J, Borradaile NM. Niacin receptor activation improves human microvascular endothelial cell angiogenic function during lipotoxicity. Atherosclerosis 237: 696‐704, 2014.
 78.Inoue D, Kimura I, Wakabayashi M, Tsumoto H, Ozawa K, Hara T, Takei Y, Hirasawa A, Ishihama Y, Tsujimoto G. Short‐chain fatty acid receptor GPR41‐mediated activation of sympathetic neurons involves synapsin 2b phosphorylation. FEBS Lett 586: 1547‐1554, 2012.
 79.Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G. Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med 7: 180‐185, 2001.
 80.Iyer A, Brown L, Whitehead JP, Prins JB, Fairlie DP. Nutrient and immune sensing are obligate pathways in metabolism, immunity, and disease. FASEB J 29: 3612‐3625, 2015.
 81.Jean‐Charles PY, Kaur S, Shenoy SK. G protein‐coupled receptor signaling through beta‐arrestin‐dependent mechanisms. J Cardiovasc Pharmacol 70: 142‐158, 2017.
 82.Kamp ME, Shim R, Nicholls AJ, Oliveira AC, Mason LJ, Binge L, Mackay CR, Wong CH. G protein‐coupled receptor 43 modulates neutrophil recruitment during acute inflammation. PLoS One 11: e0163750, 2016.
 83.Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN, Investigators BGPIS. Efficacy and safety of oral fumarate in patients with relapsing‐remitting multiple sclerosis: A multicentre, randomised, double‐blind, placebo‐controlled phase IIb study. Lancet 372: 1463‐1472, 2008.
 84.Karaki S, Mitsui R, Hayashi H, Kato I, Sugiya H, Iwanaga T, Furness JB, Kuwahara A. Short‐chain fatty acid receptor, GPR43, is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res 324: 353‐360, 2006.
 85.Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, Kuwahara A. Expression of the short‐chain fatty acid receptor, GPR43, in the human colon. J Mol Histol 39: 135‐142, 2008.
 86.Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134: 743‐756, 2008.
 87.Kataoka K, Ogasa S, Kuwahara T, Bando Y, Hagiwara M, Arimochi H, Nakanishi S, Iwasaki T, Ohnishi Y. Inhibitory effects of fermented brown rice on induction of acute colitis by dextran sulfate sodium in rats. Dig Dis Sci 53: 1601‐1608, 2008.
 88.Kebede M, Alquier T, Latour MG, Semache M, Tremblay C, Poitout V. The fatty acid receptor GPR40 plays a role in insulin secretion in vivo after high‐fat feeding. Diabetes 57: 2432‐2437, 2008.
 89.Kebede MA, Alquier T, Latour MG, Poitout V. Lipid receptors and islet function: Therapeutic implications? Diabetes Obes Metab 11(Suppl 4): 10‐20, 2009.
 90.Khan SM, Sleno R, Gora S, Zylbergold P, Laverdure JP, Labbe JC, Miller GJ, Hebert TE. The expanding roles of Gbetagamma subunits in G protein‐coupled receptor signaling and drug action. Pharmacol Rev 65: 545‐577, 2013.
 91.Kiesler P, Fuss IJ, Strober W. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 1: 154‐170, 2015.
 92.Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH. Short‐chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145: 396‐406 e391‐310, 2013.
 93.Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, Tsujimoto G. Short‐chain fatty acids and ketones directly regulate sympathetic nervous system via G protein‐coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 108: 8030‐8035, 2011.
 94.Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T, Miyauchi S, Shioi G, Inoue H, Tsujimoto G. The gut microbiota suppresses insulin‐mediated fat accumulation via the short‐chain fatty acid receptor GPR43. Nat Commun 4: 1829, 2013.
 95.Kobayashi M, Mikami D, Kimura H, Kamiyama K, Morikawa Y, Yokoi S, Kasuno K, Takahashi N, Taniguchi T, Iwano M. Short‐chain fatty acids, GPR41 and GPR43 ligands, inhibit TNF‐alpha‐induced MCP‐1 expression by modulating p38 and JNK signaling pathways in human renal cortical epithelial cells. Biochem Biophys Res Commun 486: 499‐505, 2017.
 96.Koh A, De Vadder F, Kovatcheva‐Datchary P, Backhed F. From dietary fiber to host physiology: Short‐chain fatty acids as key bacterial metabolites. Cell 165: 1332‐1345, 2016.
 97.Kotarsky K, Nilsson NE, Olde B, Owman C. Progress in methodology. Improved reporter gene assays used to identify ligands acting on orphan seven‐transmembrane receptors. Pharmacol Toxicol 93: 249‐258, 2003.
 98.Layden BT, Angueira AR, Brodsky M, Durai V, Lowe WL, Jr. Short chain fatty acids and their receptors: new metabolic targets. Transl Res 161: 131‐140, 2013.
 99.Layden BT, Durai, V, Lowe, Jr., WL. G‐protein‐coupled receptors, pancreatic islets, and diabetes. Nat Educat 3: 13, 2010.
 100.Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278: 25481‐25489, 2003.
 101.Lee H, Flaherty P, Ji HP. Systematic genomic identification of colorectal cancer genes delineating advanced from early clinical stage and metastasis. BMC Med Genomics 6: 54, 2013.
 102.Lee SU, In HJ, Kwon MS, Park BO, Jo M, Kim MO, Cho S, Lee S, Lee HJ, Kwak YS, Kim S. beta‐Arrestin 2 mediates G protein‐coupled receptor 43 signals to nuclear factor‐kappaB. Biol Pharm Bull 36: 1754‐1759, 2013.
