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      The gut microbiome’s role in the development, maintenance, and outcomes of sepsis

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          Abstract

          The gut microbiome regulates a number of homeostatic mechanisms in the healthy host including immune function and gut barrier protection. Loss of normal gut microbial structure and function has been associated with diseases as diverse as Clostridioides difficile infection, asthma, and epilepsy. Recent evidence has also demonstrated a link between the gut microbiome and sepsis. In this review, we focus on three key areas of the interaction between the gut microbiome and sepsis. First, prior to sepsis onset, gut microbiome alteration increases sepsis susceptibility through several mechanisms, including (a) allowing for expansion of pathogenic intestinal bacteria, (b) priming the immune system for a robust pro-inflammatory response, and (c) decreasing production of beneficial microbial products such as short-chain fatty acids. Second, once sepsis is established, gut microbiome disruption worsens and increases susceptibility to end-organ dysfunction. Third, there is limited evidence that microbiome-based therapeutics, including probiotics and selective digestive decontamination, may decrease sepsis risk and improve sepsis outcomes in select patient populations, but concerns about safety have limited uptake. Case reports of a different microbiome-based therapy, fecal microbiota transplantation, have shown correlation with gut microbial structure restoration and decreased inflammatory response, but these results require further validation. While much of the evidence linking the gut microbiome and sepsis has been established in pre-clinical studies, clinical evidence is lacking in many areas. To address this, we outline a potential research agenda for further investigating the interaction between the gut microbiome and sepsis.

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          Most cited references47

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          Microbiota regulates immune defense against respiratory tract influenza A virus infection.

          Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, the role of commensal bacteria in immune responses at other mucosal surfaces remains less clear. Here, we show that commensal microbiota composition critically regulates the generation of virus-specific CD4 and CD8 T cells and antibody responses following respiratory influenza virus infection. By using various antibiotic treatments, we found that neomycin-sensitive bacteria are associated with the induction of productive immune responses in the lung. Local or distal injection of Toll-like receptor (TLR) ligands could rescue the immune impairment in the antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for pro-IL-1β and pro-IL-18 at steady state. Following influenza virus infection, inflammasome activation led to migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cell priming. Our results reveal the importance of commensal microbiota in regulating immunity in the respiratory mucosa through the proper activation of inflammasomes.
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            The gut microbiome in health and in disease

            Recent technological advancements and expanded efforts have led to a tremendous growth in the collective knowledge of the human microbiome. This review will highlight some of the important recent findings in this area of research.
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              Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity.

              Gut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP), we investigate how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulations in healthy humans. We observe microbiome-cytokine interaction patterns that are stimulus specific, cytokine specific, and cytokine and stimulus specific. Validation of two predicted host-microbial interactions reveal that TNFα and IFNγ production are associated with specific microbial metabolic pathways: palmitoleic acid metabolism and tryptophan degradation to tryptophol. Besides providing a resource of predicted microbially derived mediators that influence immune phenotypes in response to common microorganisms, these data can help to define principles for understanding disease susceptibility. The three HFGP studies presented in this issue lay the groundwork for further studies aimed at understanding the interplay between microbial, genetic, and environmental factors in the regulation of the immune response in humans. PAPERCLIP.
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                Author and article information

                Contributors
                mwadelm@emory.edu
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                1 June 2020
                1 June 2020
                2020
                : 24
                : 278
                Affiliations
                [1 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Division of Infectious Diseases, Department of Medicine, , Emory University School of Medicine, ; 49 Jesse Hill Jr. Drive, Atlanta, GA 30303 USA
                [2 ]GRID grid.266102.1, ISNI 0000 0001 2297 6811, Division of Infectious Diseases, Department of Medicine, , University of California, ; San Francisco, CA USA
                [3 ]GRID grid.410305.3, ISNI 0000 0001 2194 5650, Critical Care Medicine Department, , National Institutes of Health Clinical Center, ; Bethesda, MD USA
                [4 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, , Emory University School of Medicine, ; Atlanta, GA USA
                [5 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Department of Pathology and Laboratory Medicine, , Emory University School of Medicine, ; Atlanta, GA USA
                [6 ]GRID grid.462222.2, ISNI 0000 0004 0382 6932, Emory Critical Care Center, , Emory Healthcare, ; Atlanta, GA USA
                Author information
                http://orcid.org/0000-0002-9277-6046
                Article
                2989
                10.1186/s13054-020-02989-1
                7266132
                32487252
                3edc4307-2a83-414a-bb4f-c364da74cc7b
                © The Author(s) 2020

                Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 4 February 2020
                : 12 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: K23AI144036
                Award Recipient :
                Funded by: Agency for Healthcare Research and Quality (US)
                Award ID: K08 HS-025240
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: K23HL138461-01A1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006108, National Center for Advancing Translational Sciences;
                Award ID: UL1 TR-002378
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Emergency medicine & Trauma
                sepsis, gut microbiome, review, probiotics, fecal microbiota transplant

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