Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D et al.. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461: 1282-U1119

Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
Nature (Impact Factor: 41.46). 10/2009; 461(7268):1282-6. DOI: 10.1038/nature08530
Source: PubMed


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.

Download full-text


Available from: Frederic Sierro
  • Source
    • "SCFAs, which are also an important energy source of gastrointestinal colonocytes, specifically bind the G protein-coupled receptor 43 (GPR43; also known as free fatty acid receptor 2 [FFAR2]), which also mediates their effect on colonic Tregs (Smith et al., 2013). Indeed, Gpr À/À mice exhibit lower IL-10 expression compared to wild-type controls (Smith et al., 2013) and develop more severe inflammation when their airways are challenged with OVA (Maslowski et al., 2009). Microbial-derived SCFAs are produced through the fermentation of complex carbohydrates. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses worldwide. Emerging evidence relates atopy and asthma to the composition and function of the human microbiome, the collection of microbes that reside in and on and interact with the human body. The ability to interrogate microbial ecology of the human host is due in large part to recent technological developments that permit identification of microbes and their products using culture-independent molecular detection techniques. In this review we explore the roles of respiratory, gut, and environmental microbiomes in asthma and allergic disease development, manifestation, and attenuation. Though still a relatively nascent field of research, evidence to date suggests that the airway and/or gut microbiome may represent fertile targets for prevention or management of allergic asthma and other diseases in which adaptive immune dysfunction is a prominent feature. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Cell host & microbe
  • Source
    • "It further controls the induction of response genes by immune and epithelial cells, to finally act on apoptosis/proliferation ratio and production of cytokines to regulate immune cell homeostasis (Hill and Artis, 2010). Secondary metabolites and short chain fatty acids also activate specific receptors to regulate inflammation (Maslowski et al., 2009; Kim et al., 2013). In addition, food microbes contribute to the production of bioactive peptides derived from their food matrices (Beermann and Hartung, 2013; Korhonen, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Do food ecosystems feed gut ecosystems? And if so… fuel the immune system? Recent developments in metagenomics have provided researchers tools to open the "black box" of microbiome science. These novel technologies have enabled the establishment of correlations between dysbiotic microbial communities and many diseases. The complex interaction of the commensal microbiota with the immune system is a topic of substantial interest due to its relevance to health. The human gastrointestinal tract is composed of an immense number of resident and transient microorganisms. Both may play a direct and vital role in the maintenance of human health and well-being. An understanding of the interactions and mechanisms through which commensal and food-derived microbes shape host immunity and metabolism may yield new insights into the pathogenesis of many immune-mediated diseases. Consequently, by manipulating the contribution of food microbiota to the functionality of the gut ecosystem, there is great hope for development of new prophylactic and therapeutic interventions. This paper presents some insights and comments on the possible impact of exogenous fermented food microbes on the gut homeostasis. We shed light on the similar features shared by both fermented food microbes and probiotics. In particular, the key role of microbial strains as part of food ecosystems for health and diseases is discussed through the prism of fermented dairy products and gut inflammation. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · International journal of food microbiology
  • Source
    • "Gpr43 knockout mice phenotype: Maslowski et al. 2009 1 "
    [Show abstract] [Hide abstract]
    ABSTRACT: G-protein coupled receptor 43 (GPR43) recognizes short chain fatty acids and is implicated in obesity, colitis, asthma and arthritis. Here, we present the first full characterization of the GPR43 promoter and 5'-UTR. 5'-RACE of the GPR43 transcript identified the transcription start site (TSS) and a 124 bp 5'-UTR followed by a 1335 bp intron upstream of the ATG start codon. The sequence spanning -4560 to +68 bp relative to the GPR43 TSS was found to contain strong promoter activity, increasing luciferase reporter expression by >100-fold in U937 monocytes. Stepwise deletions further narrowed the putative GPR43 promoter (-451 to +68). Site-directed mutagenesis identified XBP1 as a core cis element, the mutation of which abrogated transcriptional activity. Mutations of predicted CREB, CHOP, NFAT and STAT5 binding sites, partially reduced promoter activity. ChIP assays confirmed the binding of XBP1 to the endogenous GPR43 promoter. Consistently, GPR43 expression is reduced in monocytes upon siRNA-knockdown of XBP1, while A549 cells overexpressing XBP1 displayed elevated GPR43 levels. Based on its ability to activate XBP1, we predicted and confirmed that TNFα induces GPR43 expression in human monocytes. Altogether, our findings form the basis for strategic modulation of GPR43 expression, with a view to regulate GPR43-associated diseases.
    Full-text · Article · Jan 2015 · Scientific Reports
Show more