 103.Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, Jaeckel P, Ge H, Wang Y, Jiao X, Liu J, Kayser F, Tian H, Li Y. Identification and functional characterization of allosteric agonists for the G protein‐coupled receptor FFA2. Mol Pharmacol 74: 1599‐1609, 2008.
 104.Li G, Shi Y, Huang H, Zhang Y, Wu K, Luo J, Sun Y, Lu J, Benovic JL, Zhou N. Internalization of the human nicotinic acid receptor GPR109A is regulated by G(i), GRK2, and arrestin3. J Biol Chem 285: 22605‐22618, 2010.
 105.Li G, Su H, Zhou Z, Yao W. Identification of the porcine G protein‐coupled receptor 41 and 43 genes and their expression pattern in different tissues and development stages. PLoS One 9: e97342, 2014.
 106.Lindsley JE, Rutter J. Nutrient sensing and metabolic decisions. Comp Biochem Physiol B Biochem Mol Biol 139: 543‐559, 2004.
 107.Link A, Balaguer F, Shen Y, Lozano JJ, Leung HC, Boland CR, Goel A. Curcumin modulates DNA methylation in colorectal cancer cells. PLoS One 8: e57709, 2013.
 108.Lu Y, Fan C, Li P, Lu Y, Chang X, Qi K. Short chain fatty acids prevent high‐fat‐diet‐induced obesity in mice by regulating G protein‐coupled receptors and gut microbiota. Sci Rep 6: 37589, 2016.
 109.Lukasova M, Malaval C, Gille A, Kero J, Offermanns S. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest 121: 1163‐1173, 2011.
 110.Macfarlane S, Macfarlane GT. Regulation of short‐chain fatty acid production. Proc Nutr Soc 62: 67‐72, 2003.
 111.Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, Binge L, Thorburn AN, Chevalier N, Ang C, Marino E, Robert R, Offermanns S, Teixeira MM, Moore RJ, Flavell RA, Fagarasan S, Mackay CR. Metabolite‐sensing receptors GPR43 and GPR109A facilitate dietary fibre‐induced gut homeostasis through regulation of the inflammasome. Nat Commun 6: 6734, 2015.
 112.Magalhaes AC, Dunn H, Ferguson SS. Regulation of GPCR activity, trafficking and localization by GPCR‐interacting proteins. Br J Pharmacol 165: 1717‐1736, 2012.
 113.Mancini AD, Poitout V. The fatty acid receptor FFA1/GPR40 a decade later: How much do we know? Trends Endocrinol Metab 24: 398‐407, 2013.
 114.Mandrika I, Petrovska R, Klovins J. Evidence for constitutive dimerization of niacin receptor subtypes. Biochem Biophys Res Commun 395: 281‐287, 2010.
 115.Marino E, Richards JL, McLeod KH, Stanley D, Yap YA, Knight J, McKenzie C, Kranich J, Oliveira AC, Rossello FJ, Krishnamurthy B, Nefzger CM, Macia L, Thorburn A, Baxter AG, Morahan G, Wong LH, Polo JM, Moore RJ, Lockett TJ, Clarke JM, Topping DL, Harrison LC, Mackay CR. Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat Immunol 18: 552‐562, 2017.
 116.Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, Xavier RJ, Teixeira MM, Mackay CR. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282‐1286, 2009.
 117.Masui R, Sasaki M, Funaki Y, Ogasawara N, Mizuno M, Iida A, Izawa S, Kondo Y, Ito Y, Tamura Y, Yanamoto K, Noda H, Tanabe A, Okaniwa N, Yamaguchi Y, Iwamoto T, Kasugai K. G protein‐coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells. Inflamm Bowel Dis 19: 2848‐2856, 2013.
 118.Matsubara K, Nakamura N, Sanoh S, Ohta S, Kitamura S, Uramaru N, Miyagawa S, Iguchi T, Fujimoto N. Altered expression of the Olr59, Ethe1, and Slc10a2 genes in the liver of F344 rats by neonatal thyroid hormone disruption. J Appl Toxicol 37: 1030‐1035, 2017.
 119.McKenzie C, Tan J, Macia L, Mackay CR. The nutrition‐gut microbiome‐physiology axis and allergic diseases. Immunol Rev 278: 277‐295, 2017.
 120.McNelis JC, Lee YS, Mayoral R, van der Kant R, Johnson AM, Wollam J, Olefsky JM. GPR43 potentiates beta‐cell function in obesity. Diabetes 64: 3203‐3217, 2015.
 121.Mielenz M. Invited review: Nutrient‐sensing receptors for free fatty acids and hydroxycarboxylic acids in farm animals. Animal 11: 1008‐1016, 2017.
 122.Milligan G, Bolognini D, Sergeev E. Ligands at the free fatty acid receptors 2/3 (GPR43/GPR41). Handb Exp Pharmacol 236: 17‐32, 2017.
 123.Milligan G, Shimpukade B, Ulven T, Hudson BD. Complex pharmacology of free fatty acid receptors. Chem Rev 117: 67‐110, 2017.
 124.Milligan G, Stoddart LA, Smith NJ. Agonism and allosterism: The pharmacology of the free fatty acid receptors FFA2 and FFA3. Br J Pharmacol 158: 146‐153, 2009.
 125.Mrowietz U, Asadullah K. Dimethylfumarate for psoriasis: More than a dietary curiosity. Trends Mol Med 11: 43‐48, 2005.
 126.Nakajima A, Nakatani A, Hasegawa S, Irie J, Ozawa K, Tsujimoto G, Suganami T, Itoh H, Kimura I. The short chain fatty acid receptor GPR43 regulates inflammatory signals in adipose tissue M2‐type macrophages. PLoS One 12: e0179696, 2017.
 127.Namour F, Galien R, Van Kaem T, Van der Aa A, Vanhoutte F, Beetens J, Van't Klooster G. Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects. Br J Clin Pharmacol 82: 139‐148, 2016.
 128.Natividad JM, Pinto‐Sanchez MI, Galipeau HJ, Jury J, Jordana M, Reinisch W, Collins SM, Bercik P, Surette MG, Allen‐Vercoe E, Verdu EF. Ecobiotherapy rich in firmicutes decreases susceptibility to colitis in a humanized gnotobiotic mouse model. Inflamm Bowel Dis 21: 1883‐1893, 2015.
