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      Regulation of lung immunity and host defense by the intestinal microbiota

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          Abstract

          Every year in the United States approximately 200,000 people die from pulmonary infections, such as influenza and pneumonia, or from lung disease that is exacerbated by pulmonary infection. In addition, respiratory diseases such as, asthma, affect 300 million people worldwide. Therefore, understanding the mechanistic basis for host defense against infection and regulation of immune processes involved in asthma are crucial for the development of novel therapeutic strategies. The identification, characterization, and manipulation of immune regulatory networks in the lung represents one of the biggest challenges in treatment of lung associated disease. Recent evidence suggests that the gastrointestinal (GI) microbiota plays a key role in immune adaptation and initiation in the GI tract as well as at other distal mucosal sites, such as the lung. This review explores the current research describing the role of the GI microbiota in the regulation of pulmonary immune responses. Specific focus is given to understanding how intestinal “dysbiosis” affects lung health.

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          Most cited references93

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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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            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 role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism.

              Short-chain fatty acids (SCFAs), the end products of fermentation of dietary fibers by the anaerobic intestinal microbiota, have been shown to exert multiple beneficial effects on mammalian energy metabolism. The mechanisms underlying these effects are the subject of intensive research and encompass the complex interplay between diet, gut microbiota, and host energy metabolism. This review summarizes the role of SCFAs in host energy metabolism, starting from the production by the gut microbiota to the uptake by the host and ending with the effects on host metabolism. There are interesting leads on the underlying molecular mechanisms, but there are also many apparently contradictory results. A coherent understanding of the multilevel network in which SCFAs exert their effects is hampered by the lack of quantitative data on actual fluxes of SCFAs and metabolic processes regulated by SCFAs. In this review we address questions that, when answered, will bring us a great step forward in elucidating the role of SCFAs in mammalian energy metabolism.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                07 October 2015
                2015
                : 6
                : 1085
                Affiliations
                Section of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Sciences Center New Orleans, LA, USA
                Author notes

                Edited by: Gabriele Berg, Graz University of Technology, Austria

                Reviewed by: Jan S. Suchodolski, Texas A&M University, USA; Marius Vital, Michigan State University, USA

                *Correspondence: Judd E. Shellito, Section of Pulmonary/Critical Care and Allergy/Immunology, Department of Medicine, Louisiana State University Health Sciences Center, 1901 Perdido Street, Suite 3205, New Orleans, LA 70112, USA jshell@ 123456lsuhsc.edu

                This article was submitted to Microbial Symbioses, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2015.01085
                4595839
                26500629
                82c55fac-4b70-4e60-8e0f-216fb709decb
                Copyright © 2015 Samuelson, Welsh and Shellito.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 June 2015
                : 22 September 2015
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 90, Pages: 14, Words: 10338
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: #P01-HL076100
                Funded by: National Institute of General Medical Sciences 10.13039/100000057
                Award ID: # UG54-GM104940
                Funded by: National Institute on Alcohol Abuse and Alcoholism 10.13039/100000027
                Award ID: P60 AA009803
                Award ID: R24 AA019661
                Categories
                Microbiology
                Review

                Microbiology & Virology
                gut-lung axis,intestinal microbiota,immunology,pulmonary infections,pulmonary immunology,dysbiosis

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