Background: Short-chain fatty acids (SCFAs), which are produced by the fermentation of dietary fiber by intestinal microbiota, may positively influence immune responses and protect against gut inflammation. SCFAs bind to G protein-coupled receptor 43 (GPR43). Here, we show that SCFA–GPR43 interactions profoundly affect the gut inflammatory response.
Methods: Colitis was induced by adding dextran sulfate sodium to the drinking water of GPR43 knockout (−/−) and wild-type mice.
Results: Dextran sulfate sodium–treated GPR43−/− mice exhibited weight loss, increased disease activity index (a combined measure of weight loss, rectal bleeding, and stool consistency), decreased hematocrit, and colon shortening, resulting in significantly worse colonic inflammation than in wild-type mice. Tumor necrosis factor alpha and interleukin 17 protein levels in the colonic mucosa of GPR43−/− mice were significantly higher than in wild-type mice. Treatment of wild-type mice with 150 mM acetate in their drinking water markedly improved these disease indices, with an increase in colon length and decrease in the disease activity index; however, it had no effect on GPR43−/− mice. Mononuclear cell production of tumor necrosis factor alpha after lipopolysaccharide stimulation was suppressed by acetate. This effect was inhibited by anti-GPR43 antibody.
Conclusions: SCFA–GPR43 interactions modulate colitis by regulating inflammatory cytokine production in mononuclear cells.
Article first published online 17 October 2013
*Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan;
†Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Aichi, Japan.
Reprints: Makoto Sasaki, MD, PhD, Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan (e-mail: email@example.com).
Supported by General Incorporated Foundation from Aichi Medical University Aikeikai.
K. Kasugai received research grants from the Research Organization for Gastro-Enterological Disease Treatment (NPO-ROGET) and Daiich Sankyo Co., Ltd., and lecture fees from Daiich Sankyo Co., Ltd. and Astra Zeneca Co., Ltd. The other authors have no conflicts of interest to disclose.
Received August 21, 2013
Accepted September 11, 2013