 129.Nguyen CA, Akiba Y, Kaunitz JD. Recent advances in gut nutrient chemosensing. Curr Med Chem 19: 28‐34, 2012.
 130.Nilsson NE, Kotarsky K, Owman C, Olde B. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short‐chain fatty acids. Biochem Biophys Res Commun 303: 1047‐1052, 2003.
 131.Nohr MK, Egerod KL, Christiansen SH, Gille A, Offermanns S, Schwartz TW, Moller M. Expression of the short chain fatty acid receptor GPR41/FFAR3 in autonomic and somatic sensory ganglia. Neuroscience 290: 126‐137, 2015.
 132.Nohr MK, Pedersen MH, Gille A, Egerod KL, Engelstoft MS, Husted AS, Sichlau RM, Grunddal KV, Poulsen SS, Han S, Jones RM, Offermanns S, Schwartz TW. GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short‐chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154: 3552‐3564, 2013.
 133.Nowarski R, Jackson R, Gagliani N, de Zoete MR, Palm NW, Bailis W, Low JS, Harman CC, Graham M, Elinav E, Flavell RA. Epithelial IL‐18 equilibrium controls barrier function in colitis. Cell 163: 1444‐1456, 2015.
 134.O'Keefe SJ. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol 13: 691‐706, 2016.
 135.Offermanns S. Hydroxy‐carboxylic acid receptor actions in metabolism. Trends Endocrinol Metab 28: 227‐236, 2017.
 136.Ohira H, Tsutsui W, Mamoto R, Yamaguchi S, Nishida M, Ito M, Fujioka Y. Butyrate attenuates lipolysis in adipocytes co‐cultured with macrophages through non‐prostaglandin E2‐mediated and prostaglandin E2‐mediated pathways. Lipids Health Dis 15: 213, 2016.
 137.Ohland CL, Macnaughton WK. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol 298: G807‐G819, 2010.
 138.Oldham WM, Hamm HE. Heterotrimeric G protein activation by G‐protein‐coupled receptors. Nat Rev Mol Cell Biol 9: 60‐71, 2008.
 139.Pan P, C WS, Wang HT, Oshima K, Huang YW, Yu J, Zhang J, M MY, K AA, W RD, Chen X, Wang LS. Loss of free fatty acid receptor 2 enhances colonic adenoma development and reduces the chemopreventive effects of black raspberries in ApcMin/+ mice. Carcinogenesis 38: 86‐93, 2017.
 140.Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, Kim CH. 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, 2015.
 141.Patel DG, Singh SP. Effect of ethanol and its metabolites on glucose mediated insulin release from isolated islets of rats. Metabolism 28: 85‐89, 1979.
 142.Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, Petersen KF, Kibbey RG, Goodman AL, Shulman GI. Acetate mediates a microbiome‐brain‐beta‐cell axis to promote metabolic syndrome. Nature 534: 213‐217, 2016.
 143.Peterson LW, Artis D. Intestinal epithelial cells: Regulators of barrier function and immune homeostasis. Nat Rev Immunol 14: 141‐153, 2014.
 144.Peterson YK, Luttrell LM. The diverse roles of arrestin scaffolds in G protein‐coupled receptor signaling. Pharmacol Rev 69: 256‐297, 2017.
 145.Pierce KL, Premont RT, Lefkowitz RJ. Seven‐transmembrane receptors. Nat Rev Mol Cell Biol 3: 639‐650, 2002.
 146.Pizzonero M, Dupont S, Babel M, Beaumont S, Bienvenu N, Blanque R, Cherel L, Christophe T, Crescenzi B, De Lemos E, Delerive P, Deprez P, De Vos S, Djata F, Fletcher S, Kopiejewski S, L'Ebraly C, Lefrancois JM, Lavazais S, Manioc M, Nelles L, Oste L, Polancec D, Quenehen V, Soulas F, Triballeau N, van der Aar EM, Vandeghinste N, Wakselman E, Brys R, Saniere L. Discovery and optimization of an azetidine chemical series as a free fatty acid receptor 2 (FFA2) antagonist: From hit to clinic. J Med Chem 57: 10044‐10057, 2014.
 147.Pluznick J. A novel SCFA receptor, the microbiota, and blood pressure regulation. Gut Microbes 5: 202‐207, 2014.
 148.Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Brunet I, Wan LX, Rey F, Wang T, Firestein SJ, Yanagisawa M, Gordon JI, Eichmann A, Peti‐Peterdi J, Caplan MJ. Olfactory receptor responding to gut microbiota‐derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci U S A 110: 4410‐4415, 2013.
 149.Prentki M, Matschinsky FM, Madiraju SR. Metabolic signaling in fuel‐induced insulin secretion. Cell Metab 18: 162‐185, 2013.
 150.Priyadarshini M, Layden BT. FFAR3 modulates insulin secretion and global gene expression in mouse islets. Islets 7: e1045182, 2015.
 151.Priyadarshini M, Villa SR, Fuller M, Wicksteed B, Mackay CR, Alquier T, Poitout V, Mancebo H, Mirmira RG, Gilchrist A, Layden BT. An acetate‐specific GPCR, FFAR2, regulates insulin secretion. Mol Endocrinol 29: 1055‐1066, 2015.
 152.Priyadarshini M, Wicksteed B, Schiltz GE, Gilchrist A, Layden BT. SCFA receptors in pancreatic beta cells: Novel diabetes targets? Trends Endocrinol Metab 27: 653‐664, 2016.
 153.Priyamvada S, Gomes R, Gill RK, Saksena S, Alrefai WA, Dudeja PK. Mechanisms underlying dysregulation of electrolyte absorption in inflammatory bowel disease‐associated diarrhea. Inflamm Bowel Dis 21: 2926‐2935, 2015.
