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      Administration of Akkermansia muciniphila Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice


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          Inflammatory bowel diseases (IBDs) develop as a result of complex interactions among genes, innate immunity and environmental factors, which are related to the gut microbiota. Multiple clinical and animal data have shown that Akkermansia muciniphila is associated with a healthy mucosa. However, its precise role in colitis is currently unknown. Our study aimed to determine its protective effects and underlying mechanisms in a dextran sulfate sodium (DSS)-induced colitis mouse model. Twenty-four C57BL/6 male mice were administered A. muciniphila Muc T or phosphate-buffered saline (PBS) once daily by oral gavage for 14 days. Colitis was induced by drinking 2% DSS from days 0 to 6, followed by 2 days of drinking normal water. Mice were weighed daily and then sacrificed on day 8. We found that A. muciniphila improved DSS-induced colitis, which was evidenced by reduced weight loss, colon length shortening and histopathology scores and enhanced barrier function. Serum and tissue levels of inflammatory cytokines and chemokines (TNF-α, IL1α, IL6, IL12A, MIP-1A, G-CSF, and KC) decreased as a result of A. muciniphila administration. Analysis of 16S rDNA sequences showed that A. muciniphila induced significant gut microbiota alterations. Furthermore, correlation analysis indicated that pro-inflammatory cytokines and other injury factors were negatively associated with Verrucomicrobia, Akkermansia, Ruminococcaceae, and Rikenellaceae, which were prominently abundant in A. muciniphila-treated mice. We confirmed that A. muciniphila treatment could ameliorate mucosal inflammation either via microbe-host interactions, which protect the gut barrier function and reduce the levels of inflammatory cytokines, or by improving the microbial community. Our findings suggest that A. muciniphila may be a potential probiotic agent for ameliorating colitis.

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          Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial.

          Ulcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial.
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            Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.

            The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis.
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              Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes

              In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.

                Author and article information

                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                01 October 2019
                : 10
                : 2259
                [1] 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University , Hangzhou, China
                [2] 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University , Hangzhou, China
                Author notes

                Edited by: Andrea Masotti, Bambino Gesù Children Hospital (IRCCS), Italy

                Reviewed by: Farzam Vaziri, Pasteur Institute of Iran (PII), Iran; Federica Del Chierico, Ospedale Bambino Gesu’ Roma, Italy; Julio Galvez, University of Granada, Spain

                *Correspondence: Lanjuan Li, ljli@ 123456zju.edu.cn

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

                Copyright © 2019 Bian, Wu, Yang, Lv, Wang, Li, Ye, Fang, Wu, Jiang, Shi and Li.

                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) and the copyright owner(s) 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.

                : 21 May 2019
                : 17 September 2019
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 108, Pages: 18, Words: 0
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Original Research

                Microbiology & Virology
                akkermansia muciniphila,microbiota,ibd,dss-induced colitis,metabolism
                Microbiology & Virology
                akkermansia muciniphila, microbiota, ibd, dss-induced colitis, metabolism


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