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      Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome


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          The trillions of microorganisms in the gut microbiome have attracted much attention recently owing to their sophisticated and widespread impacts on numerous aspects of host pathophysiology. Remarkable progress in large-scale sequencing and mass spectrometry has increased our understanding of the influence of the microbiome and/or its metabolites on the onset and progression of extraintestinal cancers and the efficacy of cancer immunotherapy. Given the plasticity in microbial composition and function, microbial-based therapeutic interventions, including dietary modulation, prebiotics, and probiotics, as well as fecal microbial transplantation, potentially permit the development of novel strategies for cancer therapy to improve clinical outcomes. Herein, we summarize the latest evidence on the involvement of the gut microbiome in host immunity and metabolism, the effects of the microbiome on extraintestinal cancers and the immune response, and strategies to modulate the gut microbiome, and we discuss ongoing studies and future areas of research that deserve focused research efforts.

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          Most cited references334

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          A microbial symbiosis factor prevents intestinal inflammatory disease.

          Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.
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            The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota.

            Mucosal surfaces constantly encounter microbes. Toll-like receptors (TLRs) mediate recognition of microbial patterns to eliminate pathogens. By contrast, we demonstrate that the prominent gut commensal Bacteroides fragilis activates the TLR pathway to establish host-microbial symbiosis. TLR2 on CD4(+) T cells is required for B. fragilis colonization of a unique mucosal niche in mice during homeostasis. A symbiosis factor (PSA, polysaccharide A) of B. fragilis signals through TLR2 directly on Foxp3(+) regulatory T cells to promote immunologic tolerance. B. fragilis lacking PSA is unable to restrain T helper 17 cell responses and is defective in niche-specific mucosal colonization. Therefore, commensal bacteria exploit the TLR pathway to actively suppress immunity. We propose that the immune system can discriminate between pathogens and the microbiota through recognition of symbiotic bacterial molecules in a process that engenders commensal colonization.
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              Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.

              Commensal microbes can have a substantial impact on autoimmune disorders, but the underlying molecular and cellular mechanisms remain largely unexplored. We report that autoimmune arthritis was strongly attenuated in the K/BxN mouse model under germ-free (GF) conditions, accompanied by reductions in serum autoantibody titers, splenic autoantibody-secreting cells, germinal centers, and the splenic T helper 17 (Th17) cell population. Neutralization of interleukin-17 prevented arthritis development in specific-pathogen-free K/BxN mice resulting from a direct effect of this cytokine on B cells to inhibit germinal center formation. The systemic deficiencies of the GF animals reflected a loss of Th17 cells from the small intestinal lamina propria. Introduction of a single gut-residing species, segmented filamentous bacteria, into GF animals reinstated the lamina propria Th17 cell compartment and production of autoantibodies, and arthritis rapidly ensued. Thus, a single commensal microbe, via its ability to promote a specific Th cell subset, can drive an autoimmune disease. Copyright 2010 Elsevier Inc. All rights reserved.

                Author and article information

                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                12 October 2019
                12 October 2019
                : 4
                [1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, , Central South University, ; 410078 Hunan, China
                [2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, , Central South University, ; 410078 Changsha, Hunan China
                [3 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Key Laboratory of Tumor Models and Individualized Medicine, Department of Thoracic Surgery, Second Xiangya Hospital, , Central South University, ; 410011 Changsha, China
                [4 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Oncology, Third Xiangya Hospital, , Central South University, ; 410013 Changsha, China
                [5 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Urology, Xiangya Hospital, , Central South University, ; 410008 Changsha, China
                [6 ]ISNI 0000 0004 1803 0208, GRID grid.452708.c, Department of Thoracic and Cardiovascular Surgery, , Second Xiangya Hospital of Central South University, ; 410011 Changsha, China
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81672787
                Award Recipient :
                Review Article
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                © The Author(s) 2019

                cancer,cancer therapy,cancer metabolism
                cancer, cancer therapy, cancer metabolism


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