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      Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

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          Abstract

          Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.

          Abstract

          The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma.

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          Most cited references26

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          The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.

          The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor. Copyright © 2011 Elsevier Inc. All rights reserved.
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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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              Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces.

              Weight loss diets for humans that are based on a high intake of protein but low intake of fermentable carbohydrate may alter microbial activity and bacterial populations in the large intestine and thus impact on gut health. In this study, 19 healthy, obese (body mass index range, 30 to 42) volunteers were given in succession three different diets: maintenance (M) for 3 days (399 g carbohydrate/day) and then high protein/medium (164 g/day) carbohydrate (HPMC) and high protein/low (24 g/day) carbohydrate (HPLC) each for 4 weeks. Stool samples were collected at the end of each dietary regimen. Total fecal short-chain fatty acids were 114 mM, 74 mM, and 56 mM (P < 0.001) for M, HPMC, and HPLC diets, respectively, and there was a disproportionate reduction in fecal butyrate (18 mM, 9 mM, and 4 mM, respectively; P < 0.001) with decreasing carbohydrate. Major groups of fecal bacteria were monitored using nine 16S rRNA-targeted fluorescence in situ hybridization probes, relative to counts obtained with the broad probe Eub338. No significant change was seen in the relative counts of the bacteroides (Bac303) (mean, 29.6%) or the clostridial cluster XIVa (Erec482, 23.3%), cluster IX (Prop853, 9.3%), or cluster IV (Fprau645, 11.6%; Rbro730 plus Rfla729, 9.3%) groups. In contrast, the Roseburia spp. and Eubacterium rectale subgroup of cluster XIVa (11%, 8%, and 3% for M, HPMC, and HPLC, respectively; P < 0.001) and bifidobacteria (4%, 2.1%, and 1.9%, respectively; P = 0.026) decreased as carbohydrate intake decreased. The abundance of butyrate-producing bacteria related to Roseburia spp. and E. rectale correlated well with the decline in fecal butyrate.
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                Author and article information

                Contributors
                nathalie.chaput@gustaveroussy.fr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                1 May 2020
                1 May 2020
                2020
                : 11
                : 2168
                Affiliations
                [1 ]Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d’Immunomonitoring en Oncologie, F-94805 Villejuif, France
                [2 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, Université Paris-Saclay, Faculté de Médicine, ; Le Kremlin Bicêtre, F-94276 France
                [3 ]ISNI 0000 0001 2157 9291, GRID grid.11843.3f, Université Paris-Descartes, , Faculté de Médicine, ; F-75006 Paris, France
                [4 ]ISNI 0000 0001 2175 4109, GRID grid.50550.35, Hôpital Européen Georges Pompidou, Département de Gastroentérologie et Oncologie Digestive, , Assistance Publique-Hôpitaux de Paris, ; F-75015 Paris, France
                [5 ]Université Paris-Saclay, Institut Gustave Roussy, CNRS, Vectorologie et thérapeutiques anticancéreuses, F-94805 Villejuif, France
                [6 ]Institut Gustave Roussy, Pharmacology and Drug Analysis Department, Villejuif, F-94805 France
                [7 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, Université Paris-Saclay, , Faculté de Pharmacie, ; Chatenay-Malabry, F-92296 France
                [8 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, , Instituto Nazionale Tumori- IRCCS –Fondazione G. Pascale, ; Napoli, Italia
                [9 ]Institut Gustave Roussy, Biostatistics and Epidemiology Unit, Villejuif, F-94805 France
                [10 ]ISNI 0000 0004 0638 6872, GRID grid.463845.8, Université Paris-Saclay, , UVSQ, Inserm, CESP, ; 94807 Villejuif, France
                [11 ]Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Genomic platform Molecular Biopathology unit and Biological Resource Center, F-94805 Villejuif, France
                [12 ]Institut Gustave Roussy, Department of Medical Biology and Pathology, Microbiology unit, Villejuif, F-94805 France
                [13 ]ISNI 0000 0004 0480 0128, GRID grid.493856.5, Université Paris-Saclay, Institut Gustave Roussy, CNRS, , Stabilité génétique et oncogenèse, ; 94805 Villejuif, France
                [14 ]Institut Gustave Roussy, Dermatology Unit, Department of Medicine, Villejuif, F-94805 France
                [15 ]ISNI 0000 0001 2175 4109, GRID grid.50550.35, Hôpital du Kremlin Bicêtre Department of Gastroenterology, , Assistance Publique-Hôpitaux de Paris, ; Le Kremlin Bicêtre, France
                [16 ]ISNI 0000 0004 0522 0627, GRID grid.462293.8, Université Paris-Saclay, INRAE, AgroParisTech, , Micalis Institute, ; 78350 Jouy-en-Josas, France
                Author information
                http://orcid.org/0000-0002-8347-6957
                http://orcid.org/0000-0002-4849-0825
                http://orcid.org/0000-0002-1081-5313
                http://orcid.org/0000-0001-8373-041X
                http://orcid.org/0000-0001-5503-8821
                http://orcid.org/0000-0002-9501-6771
                http://orcid.org/0000-0002-8322-475X
                http://orcid.org/0000-0002-9493-0238
                http://orcid.org/0000-0003-3968-8669
                Article
                16079
                10.1038/s41467-020-16079-x
                7195489
                32358520
                e9fb8773-ec86-4293-9bbc-5e99905bfeb0
                © The Author(s) 2020

                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/.

                History
                : 4 April 2019
                : 8 April 2020
                Categories
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                © The Author(s) 2020

                Uncategorized
                cancer,immunology,biomarkers,tumour biomarkers
                Uncategorized
                cancer, immunology, biomarkers, tumour biomarkers

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