 154.Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR, Frost G. The short chain fatty acid propionate stimulates GLP‐1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond) 39: 424‐429, 2015.
 155.Puhl HL, III, Won YJ, Lu VB, Ikeda SR. Human GPR42 is a transcribed multisite variant that exhibits copy number polymorphism and is functional when heterologously expressed. Sci Rep 5: 12880, 2015.
 156.Rajendran VM, Nanda Kumar NS, Tse CM, Binder HJ. Na‐H exchanger isoform‐2 (NHE2) mediates butyrate‐dependent Na+ absorption in dextran sulfate sodium (DSS)‐induced colitis. J Biol Chem 290: 25487‐25496, 2015.
 157.Rakoff‐Nahoum S, Paglino J, Eslami‐Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll‐like receptors is required for intestinal homeostasis. Cell 118: 229‐241, 2004.
 158.Rezq S, Abdel‐Rahman AA. Central GPR109A activation mediates glutamate‐dependent pressor response in conscious rats. J Pharmacol Exp Ther 356: 456‐465, 2016.
 159.Richman JG, Kanemitsu‐Parks M, Gaidarov I, Cameron JS, Griffin P, Zheng H, Guerra NC, Cham L, Maciejewski‐Lenoir D, Behan DP, Boatman D, Chen R, Skinner P, Ornelas P, Waters MG, Wright SD, Semple G, Connolly DT. Nicotinic acid receptor agonists differentially activate downstream effectors. J Biol Chem 282: 18028‐18036, 2007.
 160.Rodriguez M, Luo W, Weng J, Zeng L, Yi Z, Siwko S, Liu M. PSGR promotes prostatic intraepithelial neoplasia and prostate cancer xenograft growth through NF‐kappaB. Oncogenesis 3: e114, 2014.
 161.Rodriguez M, Siwko S, Zeng L, Li J, Yi Z, Liu M. Prostate‐specific G‐protein‐coupled receptor collaborates with loss of PTEN to promote prostate cancer progression. Oncogene 35: 1153‐1162, 2016.
 162.Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and function of G‐protein‐coupled receptors. Nature 459: 356‐363, 2009.
 163.Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10: 490‐500, 2010.
 164.Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 133: 775‐787, 2008.
 165.Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, Hammer RE, Williams SC, Crowley J, Yanagisawa M, Gordon JI. Effects of the gut microbiota on host adiposity are modulated by the short‐chain fatty‐acid binding G protein‐coupled receptor, Gpr41. Proc Natl Acad Sci U S A 105: 16767‐16772, 2008.
 166.Sawzdargo M, George SR, Nguyen T, Xu S, Kolakowski LF, O'Dowd BF. 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: 543‐547, 1997.
 167.Schauber J, Svanholm C, Termen S, Iffland K, Menzel T, Scheppach W, Melcher R, Agerberth B, Luhrs H, Gudmundsson GH. Expression of the cathelicidin LL‐37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 52: 735‐741, 2003.
 168.Schmidt J, Smith NJ, Christiansen E, Tikhonova IG, Grundmann M, Hudson BD, Ward RJ, Drewke C, Milligan G, Kostenis E, Ulven T. Selective orthosteric free fatty acid receptor 2 (FFA2) agonists: Identification of the structural and chemical requirements for selective activation of FFA2 versus FFA3. J Biol Chem 286: 10628‐10640, 2011.
 169.Schroeder BO, Backhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 22: 1079‐1089, 2016.
 170.Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer 13: 800‐812, 2013.
 171.Senga T, Iwamoto S, Yoshida T, Yokota T, Adachi K, Azuma E, Hamaguchi M, Iwamoto T. LSSIG is a novel murine leukocyte‐specific GPCR that is induced by the activation of STAT3. Blood 101: 1185‐1187, 2003.
 172.Sergeev E, Hansen AH, Pandey SK, MacKenzie AE, Hudson BD, Ulven T, Milligan G. Non‐equivalence of key positively charged residues of the free fatty acid 2 receptor in the recognition and function of agonist versus antagonist ligands. J Biol Chem 291: 303‐317, 2016.
 173.Shah JH, Wongsurawat N, Aran PP. Effect of ethanol on stimulus‐induced insulin secretion and glucose tolerance. A study of mechanisms. Diabetes 26: 271‐277, 1977.
 174.Shi G, Sun C, Gu W, Yang M, Zhang X, Zhai N, Lu Y, Zhang Z, Shou P, Zhang Z, Ning G. Free fatty acid receptor 2, a candidate target for type 1 diabetes, induces cell apoptosis through ERK signaling. J Mol Endocrinol 53: 367‐380, 2014.
 175.Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A, Franke A, Ott S, Hasler R, Nikolaus S, Folsch UR, Rose‐John S, Jiang HP, Li J, Schreiber S, Rosenstiel P. G protein‐coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183: 7514‐7522, 2009.
 176.Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40: 128‐139, 2014.
 177.Sivaprakasam S, Gurav A, Paschall AV, Coe GL, Chaudhary K, Cai Y, Kolhe R, Martin P, Browning D, Huang L, Shi H, Sifuentes H, Vijay‐Kumar M, Thompson SA, Munn DH, Mellor A, McGaha TL, Shiao P, Cutler CW, Liu K, Ganapathy V, Li H, Singh N. An essential role of Ffar2 (Gpr43) in dietary fibre‐mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis 5: e238, 2016.
 178.Sivaprakasam S, Prasad PD, Singh N. Benefits of short‐chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther 164: 144‐151, 2016.
 179.Smith JS, Rajagopal S. The beta‐arrestins: Multifunctional regulators of G protein‐coupled receptors. J Biol Chem 291: 8969‐8977, 2016.
 180.Smith NJ, Ward RJ, Stoddart LA, Hudson BD, Kostenis E, Ulven T, Morris JC, Trankle C, Tikhonova IG, Adams DR, Milligan G. Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago‐allosteric modulator. Mol Pharmacol 80: 163‐173, 2011.
 181.Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS. The microbial metabolites, short‐chain fatty acids, regulate colonic Treg cell homeostasis. Science 341: 569‐573, 2013.
 182.Sonnenburg JL, Backhed F. Diet‐microbiota interactions as moderators of human metabolism. Nature 535: 56‐64, 2016.
 183.Stoddart LA, Smith NJ, Jenkins L, Brown AJ, Milligan G. Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J Biol Chem 283: 32913‐32924, 2008.
 184.Suckow AT, Briscoe CP. Key questions for translation of FFA receptors: From pharmacology to medicines. Handb Exp Pharmacol 236: 101‐131, 2017.
 185.Sun J, Furio L, Mecheri R, van der Does AM, Lundeberg E, Saveanu L, Chen Y, van Endert P, Agerberth B, Diana J. Pancreatic beta‐cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut microbiota. Immunity 43: 304‐317, 2015.
 186.Sun M, Wu W, Liu Z, Cong Y. Microbiota metabolite short chain fatty acids, GPCR, and inflammatory bowel diseases. J Gastroenterol 52: 1‐8, 2017.
 187.Suzuki T, Yoshida S, Hara H. Physiological concentrations of short‐chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr 100: 297‐305, 2008.
 188.Sykaras AG, Demenis C, Case RM, McLaughlin JT, Smith CP. Duodenal enteroendocrine I‐cells contain mRNA transcripts encoding key endocannabinoid and fatty acid receptors. PLoS One 7: e42373, 2012.
 189.Taggart AK, Kero J, Gan X, Cai TQ, Cheng K, Ippolito M, Ren N, Kaplan R, Wu K, Wu TJ, Jin L, Liaw C, Chen R, Richman J, Connolly D, Offermanns S, Wright SD, Waters MG. (D)‐beta‐Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA‐G. J Biol Chem 280: 26649‐26652, 2005.
 190.Tan J, McKenzie C, Vuillermin PJ, Goverse G, Vinuesa CG, Mebius RE, Macia L, Mackay CR. Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Rep 15: 2809‐2824, 2016.
 191.Tan JK, McKenzie C, Marino E, Macia L, Mackay CR. Metabolite‐sensing G protein‐coupled receptors‐facilitators of diet‐related immune regulation. Annu Rev Immunol 35: 371‐402, 2017.
 192.Tang C, Ahmed K, Gille A, Lu S, Grone HJ, Tunaru S, Offermanns S. Loss of FFA2 and FFA3 increases insulin secretion and improves glucose tolerance in type 2 diabetes. Nat Med 21: 173‐177, 2015.
 193.Tang Y, Chen Y, Jiang H, Nie D. The role of short‐chain fatty acids in orchestrating two types of programmed cell death in colon cancer. Autophagy 7: 235‐237, 2011.
 194.Tang Y, Chen Y, Jiang H, Nie D. Short‐chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria‐mediated apoptotic cell death. Cell Death Differ 18: 602‐618, 2011.
 195.Tang Y, Chen Y, Jiang H, Robbins GT, Nie D. G‐protein‐coupled receptor for short‐chain fatty acids suppresses colon cancer. Int J Cancer 128: 847‐856, 2011.
 196.Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki SI, Kuwahara A. Roles of short‐chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol 59(Suppl 2): 251‐262, 2008.
 197.Tazoe H, Otomo Y, Karaki S, Kato I, Fukami Y, Terasaki M, Kuwahara A. Expression of short‐chain fatty acid receptor GPR41 in the human colon. Biomed Res 30: 149‐156, 2009.
 198.Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD, Ganapathy V. GPR109A is a G‐protein‐coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res 69: 2826‐2832, 2009.
 199.Thorburn AN, Macia L, Mackay CR. Diet, metabolites, and “western‐lifestyle” inflammatory diseases. Immunity 40: 833‐842, 2014.
 200.Tiengo A, Valerio A, Molinari M, Meneghel A, Lapolla A. Effect of ethanol, acetaldehyde, and acetate on insulin and glucagon secretion in the perfused rat pancreas. Diabetes 30: 705‐709, 1981.
 201.Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, Cameron J, Grosse J, Reimann F, Gribble FM. Short‐chain fatty acids stimulate glucagon‐like peptide‐1 secretion via the G‐protein‐coupled receptor FFAR2. Diabetes 61: 364‐371, 2012.
 202.Tolhurst G, Reimann F, Gribble FM. Intestinal sensing of nutrients. Handb Exp Pharmacol 309‐335, 2012.
 203.Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom‐Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, Marsland BJ. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 20: 159‐166, 2014.
 204.Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9: 799‐809, 2009.
 205.Tvrzicka E, Kremmyda LS, Stankova B, Zak A. Fatty acids as biocompounds: Their role in human metabolism, health and disease–‐a review. Part 1: Classification, dietary sources and biological functions. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 155: 117‐130, 2011.
 206.Urban DJ, Roth BL. DREADDs (designer receptors exclusively activated by designer drugs): Chemogenetic tools with therapeutic utility. Annu Rev Pharmacol Toxicol 55: 399‐417, 2015.
