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      Gut Microbiome Influences the Efficacy of PD-1 Antibody Immunotherapy on MSS-Type Colorectal Cancer via Metabolic Pathway

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          Abstract

          Colorectal cancer (CRC) appears to be rather refractory to checkpoint blockers except the patient with deficient in mismatch repair (dMMR). Therefore, new advances in the treatment of most mismatch repair proficiency (pMMR) (also known as microsatellite stability, MSS) type of CRC patients are considered to be an important clinical issue associated with programmed death 1 (PD-1) inhibitors. In the present study, we evaluated the effects of gut microbiome of MSS-type CRC tumor-bearing mice treated with different antibiotics on PD-1 antibody immunotherapy response. Our results confirmed that the gut microbiome played a key role in the treatment of CT26 tumor-bearing mice with PD-1 antibody. After PD-1 antibody treatment, the injection of antibiotics counteracted the efficacy of PD-1 antibody in inhibiting tumor growth when compared with the Control group (mice were treated with sterile drinking water). Bacteroides_sp._CAG:927 and Bacteroidales_S24-7 were enriched in Control group. Bacteroides_sp._CAG:927, Prevotella_sp._CAG: 1031 and Bacteroides were enriched in Coli group [mice were treated with colistin (2 mg/ml)], Prevotella_sp._CAG:485 and Akkermansia_muciniphila were enriched in Vanc group [mice were treated with vancomycin alone (0.25 mg/ml)]. The metabolites were enriched in the glycerophospholipid metabolic pathway consistent with the metagenomic prediction pathway in Vanc group, Prevotella_sp._CAG:485 and Akkermansia may maintain the normal efficacy of PD-1 antibody by affecting the metabolism of glycerophospholipid. Changes in gut microbiome leaded to changes in glycerophospholipid metabolism level, which may affect the expression of immune-related cytokines IFN-γ and IL-2 in the tumor microenvironment, resulting in a different therapeutic effect of PD-1 antibody. Our findings show that changes in the gut microbiome affect the glycerophospholipid metabolic pathway, thereby regulating the therapeutic potential of PD-1 antibody in the immunotherapy of MSS-type CRC tumor-bearing mice.

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          Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease.

          Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow-cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) and show that high IgA coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA-SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with predefined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.

            Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.
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              Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A.

              Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal microbiota. However, the commensal bacteria bound by IgA are poorly characterized and the type of humoral immunity they elicit remains elusive. We used bacterial flow cytometry coupled with 16S rRNA gene sequencing (IgA-Seq) in murine models of immunodeficiency to identify IgA-bound bacteria and elucidate mechanisms of commensal IgA targeting. We found that residence in the small intestine, rather than bacterial identity, dictated induction of specific IgA. Most commensals elicited strong T-independent (TI) responses that originated from the orphan B1b lineage and from B2 cells, but excluded natural antibacterial B1a specificities. Atypical commensals including segmented filamentous bacteria and Mucispirillum evaded TI responses but elicited T-dependent IgA. These data demonstrate exquisite targeting of distinct commensal bacteria by multiple layers of humoral immunity and reveal a specialized function of the B1b lineage in TI mucosal IgA responses.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                30 April 2020
                2020
                : 11
                : 814
                Affiliations
                [1] 1Second Department of Surgery, The Fourth Hospital of Hebei Medical University , Shijiazhuang, China
                [2] 2Department of Surgery, First Hospital of Qinhuangdao , Qinhuangdao, China
                [3] 3Department of Pharmacology, Hebei Medical University , Shijiazhuang, China
                [4] 4Department of Traditional Chinese Medicine, The Fourth Hospital of Hebei Medical University , Shijiazhuang, China
                [5] 5College of Combine Traditional Chinese and Western Medicine, Hebei Medical University , Shijiazhuang, China
                [6] 6Third Department of Oncology, Hebei General Hospital , Shijiazhuang, China
                [7] 7Department of Oncology, The Fourth Hospital of Hebei Medical University , Shijiazhuang, China
                [8] 8Department of Clinical Laboratory, The Fourth Hospital of Hebei Medical University , Shijiazhuang, China
                Author notes

                Edited by: Daniel M. Altmann, Imperial College London, United Kingdom

                Reviewed by: Hridayesh Prakash, Amity University, India; Maryam Dadar, Razi Vaccine and Serum Research Institute, Iran

                *Correspondence: Zhongxin Li, lizhongxin96@ 123456163.com

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

                Article
                10.3389/fmicb.2020.00814
                7212380
                32425919
                1c9ebbe7-5299-4621-a7d3-88f5feff8e33
                Copyright © 2020 Xu, Lv, Guo, Li, Jia, Jiang, Wang, Zhang, Kong, Liu, Zhang, Lv 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.

                History
                : 17 October 2019
                : 06 April 2020
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 68, Pages: 18, Words: 0
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                gut microbiota,metabolic pathway,pd-1 antibody,immunotherapy,mss-type crc
                Microbiology & Virology
                gut microbiota, metabolic pathway, pd-1 antibody, immunotherapy, mss-type crc

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