1. Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia
2. Cooperative Research Center for Asthma and Airways, Camperdown, New South Wales 2050, Australia
3. St Vincent's Clinical School, University of New South Wales, New South Wales 2010, Australia
4. Department of Biochemistry and Immunology, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
5. Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA
6. Faculty of Medicine, Monash University, Wellington Road, Clayton, Victoria 3800, Australia
7. School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

Correspondence to: Charles R. Mackay^1,2,3,6 Correspondence and requests for materials should be addressed to C.R.M. (Email: charles.mackay@med.monash.edu.au).

Abstract

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 diseases^{1, 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 colitis^{5, 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.

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