 207.Veprik A, Laufer D, Weiss S, Rubins N, Walker MD. GPR41 modulates insulin secretion and gene expression in pancreatic beta‐cells and modifies metabolic homeostasis in fed and fasting states. FASEB J 30: 3860‐3869, 2016.
 208.Vieira AT, Macia L, Galvao I, Martins FS, Canesso MC, Amaral FA, Garcia CC, Maslowski KM, De Leon E, Shim D, Nicoli JR, Harper JL, Teixeira MM, Mackay CR. A role for gut microbiota and the metabolite‐sensing receptor GPR43 in a murine model of gout. Arthritis Rheumatol 67: 1646‐1656, 2015.
 209.Villa SR, Priyadarshini M, Fuller MH, Bhardwaj T, Brodsky MR, Angueira AR, Mosser RE, Carboneau BA, Tersey SA, Mancebo H, Gilchrist A, Mirmira RG, Gannon M, Layden BT. Loss of free fatty acid receptor 2 leads to impaired islet mass and beta cell survival. Sci Rep 6: 28159, 2016.
 210.Vinolo MA, Ferguson GJ, Kulkarni S, Damoulakis G, Anderson K, Bohlooly YM, Stephens L, Hawkins PT, Curi R. SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PLoS One 6: e21205, 2011.
 211.Volk N, Lacy B. Anatomy and physiology of the small bowel. Gastrointest Endosc Clin N Am 27: 1‐13, 2017.
 212.Walters RW, Shukla AK, Kovacs JJ, Violin JD, DeWire SM, Lam CM, Chen JR, Muehlbauer MJ, Whalen EJ, Lefkowitz RJ. beta‐Arrestin1 mediates nicotinic acid‐induced flushing, but not its antilipolytic effect, in mice. J Clin Invest 119: 1312‐1321, 2009.
 213.Wang J, Wu X, Simonavicius N, Tian H, Ling L. Medium‐chain fatty acids as ligands for orphan G protein‐coupled receptor GPR84. J Biol Chem 281: 34457‐34464, 2006.
 214.Wang L, Llorente C, Hartmann P, Yang AM, Chen P, Schnabl B. Methods to determine intestinal permeability and bacterial translocation during liver disease. J Immunol Methods 421: 44‐53, 2015.
 215.Wang N, Guo DY, Tian X, Lin HP, Li YP, Chen SJ, Fu YC, Xu WC, Wei CJ. Niacin receptor GPR109A inhibits insulin secretion and is down‐regulated in type 2 diabetic islet beta‐cells. Gen Comp Endocrinol 237: 98‐108, 2016.
 216.Wang Y, Jiao X, Kayser F, Liu J, Wang Z, Wanska M, Greenberg J, Weiszmann J, Ge H, Tian H, Wong S, Schwandner R, Lee T, Li Y. The first synthetic agonists of FFA2: Discovery and SAR of phenylacetamides as allosteric modulators. Bioorg Med Chem Lett 20: 493‐498, 2010.
 217.Wellendorph P, Johansen LD, Brauner‐Osborne H. The emerging role of promiscuous 7TM receptors as chemosensors for food intake. Vitam Horm 84: 151‐184, 2010.
 218.Wu H, Tremaroli V, Backhed F. Linking microbiota to human diseases: A systems biology perspective. Trends Endocrinol Metab 26: 758‐770, 2015.
 219.Wu J, Zhou Z, Hu Y, Dong S. Butyrate‐induced GPR41 activation inhibits histone acetylation and cell growth. J Genet Genomics 39: 375‐384, 2012.
 220.Wu W, Sun M, Chen F, Cao AT, Liu H, Zhao Y, Huang X, Xiao Y, Yao S, Zhao Q, Liu Z, Cong Y. Microbiota metabolite short‐chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunol 10: 946‐956, 2017.
 221.Xia C, Ma W, Wang F, Hua S, Liu M. Identification of a prostate‐specific G‐protein coupled receptor in prostate cancer. Oncogene 20: 5903‐5907, 2001.
 222.Ximenes HM, Hirata AE, Rocha MS, Curi R, Carpinelli AR. Propionate inhibits glucose‐induced insulin secretion in isolated rat pancreatic islets. Cell Biochem Funct 25: 173‐178, 2007.
 223.Xiong Y, Miyamoto N, Shibata K, Valasek MA, Motoike T, Kedzierski RM, Yanagisawa M. Short‐chain fatty acids stimulate leptin production in adipocytes through the G protein‐coupled receptor GPR41. Proc Natl Acad Sci U S A 101: 1045‐1050, 2004.
 224.Xu LL, Stackhouse BG, Florence K, Zhang W, Shanmugam N, Sesterhenn IA, Zou Z, Srikantan V, Augustus M, Roschke V, Carter K, McLeod DG, Moul JW, Soppett D, Srivastava S. PSGR, a novel prostate‐specific gene with homology to a G protein‐coupled receptor, is overexpressed in prostate cancer. Cancer Res 60: 6568‐6572, 2000.
 225.Yang S, Li X, Wang N, Yin G, Ma S, Fu Y, Wei C, Chen Y, Xu W. GPR109A expression in the murine Min6 pancreatic beta cell line, and its relation with glucose metabolism and inflammation. Ann Clin Lab Sci 45: 315‐322, 2015.
 226.Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA. Lipid G protein‐coupled receptor ligand identification using beta‐arrestin PathHunter assay. J Biol Chem 284: 12328‐12338, 2009.
 227.Yonezawa T, Kobayashi Y, Obara Y. Short‐chain fatty acids induce acute phosphorylation of the p38 mitogen‐activated protein kinase/heat shock protein 27 pathway via GPR43 in the MCF‐7 human breast cancer cell line. Cell Signal 19: 185‐193, 2007.
 228.Zaibi MS, Stocker CJ, O'Dowd J, Davies A, Bellahcene M, Cawthorne MA, Brown AJ, Smith DM, Arch JR. Roles of GPR41 and GPR43 in leptin secretory responses of murine adipocytes to short chain fatty acids. FEBS Lett 584: 2381‐2386, 2010.
 229.Zandi‐Nejad K, Takakura A, Jurewicz M, Chandraker AK, Offermanns S, Mount D, Abdi R. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J 27: 4366‐4374, 2013.
 230.Zellner C, Pullinger CR, Aouizerat BE, Frost PH, Kwok PY, Malloy MJ, Kane JP. Variations in human HM74 (GPR109B) and HM74A (GPR109A) niacin receptors. Hum Mutat 25: 18‐21, 2005.

