腸管微生物叢と化学誘引物質受容体GPR43による炎症応答の調節

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. Mackay1,2,3,6 Correspondence and requests for materials should be addressed to C.R.M. (Email: charles.mackay@med.monash.edu.au).

免疫系では、危険な外来病原体の識別を行うToll様受容体（TLR）をはじめとするさまざまなパターン認識分子の働きによって、病原体に対する応答が起こる。しかし、最近得られた証拠により、正常な腸管微生物叢が免疫応答に有益な影響を与え、炎症性疾患の発症を防いでいる可能性が示唆されている。これにかかわる要因の1つと考えられているのが短鎖脂肪酸（SCFA）で、これは腸管微生物叢による食物繊維の発酵によって生じる。ヒトの潰瘍性大腸炎などの大腸炎の特徴の1つは、ビフィズス菌（Bifidobacterium）やバクテロイデス類（Bacteroides）のような「有益な」微生物叢の変化と、それに伴うSCFAの減少である。また、発酵性の食物繊維やSCFAの摂取量を増やすと、大腸炎の治療に臨床効果があるらしい。SCFAはGタンパク質共役型受容体43（GPR43、FFAR2ともよばれる）に結合する。今回我々は、SCFAとGPR43の相互作用が炎症応答に大きく影響することを明らかにする。GPR43欠失（GPR43?/?）マウスでは、大腸炎、関節炎、喘息モデルの炎症応答が消失しなかったり、炎症の悪化がみられたりするので、ある種の炎症応答が正常に消失するためにはSCFAによるGPR43の刺激が必要であるとわかった。これには、GPR43?/?免疫細胞による炎症性メディエーター生産の増加や、免疫細胞の動員の亢進が関係しているらしい。細菌が存在せず、SCFAがほとんど、あるいは全く発生しない無菌マウスでは、炎症応答の同様の調節異常がみられた。このように、SCFAとGPR43の結合が、食物、消化管内の細菌による代謝、免疫応答、炎症応答を分子レベルで結びつけている可能性がある。

[原文]
Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

Kendle M. Maslowski1,2,3, Angelica T. Vieira1,4, Aylwin Ng5, Jan Kranich1,2, Frederic Sierro1, Di Yu1, Heidi C. Schilter1,2,3, Michael S. Rolph1,2, Fabienne Mackay1,6, David Artis7, Ramnik J. Xavier5,8, Mauro M. Teixeira4 & Charles R. Mackay1,2,3,6

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. Mackay1,2,3,6 Correspondence and requests for materials should be addressed to C.R.M. (Email: charles.mackay@med.monash.edu.au).

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 diseases1, 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 Bacteroides 3, and a concurrent reduction in SCFAs4. Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis5, 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.