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      Chemopreventive Metabolites Are Correlated with a Change in Intestinal Microbiota Measured in A-T Mice and Decreased Carcinogenesis

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          Abstract

          Intestinal microbiota play a significant role in nutrient metabolism, modulation of the immune system, obesity, and possibly in carcinogenesis, although the underlying mechanisms resulting in disease or impacts on longevity caused by different intestinal microbiota are mostly unknown. Herein we use isogenic Atm-deficient and wild type mice as models to interrogate changes in the metabolic profiles of urine and feces of these mice, which are differing in their intestinal microbiota. Using high resolution mass spectrometry approach we show that the composition of intestinal microbiota modulates specific metabolic perturbations resulting in a possible alleviation of a glycolytic phenotype. Metabolites including 3-methylbutyrolactone, kyneurenic acid and 3-methyladenine known to be onco-protective are elevated in Atm-deficient and wild type mice with restricted intestinal microbiota. Thus our approach has broad applicability to study the direct influence of gut microbiome on host metabolism and resultant phenotype. These results for the first time suggest a possible correlation of metabolic alterations and carcinogenesis, modulated by intestinal microbiota in A-T mice.

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          Most cited references57

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          Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.

          Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is critical for the protection against gut injury and associated mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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            MetaboAnalyst 2.0—a comprehensive server for metabolomic data analysis

            First released in 2009, MetaboAnalyst (www.metaboanalyst.ca) was a relatively simple web server designed to facilitate metabolomic data processing and statistical analysis. With continuing advances in metabolomics along with constant user feedback, it became clear that a substantial upgrade to the original server was necessary. MetaboAnalyst 2.0, which is the successor to MetaboAnalyst, represents just such an upgrade. MetaboAnalyst 2.0 now contains dozens of new features and functions including new procedures for data filtering, data editing and data normalization. It also supports multi-group data analysis, two-factor analysis as well as time-series data analysis. These new functions have also been supplemented with: (i) a quality-control module that allows users to evaluate their data quality before conducting any analysis, (ii) a functional enrichment analysis module that allows users to identify biologically meaningful patterns using metabolite set enrichment analysis and (iii) a metabolic pathway analysis module that allows users to perform pathway analysis and visualization for 15 different model organisms. In developing MetaboAnalyst 2.0 we have also substantially improved its graphical presentation tools. All images are now generated using anti-aliasing and are available over a range of resolutions, sizes and formats (PNG, TIFF, PDF, PostScript, or SVG). To improve its performance, MetaboAnalyst 2.0 is now hosted on a much more powerful server with substantially modified code to take advantage the server’s multi-core CPUs for computationally intensive tasks. MetaboAnalyst 2.0 also maintains a collection of 50 or more FAQs and more than a dozen tutorials compiled from user queries and requests. A downloadable version of MetaboAnalyst 2.0, along detailed instructions for local installation is now available as well.
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              Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase.

              A group of phosphoinositide 3-kinase (PI3K) inhibitors, such as 3-methyladenine (3-MA) and wortmannin, have been widely used as autophagy inhibitors based on their inhibitory effect on class III PI3K activity, which is known to be essential for induction of autophagy. In this study, we systematically examined and compared the effects of these two inhibitors on autophagy under both nutrient-rich and deprivation conditions. To our surprise, 3-MA is found to promote autophagy flux when treated under nutrient-rich conditions with a prolonged period of treatment, whereas it is still capable of suppressing starvation-induced autophagy. We first observed that there are marked increases of the autophagic markers in cells treated with 3-MA in full medium for a prolonged period of time (up to 9 h). Second, we provide convincing evidence that the increase of autophagic markers is the result of enhanced autophagic flux, not due to suppression of maturation of autophagosomes or lysosomal function. More importantly, we found that the autophagy promotion activity of 3-MA is due to its differential temporal effects on class I and class III PI3K; 3-MA blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Because 3-MA has been widely used as an autophagy inhibitor in the literature, understanding the dual role of 3-MA in autophagy thus suggests that caution should be exercised in the application of 3-MA in autophagy study.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 April 2016
                2016
                : 11
                : 4
                : e0151190
                Affiliations
                [1 ]Department of Oncology, Georgetown University Medical Center, Washington, D.C., United States of America
                [2 ]Department of Biochemistry, Molecular and Cellular Biology, Georgetown University Medical Center, Washington, D.C., United States of America
                [3 ]Department of Environmental Health Sciences, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America
                [4 ]Department of Biostatistics, Biomathematics and Bioinformatics, Georgetown University Medical Center, Washington, D.C., United States of America
                [5 ]Department of Plant Pathology and Microbiology, University of California Riverside, Riverside, California, United States of America
                [6 ]Department of Pathology Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                [7 ]Department of Radiation Oncology, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
                Medical University of South Carolina, UNITED STATES
                Author notes

                Competing Interests: RHS is the owner of Microbio Pharma, Holding, Inc. with no salary. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: RHS AKC IM AF. Performed the experiments: IM AKC RS PMR JB. Analyzed the data: IM AKC YW TD. Contributed reagents/materials/analysis tools: RHS AKC AF IM JB. Wrote the paper: AKC IM RHS AF JB.

                Article
                PONE-D-15-39203
                10.1371/journal.pone.0151190
                4830457
                27073845
                d89bda29-cabe-4a5a-833d-184ecea2b190
                © 2016 Cheema et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 September 2015
                : 24 February 2016
                Page count
                Figures: 5, Tables: 7, Pages: 19
                Funding
                This work was supported by RO1ES0951907 to RHS.
                Categories
                Research Article
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbiome
                Biology and Life Sciences
                Genetics
                Genomics
                Microbial Genomics
                Microbiome
                Biology and Life Sciences
                Microbiology
                Microbial Genomics
                Microbiome
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Metabolites
                Biology and Life Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Medicine and Health Sciences
                Anatomy
                Digestive System
                Gastrointestinal Tract
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Urine
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Metabolomics
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Metabolic Pathways
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Hematologic Cancers and Related Disorders
                Lymphomas
                Medicine and Health Sciences
                Hematology
                Hematologic Cancers and Related Disorders
                Lymphomas
                Custom metadata
                All files for this dataset have been uploaded in a universal format (netcdf) onto a public repository which can be accessed using the following link: http://datadryad.org/review?doi=doi:10.5061/dryad.s4617.

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