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      Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome

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          Summary

          The intestinal tract is inhabited by a large diverse community of microbes collectively referred to as gut microbiota. While gut microbiota provide important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease (IBD) and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multilayered mucus structures that cover the intestinal surface thus allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine 1 . Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro 2 , might be promoting the post-mid 20th century increase in IBD 3 . Herein, we observed that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in WT hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition, and increased pro-inflammatory potential. Use of germ-free mice and fecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that broad use of emulsifying agents might be contributing to increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.

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          IBD-what role do Proteobacteria play?

          The gastrointestinal microbiota has come to the fore in the search for the causes of IBD. This shift has largely been driven by the finding of genetic polymorphisms involved in gastrointestinal innate immunity (particularly polymorphisms in NOD2 and genes involved in autophagy) and alterations in the composition of the microbiota that might result in inflammation (so-called dysbiosis). Microbial diversity studies have continually demonstrated an expansion of the Proteobacteria phylum in patients with IBD. Individual Proteobacteria, in particular (adherent-invasive) Escherichia coli, Campylobacter concisus and enterohepatic Helicobacter, have all been associated with the pathogenesis of IBD. In this Review, we comprehensively describe the various associations of Proteobacteria and IBD. We also examine the importance of pattern recognition in the extracellular innate immune response of the host with particular reference to Proteobacteria, and postulate that Proteobacteria with adherent and invasive properties might exploit host defenses, drive proinflammatory change, alter the intestinal microbiota in favor of dysbiosis and ultimately lead to the development of IBD.
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            Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice.

            Colitis results from breakdown of homeostasis between intestinal microbiota and the mucosal immune system, with both environmental and genetic influencing factors. Flagellin receptor TLR5-deficient mice (T5KO) display elevated intestinal proinflammatory gene expression and colitis with incomplete penetrance, providing a genetically sensitized system to study the contribution of microbiota to driving colitis. Both colitic and noncolitic T5KO exhibited transiently unstable microbiotas, with lasting differences in colitic T5KO, while their noncolitic siblings stabilized their microbiotas to resemble wild-type mice. Transient high levels of proteobacteria, especially enterobacteria species including E. coli, observed in close proximity to the gut epithelium were a striking feature of colitic microbiota. A Crohn's disease-associated E. coli strain induced chronic colitis in T5KO, which persisted well after the exogenously introduced bacterial species had been eliminated. Thus, an innate immune deficiency can result in unstable gut microbiota associated with low-grade inflammation, and harboring proteobacteria can drive and/or instigate chronic colitis. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Toll-like receptor 9-induced type I IFN protects mice from experimental colitis.

              Experimental colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of experimental colitis in RAG1-/- but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-alpha/beta) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-beta mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-alpha/beta receptor exhibited more severe colitis than wild-type mice did upon induction of experimental colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                18 January 2015
                25 February 2015
                5 March 2015
                16 June 2016
                : 519
                : 7541
                : 92-96
                Affiliations
                [1 ] Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA
                [2 ] Faculty of Medicine, Bar Ilan University, Safed, Israel
                [3 ] Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY
                [4 ] Digestive Diseases Division, Department of Medicine, Emory University School of Medicine, Atlanta GA
                Author notes
                Corresponding Author: Andrew T. Gewirtz, PhD, Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta GA 30303, agewirtz@ 123456gsu.edu , Ph: 404-413-3586, Fax: 404-413-3580
                Article
                NIHMS656221
                10.1038/nature14232
                4910713
                25731162
                22fe3340-e3f6-4dd0-ae1d-a7f3fa1fb9a8

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Uncategorized
                mucus,inflammation,innate immunity,flagellin,lps,il10,tlr5
                Uncategorized
                mucus, inflammation, innate immunity, flagellin, lps, il10, tlr5

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