 

Further Reading List

Pavlos NJ, Friedman PA. GPCR Signaling and Trafficking: The Long and Short of It. Trends Endocrinol Metab  28:213-226, 2017.

Rajagopal S, Shenoy SK. GPCR desensitization: Acute and prolonged phases. Cell Signal pii: S0898-6568(17)30030-X, 2017.

Sjögren B. The evolution of regulators of G protein signalling proteins as drug targets - 20 years in the making: IUPHAR Review 21. Br J Pharmacol 174:427-437, 2017.

Komolov KE, Benovic JL. G protein-coupled receptor kinases: Past, present and future. Cell Signal pii: S0898-6568(17)30182-1, 2017.

Ranjan R, Dwivedi H, Baidya M, Kumar M, Shukla AK. Novel Structural Insights into GPCR-?-Arrestin Interaction and Signaling. Trends Cell Biol pii: S0962-8924(17)30087-9, 2017.

Brand MW, Wannemuehler MJ, Phillips GJ, Proctor A, Overstreet A, Jergens AE, Orcutt RP, Fox JG. The Altered Schaedler Flora: Continued Applications of a Defined Murine Microbial Community. ILAR J 56: 169-178, 2015.

 

 

Teaching Material

M. Priyadarshini, K. U. Kotlo, P. K. Dudeja, B. T. Layden. Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology. Compr Physiol 8: 2018, 1091-1115.

Didactic Synopsis

Major Teaching Points:

  1. Short chain fatty acids (SCFAs) produced by gut microbial fermentation serve both as an energy source and signaling molecules.
  2. Molecular sensors for these SCFAs are G-protein coupled receptors. These GPCRs, namely, FFA2 and FFA3 and GPR109a have immune as well as metabolic roles.
  3. These receptors, including Olfr78, have overlapping ligand profiles and some functional redundancy, but their restricted expression pattern in various cell types in the gut (and other tissues) and distinct G-protein-coupling profiles allows for specific physiologic effects.
  4. FFA2 and GPR109a modify the gut immune cell repertoire and inflammatory responses regulating immune homeostasis, guard intestinal epithelial barrier against pathogenic intrusion and tumor growth.
  5. FFA2 and FFA3 appear to regulate GLP-1, GIP, and PYY secretion exerting effects on glucose homeostasis.
  6. These roles signify a link between gut microbiota and host physiology through SCFA receptors.
  7. Targeted modulation of these SCFA receptors may promote intestinal health.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points:

  1. GPCRs are membrane bound proteins having seven transmembrane domains.
  2. GPCR interacting guanine nucleotide binding proteins (G-proteins) are heterotrimeric composed of three different subunits namely Gα, Gβ, and Gγ.
  3. In absence of an agonist (inactive state), Gα has a bound GDP (guanosine diphosphate). Upon binding of the agonist to the receptor (active state), Gα subunit releases GDP, and occupies GTP (guanosine triphosphate). Following this, active Gα subunit and Gβγ dimer dissociate from the receptor initiating downstream signaling cascade.
  4. There are four main Gα subunit protein classes, Gαq, Gαs, Gαi, and Gα12/13. Each GPCR can couple with one or more Gα subunits.
  5. Activated G protein subunits stimulate downstream effectors like adenylyl cyclase (AC) generating secondary messengers like cyclic adenosine monophosphate (cAMP).
  6. For example, Gαq/11 subunit family members bind and activate phospholipase C (PLC) which catalyzes production of two secondary messengers diacylglycerol (DAG) and inositol triphosphate (IP3) from phosphotidylinositol 4,5-bisphosphate (PIP2) leading to mobilization of calcium from intracellular stores. Gαs subunit activates AC, which increases intracellular concentration of the secondary cAMP leading to activation of protein kinase A (PKA). Gαi subunit inhibits AC and reduces intracellular cAMP concentration. Gα12/13 can activate Rho kinases.
  7. The Gβγ subunit dimer can activate various kinases, phosphoinositide 3 kinase γ (PI3Kγ), protein kinases (PKD), and PLC.
  8. Ultimately, GPCR activation event is transduced to a cellular response like hormone secretion.
  9. Various short chain fatty acid receptors (highlighted in blue color) are listed based on their G-protein-coupling preference. FFA2/3, free fatty acid receptor 2/3; Olfr78, olfactory receptor 78; GPR109a, G-protein-coupled receptor 109a.

