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Abstract
The bacterial flora of the gastrointestinal tract shapes the development of the
immune system. Recent evidence indicates that normal intestinal microbiota
might protect against the development of inflammatory diseases. The gut
microbiota have been proposed to produce factors that are beneficial to the host for the regulation of immune responses. These factors have been termed symbiosis factors. One of these symbiosis factors may be short-chain fatty acids (SCFA), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis, asthma and Rheumatoid arthritis is a change in ‘healthy’ microbiota such as Bifidobacterium and Bacteriodes. In colitis this change in microbiota has also been shown to be concurrent with a reduction in SCFA. Moreover, increased intake of fermentable dietary fibre, or SCFA, is clinically beneficial in the treatment of colitis. SCFA bind the G-protein coupled receptor 43 (GPR43, also known as FFAR2), and here we show that SCFA–GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFA was necessary for the normal resolution of inflammatory responses. GPR43-deficient (Gpr43-/-) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This related to increased production of inflammatory mediators by Gpr43-
/- immune cells, increased immune cell recruitment and intrinsic defects in Gpr43-/- neutrophils. Germ-free mice, which are devoid of bacteria and produce little or no SCFA, showed a similar dysregulation of certain inflammatory responses. Altered composition of the gut microflora, caused by Western diet, or use of antibiotics, has been suggested as a reason for the increased incidence of allergies and asthma in humans. SCFA-GPR43 interactions could represent a central mechanism to account for affects of diet and gut microflora on immune responses and may represent new avenues for understanding and potentially manipulating immune responses.