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 diseases. 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, and a concurrent reduction in SCFAs. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis. SCFAs 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 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.
Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
Kendle M
KM
Maslowski
Angelica T
AT
Vieira
Aylwin
A
Ng
Jan
J
Kranich
Frederic
F
Sierro
Di
D
Yu
Heidi C
HC
Schilter
Michael S
MS
Rolph
Fabienne
F
Mackay
David
D
Artis
Ramnik J
RJ
Xavier
Mauro M
MM
Teixeira
Charles R
CR
Mackay
D000085:Acetates / Q000627:therapeutic use; D000818:Animals; D001168:Arthritis / Q000378:metabolism; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000378:metabolism*; D003092:Colitis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D005232:Fatty Acids, Volatile / Q000378:metabolism; D005856:Germ-Free Life; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology*; D007422:Intestines / Q000382:microbiology*; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D040081:Protein Array Analysis; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*
D000085:Acetates; D002630:Chemotactic Factors; D005232:Fatty Acids, Volatile; C506481:Ffar2 protein, mouse; D043562:Receptors, G-Protein-Coupled