Journal Article

Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

Mackay, Charles R., Schilter, Heidi C., Maslowski, Kendle M., Mackay, Fabienne, Rolph, Michael S., Vieira, Angelica T., Xavier, Ramnik J., Artis, David, Di Yu, Teixeira, Mauro M., Ng, Aylwin, Sierro, Frederic, Kranich, Jan

2009

Overview

GPR43 receptor as anti-inflammatory target Recent evidence has suggested that the products of 'friendly' intestinal microbes can help counter inflammatory disease and Type 1 diabetes in the host. Commensal bacteria in the colon are known to ferment dietary fibres to produce short-chain fatty acids, and now a study of a mouse model of colitis shows that these fatty acids down-regulate innate and inflammatory responses by stimulating the chemoattractant receptor GPR43 on neutrophils. This identifies interactions between short-chain fatty acids and GPR43 as a possible target for the manipulation of immune responses. Recent evidence indicates that normal intestinal microbiota may positively influence immune responses and protect against the development of inflammatory diseases. One of the potential protective elements in this process are short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota and bind the G-protein-coupled receptor 43 (GPR43). Here it is shown that SCFA–GPR43 interactions profoundly affect inflammatory responses in mice. 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 Bacteriodes 3 , and a concurrent reduction in SCFAs 4 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Acetates - therapeutic use / Animals / Apoptosis / Arthritis - metabolism / Bacteria / Biological and medical sciences / Bone marrow / Cell adhesion & migration / Cell receptors / Cells, Cultured / Chemotactic Factors - metabolism / Colitis - drug therapy / Colitis - metabolism / Colitis - microbiology / Correlation analysis / Development and progression / Dietary fiber / Diseases of the digestive system / Diseases of the osteoarticular system / Drinking water / Fatty acids / Fatty Acids, Volatile - metabolism / Fermentation / Gastroenterology. Liver. Pancreas. Abdomen / Genetic aspects / Germ-Free Life / Health aspects / Humanities and Social Sciences / Humans / Immune response / Immune system / Inflammation / Inflammation - drug therapy / Inflammation - metabolism / Inflammation - microbiology / Inflammatory bowel disease / Intestines - microbiology / letter / Medical sciences / Metagenome / Mice / Mice, Inbred C57BL / Microbiota (Symbiotic organisms) / Miscellaneous. Osteoarticular involvement in other diseases / multidisciplinary / Neutrophils - metabolism / Oligonucleotide Array Sequence Analysis / Other diseases. Semiology / Pathogens / Pattern recognition / Physiological aspects / Protein Array Analysis / Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects) / Receptors, G-Protein-Coupled - deficiency / Receptors, G-Protein-Coupled - metabolism / Rodents / Science / Science (multidisciplinary) / Staphylococcus infections / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus