title: Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice.
abstract: OBJECTIVE
  Short-chain fatty acids (SCFAs), the most abundant microbial metabolites in the intestine, activate cells via G-protein-coupled receptors (GPRs), such as GPR41 and GPR43. We studied regulation of the immune response by SCFAs and their receptors in the intestines of mice.
  
  
  METHODS
  Inflammatory responses were induced in GPR41(-/-), GPR43(-/-), and C57BL6 (control) mice by administration of ethanol; 2, 4, 6-trinitrobenzene sulfonic-acid (TNBS); or infection with Citrobacter rodentium. We examined the effects of C rodentium infection on control mice fed SCFAs and/or given injections of antibodies that delay the immune response. We also studied the kinetics of cytokine and chemokine production, leukocyte recruitment, intestinal permeability, and T-cell responses. Primary colon epithelial cells were isolated from GPR41(-/-), GPR43(-/-), and control mice; signaling pathways regulated by SCFAs were identified using immunohistochemical, enzyme-linked immunosorbent assay, and flow cytometry analyses.
  
  
  RESULTS
  GPR41(-/-) and GPR43(-/-) mice had reduced inflammatory responses after administration of ethanol or TNBS compared with control mice, and had a slower immune response against C rodentium infection, clearing the bacteria more slowly. SCFAs activated intestinal epithelial cells to produce chemokines and cytokines in culture and mice after administration of ethanol, TNBS, or C rodentium. These processes required GPR41 and GPR43 and were required to recruit leukocytes and activate effector T cells in the intestine. GPR41 and GPR43 activated extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling pathways in epithelial cells to induce production of chemokines and cytokines during immune responses.
  
  
  CONCLUSIONS
  SCFAs activate GPR41 and GPR43 on intestinal epithelial cells, leading to mitogen-activated protein kinase signaling and rapid production of chemokines and cytokines. These pathways mediate protective immunity and tissue inflammation in mice.
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Myung H
authors.initials: MH
authors.lastname: Kim
authors.forename: Seung G
authors.initials: SG
authors.lastname: Kang
authors.forename: Jeong H
authors.initials: JH
authors.lastname: Park
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Chang H
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium; D003092:Colitis / Q000276:immunology*; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology*; D000431:Ethanol / Q000276:immunology; D005232:Fatty Acids, Volatile / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid / Q000276:immunology
chemical_list: D005232:Fatty Acids, Volatile; C506481:Ffar2 protein, mouse; C506482:Gpcr41 protein, mouse; D043562:Receptors, G-Protein-Coupled; D000431:Ethanol; D014302:Trinitrobenzenesulfonic Acid
keywords: 2, 4, 6-trinitrobenzene sulfonic-acid; ATF2; C2; C3; C4; CFU; Colonic Inflammation; ECs; ERK; FITC; G-protein−coupled receptor; GPR; IL; Intestinal Barrier Leakage; KO; MAPK; Mouse Model; Pathogen; SCFAs; T-helper cell; TNBS; Th; WT; acetate; activating transcription factor 2; butyrate; colony-forming unit; epithelial cells; extracellular signal-regulated kinase; fluorescein isothiocyanate; interleukin; knock-out; mitogen-activated protein kinase; propionate; short-chain fatty acids; wild type