Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Exacerbated colitis in germ-free mice is ameliorated by acetate.
Figure 2: GPR43 expression and role in inflammatory responses.
Figure 3: Inflammatory arthritis and allergic airway disease and GPR43 deficiency.
Figure 4: GPR43 signalling and immune cell functions.


  1. 1

    Wen, L. et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 455, 1109–1113 (2008)

    CAS  Article  ADS  Google Scholar 

  2. 2

    Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008)

    CAS  Article  ADS  Google Scholar 

  3. 3

    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)

    CAS  Article  ADS  Google Scholar 

  4. 4

    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)

    CAS  Article  Google Scholar 

  5. 5

    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)

    CAS  Article  Google Scholar 

  6. 6

    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)

    CAS  Article  Google Scholar 

  7. 7

    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)

    CAS  Article  Google Scholar 

  8. 8

    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)

    CAS  Article  Google Scholar 

  9. 9

    Vernia, P. et al. Short-chain fatty acid topical treatment in distal ulcerative colitis. Aliment. Pharmacol. Ther. 9, 309–313 (1995)

    CAS  Article  Google Scholar 

  10. 10

    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)

    CAS  Article  Google Scholar 

  11. 11

    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)

    CAS  Article  Google Scholar 

  12. 12

    Macfarlane, S. & Macfarlane, G. T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 (2003)

    CAS  Article  Google Scholar 

  13. 13

    Høverstad, T. & Midtvedt, T. Short-chain fatty acids in germfree mice and rats. J. Nutr. 116, 1772–1776 (1986)

    Article  Google Scholar 

  14. 14

    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)

    CAS  Article  Google Scholar 

  15. 15

    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)

    CAS  Article  Google Scholar 

  16. 16

    Segain, J. P. et al. Butyrate inhibits inflammatory responses through NFκB inhibition: implications for Crohn’s disease. Gut 47, 397–403 (2000)

    CAS  Article  Google Scholar 

  17. 17

    Lührs, H. et al. Butyrate-enhanced TNFα-induced apoptosis is associated with inhibition of NF-κB. Anticancer Res. 22, 1561–1568 (2002)

    PubMed  Google Scholar 

  18. 18

    Jeffrey, K. L. et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nature Immunol. 7, 274–283 (2006)

    CAS  Article  Google Scholar 

  19. 19

    Bader, G. D. & Hogue, C. W. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 4, 2 (2003)

    Article  Google Scholar 

  20. 20

    Lee, T. et al. Identification and functional characterization of allosteric agonists for the G protein-coupled receptor FFA2. Mol. Pharmacol. 74, 1599–1609 (2008)

    CAS  Article  Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

    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)

    CAS  Article  Google Scholar 

  23. 23

    Grunstein, M. Histone acetylation in chromatin structure and transcription. Nature 389, 349–352 (1997)

    CAS  Article  ADS  Google Scholar 

  24. 24

    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)

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008)

    CAS  Article  ADS  Google Scholar 

  26. 26

    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)

    CAS  Article  Google Scholar 

  27. 27

    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)

    CAS  Article  Google Scholar 

  28. 28

    Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006)

    CAS  Article  ADS  Google Scholar 

  29. 29

    Shreiner, A., Huffnagle, G. B. & Noverr, M. C. The “Microflora Hypothesis” of allergic disease. Adv. Exp. Med. Biol. 635, 113–134 (2008)

    CAS  Article  Google Scholar 

  30. 30

    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)

    CAS  Article  Google Scholar 

  31. 31

    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)

    CAS  Article  ADS  Google Scholar 

  32. 32

    Saldanha, A. J. Java Treeview—extensible visualization of microarray data. Bioinformatics 20, 3246–3248 (2004)

    CAS  Article  Google Scholar 

  33. 33

    Mishra, G. R. et al. Human protein reference database—2006 update. Nucleic Acids Res. 34, D411–D414 (2006)

    CAS  Article  Google Scholar 

  34. 34

    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)

    CAS  Article  Google Scholar 

  35. 35

    Souza, D. G. et al. The essential role of the intestinal microbiota in facilitating acute inflammatory responses. J. Immunol. 173, 4137–4146 (2004)

    CAS  Article  Google Scholar 

  36. 36

    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)

    CAS  Article  Google Scholar 

  37. 37

    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)

    CAS  Article  Google Scholar 

  38. 38

    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)

    CAS  PubMed  Google Scholar 

  39. 39

    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)

    CAS  Article  Google Scholar 

  40. 40

    Korganow, A. S. et al. From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10, 451–461 (1999)

    CAS  Article  Google Scholar 

  41. 41

    Lee, D. M. et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297, 1689–1692 (2002)

    CAS  Article  ADS  Google Scholar 

  42. 42

    Gross, S. et al. Bioluminescence imaging of myeloperoxidase activity in vivo. Nature Med. 15, 455–461 (2009)

    CAS  Article  Google Scholar 

  43. 43

    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)

    CAS  Article  Google Scholar 

  44. 44

    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)

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Charles R. Mackay.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-11 with Legends. (PDF 1860 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

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).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing