The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases1,2. One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in ‘healthy’ microbiota such as Bifidobacterium and Bacteriodes3, and a concurrent reduction in SCFAs4. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis5,6,7,8,9. SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2)10,11, and here we show that SCFA–GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43-/-) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43-/- immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Communications Open Access 14 October 2022
Scientific Reports Open Access 03 October 2022
Microbiome Open Access 30 July 2022
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008)
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008)
Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007)
Treem, W. R., Ahsan, N., Shoup, M. & Hyams, J. S. Fecal short-chain fatty acids in children with inflammatory bowel disease. J. Pediatr. Gastroenterol. Nutr. 18, 159–164 (1994)
Harig, J. M., Soergel, K. H., Komorowski, R. A. & Wood, C. M. Treatment of diversion colitis with short-chain-fatty acid irrigation. N. Engl. J. Med. 320, 23–28 (1989)
Kanauchi, O. et al. Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial. J. Gastroenterol. 37 (suppl. 14). 67–72 (2002)
Breuer, R. I. et al. Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Preliminary report. Dig. Dis. Sci. 36, 185–187 (1991)
Scheppach, W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebo-controlled trial. German-Austrian SCFA Study Group. Dig. Dis. Sci. 41, 2254–2259 (1996)
Vernia, P. et al. Short-chain fatty acid topical treatment in distal ulcerative colitis. Aliment. Pharmacol. Ther. 9, 309–313 (1995)
Brown, A. J. et al. 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)
Le Poul, E. et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 278, 25481–25489 (2003)
Macfarlane, S. & Macfarlane, G. T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 (2003)
Høverstad, T. & Midtvedt, T. Short-chain fatty acids in germfree mice and rats. J. Nutr. 116, 1772–1776 (1986)
Tedelind, S., Westberg, F., Kjerrulf, M. & Vidal, A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J. Gastroenterol. 13, 2826–2832 (2007)
Cavaglieri, C. R. et al. Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci. 73, 1683–1690 (2003)
Segain, J. P. et al. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn’s disease. Gut 47, 397–403 (2000)
Lührs, H. et al. Butyrate-enhanced TNFα-induced apoptosis is associated with inhibition of NF-κB. Anticancer Res. 22, 1561–1568 (2002)
Jeffrey, K. L. et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nature Immunol. 7, 274–283 (2006)
Bader, G. D. & Hogue, C. W. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 4, 2 (2003)
Lee, T. et al. Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol. Pharmacol. 74, 1599–1609 (2008)
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)
Pomare, E. W., Branch, W. J. & Cummings, J. H. Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J. Clin. Invest. 75, 1448–1454 (1985)
Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 389, 349–352 (1997)
Mørland, B. & Midtvedt, T. Phagocytosis, peritoneal influx, and enzyme activities in peritoneal macrophages from germfree, conventional, and ex-germfree mice. Infect. Immun. 44, 750–752 (1984)
Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008)
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)
Serhan, C. N., Chiang, N. & Van Dyke, T. E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nature Rev. Immunol. 8, 349–361 (2008)
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006)
Shreiner, A., Huffnagle, G. B. & Noverr, M. C. The “Microflora Hypothesis” of allergic disease. Adv. Exp. Med. Biol. 635, 113–134 (2008)
Liu, S. M. et al. Immune cell transcriptome datasets reveal novel leukocyte subset-specific genes and genes associated with allergic processes. J. Allergy Clin. Immunol. 118, 496–503 (2006)
Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)
Saldanha, A. J. Java Treeview—extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004)
Mishra, G. R. et al. Human protein reference database—2006 update. Nucleic Acids Res. 34, D411–D414 (2006)
Heath, H. et al. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J. Clin. Invest. 99, 178–184 (1997)
Souza, D. G. et al. The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J. Immunol. 173, 4137–4146 (2004)
Zaph, C. et al. Commensal-dependent expression of IL-25 regulates the IL-23–IL-17 axis in the intestine. J. Exp. Med. 205, 2191–2198 (2008)
Souza, D. G. et al. The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice. J. Immunol. 179, 8533–8543 (2007)
Cooper, H. S., Murthy, S. N., Shah, R. S. & Sedergran, D. J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 69, 238–249 (1993)
Vieira, A. T. et al. Mechanisms of the anti-inflammatory effects of the natural secosteroids physalins in a model of intestinal ischaemia and reperfusion injury. Br. J. Pharmacol. 146, 244–251 (2005)
Korganow, A. S. et al. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10, 451–461 (1999)
Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002)
Gross, S. et al. Bioluminescence imaging of myeloperoxidase activity in vivo. Nature Med. 15, 455–461 (2009)
Shum, B. O. et al. The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J. Clin. Invest. 116, 2183–2192 (2006)
Strath, M., Warren, D. J. & Sanderson, C. J. Detection of eosinophils using an eosinophil peroxidase assay. Its use as an assay for eosinophil differentiation factors. J. Immunol. Methods 83, 209–215 (1985)
The authors thank P. Silvera and S. Tangye for supply of certain Genechip data sets, L. Tsai for help with heatmaps, and D. Kobuley, J. Nicoli and M. Abt for help in the germ-free animal facilities. K.M.M. and C.R.M. are supported by the Australian NHMRC, and the CRC for Asthma and Airways. A.N. is a recipient of a Fellowship award from the Crohn’s and Colitis Foundation of America. F.S. and D.Y. are Cancer Institute NSW Fellows.
Author Contributions C.R.M. conceived and supervised the project, and K.M.M. performed the vast majority of the in vitro and in vivo experiments (other than those detailed below) and provided intellectual input to scientific direction and interpretations. A.T.V., M.M.T. and D.A. contributed to experiments with germ-free mice. F.M., M.S.R. and F.S. identified GPR43 as a receptor with an interesting transcript expression, and A.N. and R.J.X. were responsible for all of the subsequent bioinformatic analyses. H.C.S., D.Y. and J.K. provided general support for many of the experiments.
About this article
Cite this article
Maslowski, K., Vieira, A., Ng, A. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 . Nature 461, 1282–1286 (2009). https://doi.org/10.1038/nature08530
This article is cited by
Cancer Cell International (2022)
Dietary resistant starch ameliorating lipopolysaccharide-induced inflammation in meat ducks associated with the alteration in gut microbiome and glucagon-like peptide 1 signaling
Journal of Animal Science and Biotechnology (2022)
TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target
Molecular Neurodegeneration (2022)
Mucosal Immunology (2022)