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      Inulin impacts tumorigenesis promotion by colibactin-producing Escherichia coli in Apc Min/+ mice

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          Abstract

          Introduction

          The prebiotic inulin has previously shown both protective and tumor-promoting effects in colorectal cancer (CRC). These inconsistencies may be due to the gut microbial composition as several bacteria have been associated with CRC. Specifically, polyketide synthase-positive ( pks+) Escherichia coli promotes carcinogenesis and facilitates CRC progression through the production of colibactin, a genotoxin that induces double-strand DNA breaks (DSBs). We investigated whether colibactin-producing Escherichia coli changed the protection conferred by inulin against tumor growth and progression using the Apc Min/+ mouse model of CRC.

          Methods

          Mice received a 2% dextran sodium sulfate (DSS) solution followed by oral gavage with the murine pks + E. coli strain NC101 (EcNC101) and were fed a diet supplemented with 10% cellulose as control or 10% inulin for 4 weeks.

          Results

          Inulin supplementation led to increase EcNC101 colonization compared to mice receiving the control diet. The increased colonization of EcNC101 resulted in more DSBs, tumor burden, and tumor progression in Apc Min/+ mice. The tumorigenic effect of EcN101 in Apc Min/+ mice mediated by inulin was dependent on colibactin production. Pasteurized E. coli Nissle 1917 (EcN), a probiotic, suppressed the inulin-driven EcNC101 expansion and impacted tumor progression.

          Discussion

          Our results suggest that the presence of pks + E. coli influences the outcome of inulin supplementation in CRC and that microbiota-targeted interventions may mitigate this effect. Given the prevalence of pks + E. coli in both healthy and CRC populations and the importance of a fiber-rich diet, inulin supplementation in individuals colonized with pks + bacteria should be considered with caution.

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          Most cited references63

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          Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics

          With the continued interest in the role of the gut microbiota in health, attention has now turned to how to harness the microbiota for the benefit of the host. This Consensus Statement outlines the definition and scope of the term 'prebiotic' as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in December 2016.
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            Global colorectal cancer burden in 2020 and projections to 2040

            • There are estimated 1.93 million new CRC cases diagnosed, and 0.94 million CRC caused deaths in 2020 worldwide. • The global new CRC cases is predicted to reach 3.2 million in 2040. • China and the United States have the highest estimated number of new CRC cases in the next 20 years. • The number of new CRC cases is increased from 0.56 million (2020) to 0.91 million (2040) in China. • The number of new CRC cases is increased from 0.16 million (2020) to 0.21 million (2040) in the United States. As the third most common malignancy and the second most deadly cancer, colorectal cancer (CRC) induces estimated 1.9 million incidence cases and 0.9 million deaths worldwide in 2020. The incidence of CRC is higher in highly developed countries, and it is increasing in middle- and low-income countries due to westernization. Moreover, a rising incidence of early-onset CRC is also emerging. The large number of CRC cases poses a growing global public health challenge. Raising awareness of CRC is important to promote healthy lifestyle choices, novel strategies for CRC management, and implementation of global screening programs, which are critical to reducing CRC morbidity and mortality in the future. CRC is a heterogeneous disease, and its subtype affiliation influences prognosis and therapeutic response. An accurate CRC subtype classification system is of great significance for basic research and clinical outcome. Here, we present the global epidemiology of CRC in 2020 and projections for 2040, review the major CRC subtypes to better understand CRC molecular basis, and summarize current risk factors, prevention, and screening strategies for CRC.
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              gammaH2AX: a sensitive molecular marker of DNA damage and repair.

              Phosphorylation of the Ser-139 residue of the histone variant H2AX, forming gammaH2AX, is an early cellular response to the induction of DNA double-strand breaks. Detection of this phosphorylation event has emerged as a highly specific and sensitive molecular marker for monitoring DNA damage initiation and resolution. Further, analysis of gammaH2AX foci has numerous other applications including, but not limited to, cancer and aging research. Quantitation of gammaH2AX foci has also been applied as a useful tool for the evaluation of the efficacy of various developmental drugs, particularly, radiation modifying compounds. This review focuses on the current status of gammaH2AX as a marker of DNA damage and repair in the context of ionizing radiation. Although the emphasis is on gamma-radiation-induced gammaH2AX foci, the effects of other genotoxic insults including exposure to ultraviolet rays, oxidative stress and chemical agents are also discussed.
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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
                02 February 2023
                2023
                : 14
                : 1067505
                Affiliations
                [1] 1Nutrition and Microbiome Laboratory, Institut du cancer de Montréal, Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM) , Montréal, QC, Canada
                [2] 2Department of Surgery, Faculty of Medicine, Université de Montréal , Montréal, QC, Canada
                [3] 3Department of Medicine, Faculty of Medicine, Université de Montréal , Montréal, QC, Canada
                Author notes

                Edited by: Allen D. Smith, Beltsville Human Nutrition Research Center, Agricultural Research Service (USDA), United States

                Reviewed by: Kamal Datta, Georgetown University, United States; Michihiro Mutoh, Kyoto Prefectural University of Medicine, Japan

                *Correspondence: Manuela M. Santos, ✉ manuela.santos@ 123456umontreal.ca

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

                Article
                10.3389/fmicb.2023.1067505
                9932902
                36819017
                46ae720f-a76b-4341-932f-ffe3d75039e0
                Copyright © 2023 Oliero, Hajjar, Cuisiniere, Fragoso, Calvé and Santos.

                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 2022
                : 17 January 2023
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 64, Pages: 11, Words: 7896
                Funding
                Funded by: Canadian Institutes of Health Research, doi 10.13039/501100000024;
                Award ID: CIHR, grant PJT-159775
                Funded by: Natural Sciences and Engineering Research Council of Canada, doi 10.13039/501100000038;
                Award ID: NSERC, grant RGPIN-2018-06442
                Categories
                Microbiology
                Original Research

                Microbiology & Virology
                inulin,apcmin/+ mouse,colibactin,tumorigenesis,double-strand dna breaks,pks+ e. coli, e. coli nissle

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