Figure 2. Teaching points: Several mechanisms control GPCR signaling to maintain an optimal level of cellular response. Few mechanisms are illustrated here.

  1. First level of regulation is provided by special proteins, regulator of G-protein-signaling (RGS) proteins, that increase rate of hydrolysis GTP bound to Gα subunit to GDP and generate GDP-Gα free to associate with Gβγ. The heterotrimeric G protein complex can realign with the GPCR.
  2. At the second level, GPCR signaling can be terminated by GPCR kinases (GRK) that phosphorylate GPCRs enhancing their affinity for another protein, β arrestin, which prevents further interaction of the G protein with the GPCR and desensitizes it.
  3. At the third level, β arrestin directs the phosphorylated receptor to the clathrin-coated pits (part of the endocytic machinery) which are then internalized as endosomes (sorting vesicles directing cargo to intracellular compartment). Internalized receptor can be degraded (β-arrestin is shed off and GPCR is directed to lysosomes) or recycled back to cell membrane. β-arrestin on the GPCR-β-arrestin endosome can act as an adaptor for various kinases forming a “signalosome” and initiate distinct signaling pathways.
  4. At the fourth level, the type of the ligand can determine the GPCR signaling response by favoring either G-protein or β-arrestin pathway.
  5. At the fifth level, transcription of GPCR gene can be regulated by activity of factors that can bind to the gene promoter or affect acetylation/methylation of the chromatin.
  6. At the sixth level, GPCRs can oligomerize. Such oligomerization in response to activation by the agonist can influence receptor internalization, receptor activity, and downstream signaling. Oligomerization may also be important for transport of the receptor to the cell surface.
  7. Short chain fatty acid receptors (highlighted in blue color font) are listed based on regulatory mechanism reported for them. FFA2/3, free fatty acid receptor 2/3; GPR109a, G-protein-coupled receptor 109a.

Figure 3 Teaching points:

  1. Short chain fatty acid concentrations are highest at the site of their production, that is, in the intestine (left upper panel).
  2. SCFA concentrations are higher in portal blood than in systemic circulation (left lower panel).
  3. Similarly, expression of SCFA receptors varies in different tissues.

Figure 4 Teaching points:

  1. Activated FFA2 can couple with Gαq/11 (downstream stimulatory response), with Gαi/o (downstream inhibitory response) or with β arrestin (G-protein-independent response).
  2. Activated FFA3 couples exclusively with Gαi/o exerting inhibitory response.
  3. Activated GPR109a can couple with Gαi/o or can signal independent of G-proteins via β-arrestin.
  4. Receptor activation is thus followed by pleiotropic physiological effects.

Figure 5 Teaching points:

  1. Short chain fatty acids produced by gut microbiota bind and activate receptors on intestinal epithelial cells and immune cells like macrophages, neutrophils, and dendritic cells.
  2. In intestinal epithelial cells, acetate and butyrate activation of FFA2 and GPR109a, respectively, result in activation of inflammasome through GPCR-mediated increase in intracellular calcium mobilization, and this, in turn, leads to production of IL-18 that mediates cytoprotection and promote repair.
  3. FFA2 is the chief “neutrophil short chain fatty acid receptor” responsible for chemotaxis (migration to the site of inflammation).
  4. FFA2 mediates dendritic cell dependent production of IgA from activated B cells (plasma cells). IgA is secreted across the epithelial membrane and provides resistance against infection.
  5. FFA2 and GPR109a promote Treg cell differentiation and proliferation which reduce production of proinflammatory mediators by effects on proinflammatory Th1and/or Th17 cells.
  6. FFA2 activation and GPR109a activation on macrophages and dendritic cells enhances production of anti-inflammatory cytokine, IL-10.
  7. Taken together, these processes promote epithelial barrier integrity, adequate neutrophil migration, balanced proinflammatory (Th1 and Th17) and immunosuppressive (Treg) responses under conditions of inflammatory insult.
  8. CD, cluster of differentiation; IgA, immunoglobulin A; Th, T helper cells; Treg, regulatory T cells; short chain fatty acids are represented by □; FFA2 and GPR109a, respectively on immune cells are represented by □; red upward arrow signifies increase; blue downward arrow signifies decrease.

Figure 6 Teaching points:

  1. To appreciate specific physiological roles of various short chain fatty acid receptors several approaches are being tried or developed.
  2. Efforts are directed for development of discriminative ligands, designer receptors, and in vivo models. This will help understand receptor specific effects, discern signaling properties of human, and mouse orthologs of the receptor, and clear doubts about the expression pattern of these receptors.
  3. Use of novel mouse models with multiple receptor KO, tissue specific KO, and knock-in of human receptor ortholog along with modulation of gut micorbiota will help understand the interplay of diet, gut microbiota, and receptor signaling and its contribution to (patho)physiology.

Figure 7 Teaching points:

  1. Through the activity of gut microbiota dietary fiber gets converted to short chain fatty acids (SCFAs).
  2. Activity of SCFAs at their cognate receptors on gut immune and epithelial cells is protective against breach of epithelial barrier and immune homeostasis.
  3. Dietary fiber also alters gut microbiota composition selecting for beneficial bacteria.
  4. Besides diet, genetic makeup of the host also influences gut microbiota composition.

 


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Medha Priyadarshini, Kumar U. Kotlo, Pradeep K. Dudeja, Brian T. Layden. Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology. Compr Physiol 2018, 8: 1091-1115. doi: 10.1002/cphy.c170050