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      AllergoOncology: Microbiota in allergy and cancer—A European Academy for Allergy and Clinical Immunology position paper

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          Abstract

          The microbiota can play important roles in the development of human immunity and the establishment of immune homeostasis. Lifestyle factors including diet, hygiene, and exposure to viruses or bacteria, and medical interventions with antibiotics or anti‐ulcer medications, regulate phylogenetic variability and the quality of cross talk between innate and adaptive immune cells via mucosal and skin epithelia. More recently, microbiota and their composition have been linked to protective effects for health. Imbalance, however, has been linked to immune‐related diseases such as allergy and cancer, characterized by impaired, or exaggerated immune tolerance, respectively. In this AllergoOncology position paper, we focus on the increasing evidence defining the microbiota composition as a key determinant of immunity and immune tolerance, linked to the risk for the development of allergic and malignant diseases. We discuss novel insights into the role of microbiota in disease and patient responses to treatments in cancer and in allergy. These may highlight opportunities to improve patient outcomes with medical interventions supported through a restored microbiome.

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          Most cited references75

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          The microbiome and innate immunity.

          The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host-microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.
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            Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease.

            Proinflammatory cytokines are key factors in the pathogenesis of Crohn's disease (CD). Activation of nuclear factor kappa B (NFkappaB), which is involved in their gene transcription, is increased in the intestinal mucosa of CD patients. As butyrate enemas may be beneficial in treating colonic inflammation, we investigated if butyrate promotes this effect by acting on proinflammatory cytokine expression. Intestinal biopsy specimens, isolated lamina propria cells (LPMC), and peripheral blood mononuclear cells (PBMC) were cultured with or without butyrate for assessment of secretion of tumour necrosis factor (TNF) and mRNA levels. NFkappaB p65 activation was determined by immunofluorescence and gene reporter experiments. Levels of NFkappaB inhibitory protein (IkappaBalpha) were analysed by western blotting. The in vivo efficacy of butyrate was assessed in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis. Butyrate decreased TNF production and proinflammatory cytokine mRNA expression by intestinal biopsies and LPMC from CD patients. Butyrate abolished lipopolysaccharide (LPS) induced expression of cytokines by PBMC and transmigration of NFkappaB from the cytoplasm to the nucleus. LPS induced NFkappaB transcriptional activity was decreased by butyrate while IkappaBalpha levels were stable. Butyrate treatment also improved TNBS induced colitis. Butyrate decreases proinflammatory cytokine expression via inhibition of NFkappaB activation and IkappaBalpha degradation. These anti-inflammatory properties provide a rationale for assessing butyrate in the treatment of CD.
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              Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

              Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.
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                Author and article information

                Contributors
                sophia.karagiannis@kcl.ac.uk
                erika.jensen-jarolim@meduniwien.ac.at
                Journal
                Allergy
                Allergy
                10.1111/(ISSN)1398-9995
                ALL
                Allergy
                John Wiley and Sons Inc. (Hoboken )
                0105-4538
                1398-9995
                06 March 2019
                June 2019
                : 74
                : 6 ( doiID: 10.1111/all.2019.74.issue-6 )
                : 1037-1051
                Affiliations
                [ 1 ] Institute of Pathophysiology and Allergy Research Center of Pathophysiology, Infectiology and Immunology Medical University Vienna Vienna Austria
                [ 2 ] St. John's Institute of Dermatology School of Basic & Medical Biosciences King's College London Guy's Hospital London UK
                [ 3 ] School of Cancer and Pharmaceutical Sciences King's College London Guy's Hospital London UK
                [ 4 ] ENT Research Institute for Clinical Studies Essen Germany
                [ 5 ] Comparative Medicine The Interuniversity Messerli Research Institute University of Veterinary Medicine Vienna Medical University Vienna University Vienna Vienna Austria
                [ 6 ] Center for Genetic Epidemiology Department of Preventive Medicine Keck School of Medicine of University of Southern California Los Angeles California USA
                [ 7 ] Department of Pathology Keck School of Medicine of University of Southern California Los Angeles California USA
                [ 8 ] Norris Comprehensive Cancer Center Keck School of Medicine of Los Angeles Los Angeles California USA
                [ 9 ] Randall Centre for Cell and Molecular Biophysics School of Basic & Medical Biosciences King's College London New Hunt's House London UK
                [ 10 ] Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma London UK
                [ 11 ] Department of Dermatology University of Luebeck Luebeck Germany
                [ 12 ] Pharmacology and Experimental Therapeutics Unit School of Pharmacy Faculty of Medicine The Institute for Drug Research The Hebrew University of Jerusalem Jerusalem Israel
                [ 13 ] Division of Surgical Oncology Department of Surgery David Geffen School of Medicine University of California, Los Angeles California USA
                [ 14 ] Department of Microbiology, Immunology and Molecular Genetics David Geffen School of Medicine University of California, Los Angeles California USA
                [ 15 ] Jonsson Comprehensive Cancer Center University of California Los Angeles California USA
                [ 16 ] The Molecular Biology Institute University of California Los Angeles California USA
                [ 17 ] UCLA AIDS Institute Los Angeles California USA
                [ 18 ] Departments of Medicine and Microbiology APC Microbiome Ireland National University of Ireland Cork Ireland
                [ 19 ] Department of Infection and Immunity Luxembourg Institute of Health Esch‐sur‐Alzette Luxembourg
                [ 20 ] Division of Pharmacology Faculty of Science Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands
                [ 21 ] Barcelona Institute for Global Health (ISGlobal) Barcelona Spain
                [ 22 ] Universitat Pompeu Fabra (UPF) Barcelona Spain
                [ 23 ] CIBER Epidemiología y Salud Pública (CIBERESP) Madrid Spain
                [ 24 ] McLaughlin Centre for Population Health Risk Assessment University of Ottawa Ottawa Ontario Canada
                [ 25 ] Department of Biomedical Sciences Nazarbayev University School of Medicine Astana Kazakhstan
                Author notes
                [*] [* ] Correspondence

                Erika Jensen‐Jarolim, Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria.

                Email: erika.jensen-jarolim@ 123456meduniwien.ac.at

                and

                Sophia Karagiannis, St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, Guy's Hospital, London, UK.

                Email: sophia.karagiannis@ 123456kcl.ac.uk

                Author information
                https://orcid.org/0000-0002-1963-499X
                https://orcid.org/0000-0003-0351-6937
                https://orcid.org/0000-0003-3415-8247
                https://orcid.org/0000-0003-4705-3583
                https://orcid.org/0000-0001-5005-9228
                https://orcid.org/0000-0003-0764-5031
                https://orcid.org/0000-0002-4100-7810
                https://orcid.org/0000-0003-4019-5765
                Article
                ALL13718
                10.1111/all.13718
                6563061
                30636005
                c87c4285-9c99-4f21-9221-01c85fa00f70
                © 2019 The Authors. Allergy Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 December 2018
                : 27 December 2018
                : 28 December 2018
                Page count
                Figures: 2, Tables: 4, Pages: 14, Words: 10361
                Funding
                Funded by: NIHR National Institute for Health Research
                Award ID: IS‐BRC‐1215‐20006
                Funded by: European Academy of Allergy ande Clinical immunology
                Funded by: Foundation for the National Institutes of Health
                Award ID: R01 CA181115
                Award ID: R01CA196266
                Award ID: R01CA196266‐01A1:S1
                Award ID: R03CA173842
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: HA 2393/6‐1
                Funded by: Aimwell Charitable Trust and Emailie Gutterman Memorial Endowed Fund
                Funded by: Departament de Salut, Generalitat de Catalunya
                Award ID: SLT002/16/00232
                Funded by: IGEM Therapeutics Ltd
                Funded by: Austrian Science Fund
                Award ID: F4606‐B28
                Award ID: KLI284
                Award ID: P23398‐B11
                Funded by: The Academy of Medical Sciences
                Funded by: Cancer Research UK
                Award ID: C30122/A11527
                Award ID: C30122/A15774
                Funded by: Medical Research Council
                Award ID: MR/L023091/1
                Funded by: Israel Science Foundation
                Award ID: #213/05
                Funded by: Israel Cancer Association
                Award ID: #20161131
                Funded by: American Society of Hematology
                Funded by: Breast Cancer Now
                Award ID: C10355/A15587
                Funded by: Stop Cancer‐USC Norris Comprehensive Cancer Center
                Funded by: Israel Science Foundation “Center of Excellence /MOKED”
                Funded by: Israel Ministry of Science, Technology and Space “Personalized Medicine”
                Funded by: EUE, FRW and EJJ are experts of the Austrian Microbiome initiative amici.
                Categories
                Position Paper
                Position Paper
                Custom metadata
                2.0
                all13718
                June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:13.06.2019

                Immunology
                allergy,cancer,hygiene hypothesis,microbiota,oncoimmunology
                Immunology
                allergy, cancer, hygiene hypothesis, microbiota, oncoimmunology

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