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The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

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      Summary

      Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.

      Highlights

      • The microbiota contributes to helminth-induced modulation of allergic asthma
      • Cecal microbial communities are altered in helminth-infected mice
      • Helminth infection increases microbial-derived short chain fatty acids
      • GPR41 mediates helminth-induced Treg cell suppressor function

      Abstract

      Intestinal helminths are well known to possess potent immunomodulatory capacities. Harris and colleagues demonstrate in mice that helminth infection alters the bacterial microbiota and increases the concentration of short chain fatty acids (SCFAs), which reduce allergic asthma via GPR41. Increased intestinal SCFA concentrations were conserved across multiple parasite and host species.

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      Most cited references 50

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      Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa.

      Gut microbial composition depends on different dietary habits just as health depends on microbial metabolism, but the association of microbiota with different diets in human populations has not yet been shown. In this work, we compared the fecal microbiota of European children (EU) and that of children from a rural African village of Burkina Faso (BF), where the diet, high in fiber content, is similar to that of early human settlements at the time of the birth of agriculture. By using high-throughput 16S rDNA sequencing and biochemical analyses, we found significant differences in gut microbiota between the two groups. BF children showed a significant enrichment in Bacteroidetes and depletion in Firmicutes (P < 0.001), with a unique abundance of bacteria from the genus Prevotella and Xylanibacter, known to contain a set of bacterial genes for cellulose and xylan hydrolysis, completely lacking in the EU children. In addition, we found significantly more short-chain fatty acids (P < 0.001) in BF than in EU children. Also, Enterobacteriaceae (Shigella and Escherichia) were significantly underrepresented in BF than in EU children (P < 0.05). We hypothesize that gut microbiota coevolved with the polysaccharide-rich diet of BF individuals, allowing them to maximize energy intake from fibers while also protecting them from inflammations and noninfectious colonic diseases. This study investigates and compares human intestinal microbiota from children characterized by a modern western diet and a rural diet, indicating the importance of preserving this treasure of microbial diversity from ancient rural communities worldwide.
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        Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.

        Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.
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          The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

          Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
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            Author and article information

            Affiliations
            [1 ]Global Health Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland
            [2 ]Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland
            [3 ]Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern 3012, Switzerland
            [4 ]Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland
            [5 ]Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
            [6 ]Microbiology Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, UK
            [7 ]Bioinformatics and Biostatistics Core Facility, École Polytechnique Fédérale de Lausanne (EPFL) and Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
            [8 ]Department of Virology, Parasitology and Immunology, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
            [9 ]Maurice Müller Laboratories (DKF), University Hospital of Bern, Bern 3010, Switzerland
            [10 ]Department of Gastroenterology and Hepatology, The Prince Charles Hospital, Chermside, Brisbane, QLD 4032, Australia
            [11 ]Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4870, Australia
            [12 ]Novartis Pharma AG, Basel 4056, Switzerland
            [13 ]Faculty of Biology and Medicine, University of Lausanne, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1011, Switzerland
            Author notes
            []Corresponding author nicola.harris@ 123456epfl.ch
            Contributors
            Journal
            Immunity
            Immunity
            Immunity
            Cell Press
            1074-7613
            1097-4180
            17 November 2015
            17 November 2015
            : 43
            : 5
            : 998-1010
            26522986 4658337 S1074-7613(15)00397-0 10.1016/j.immuni.2015.09.012
            © 2015 The Authors

            This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

            Categories
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            Immunology

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