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      Fecal Microbiota, Fecal Metabolome, and Colorectal Cancer Interrelations

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          Abstract

          Background and Aims

          Investigation of microbe-metabolite relationships in the gut is needed to understand and potentially reduce colorectal cancer (CRC) risk.

          Methods

          Microbiota and metabolomics profiling were performed on lyophilized feces from 42 CRC cases and 89 matched controls. Multivariable logistic regression was used to identify statistically independent associations with CRC. First principal coordinate-component pair (PCo1-PC1) and false discovery rate (0.05)-corrected P-values were calculated for 116,000 Pearson correlations between 530 metabolites and 220 microbes in a sex*case/control meta-analysis.

          Results

          Overall microbe-metabolite PCo1-PC1 was more strongly correlated in cases than in controls (Rho 0.606 vs 0.201, P = 0.01). CRC was independently associated with lower levels of Clostridia, Lachnospiraceae, p-aminobenzoate and conjugated linoleate, and with higher levels of Fusobacterium, Porphyromonas, p-hydroxy-benzaldehyde, and palmitoyl-sphingomyelin. Through postulated effects on cell shedding (palmitoyl-sphingomyelin), inflammation (conjugated linoleate), and innate immunity ( p-aminobenzoate), metabolites mediated the CRC association with Fusobacterium and Porphyromonas by 29% and 34%, respectively. Overall, palmitoyl-sphingomyelin correlated directly with abundances of Enterobacteriaceae (Gammaproteobacteria), three Actinobacteria and five Firmicutes. Only Parabacteroides correlated inversely with palmitoyl-sphingomyelin. Other lipids correlated inversely with Alcaligenaceae (Betaproteobacteria). Six Bonferroni-significant correlations were found, including low indolepropionate and threnoylvaline with Actinobacteria and high erythronate and an uncharacterized metabolite with Enterobacteriaceae.

          Conclusions

          Feces from CRC cases had very strong microbe-metabolite correlations that were predominated by Enterobacteriaceae and Actinobacteria. Metabolites mediated a direct CRC association with Fusobacterium and Porphyromonas, but not an inverse association with Clostridia and Lachnospiraceae. This study identifies complex microbe-metabolite networks that may provide insights on neoplasia and targets for intervention.

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          Most cited references26

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          The role of the immune system in governing host-microbe interactions in the intestine.

          The mammalian intestinal tract harbors a diverse community of trillions of microorganisms, which have co-evolved with the host immune system for millions of years. Many of these microorganisms perform functions critical for host physiology, but the host must remain vigilant to control the microbial community so that the symbiotic nature of the relationship is maintained. To facilitate homeostasis, the immune system ensures that the diverse microbial load is tolerated and anatomically contained, while remaining responsive to microbial breaches and invasion. Although the microbiota is required for intestinal immune development, immune responses also regulate the structure and composition of the intestinal microbiota. Here we discuss recent advances in our understanding of these complex interactions and their implications for human health and disease.
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            Integrative analysis of the microbiome and metabolome of the human intestinal mucosal surface reveals exquisite inter-relationships

            Background Consistent compositional shifts in the gut microbiota are observed in IBD and other chronic intestinal disorders and may contribute to pathogenesis. The identities of microbial biomolecular mechanisms and metabolic products responsible for disease phenotypes remain to be determined, as do the means by which such microbial functions may be therapeutically modified. Results The composition of the microbiota and metabolites in gut microbiome samples in 47 subjects were determined. Samples were obtained by endoscopic mucosal lavage from the cecum and sigmoid colon regions, and each sample was sequenced using the 16S rRNA gene V4 region (Illumina-HiSeq 2000 platform) and assessed by UPLC mass spectroscopy. Spearman correlations were used to identify widespread, statistically significant microbial-metabolite relationships. Metagenomes for identified microbial OTUs were imputed using PICRUSt, and KEGG metabolic pathway modules for imputed genes were assigned using HUMAnN. The resulting metabolic pathway abundances were mostly concordant with metabolite data. Analysis of the metabolome-driven distribution of OTU phylogeny and function revealed clusters of clades that were both metabolically and metagenomically similar. Conclusions The results suggest that microbes are syntropic with mucosal metabolome composition and therefore may be the source of and/or dependent upon gut epithelial metabolites. The consistent relationship between inferred metagenomic function and assayed metabolites suggests that metagenomic composition is predictive to a reasonable degree of microbial community metabolite pools. The finding that certain metabolites strongly correlate with microbial community structure raises the possibility of targeting metabolites for monitoring and/or therapeutically manipulating microbial community function in IBD and other chronic diseases.
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              Baseline survey of the anatomical microbial ecology of an important food plant: Solanum lycopersicum (tomato)

              Background Research to understand and control microbiological risks associated with the consumption of fresh fruits and vegetables has examined many environments in the farm to fork continuum. An important data gap however, that remains poorly studied is the baseline description of microflora that may be associated with plant anatomy either endemically or in response to environmental pressures. Specific anatomical niches of plants may contribute to persistence of human pathogens in agricultural environments in ways we have yet to describe. Tomatoes have been implicated in outbreaks of Salmonella at least 17 times during the years spanning 1990 to 2010. Our research seeks to provide a baseline description of the tomato microbiome and possibly identify whether or not there is something distinctive about tomatoes or their growing ecology that contributes to persistence of Salmonella in this important food crop. Results DNA was recovered from washes of epiphytic surfaces of tomato anatomical organs; leaves, stems, roots, flowers and fruits of Solanum lycopersicum (BHN602), grown at a site in close proximity to commercial farms previously implicated in tomato-Salmonella outbreaks. DNA was amplified for targeted 16S and 18S rRNA genes and sheared for shotgun metagenomic sequencing. Amplicons and metagenomes were used to describe “native” bacterial microflora for diverse anatomical parts of Virginia-grown tomatoes. Conclusions Distinct groupings of microbial communities were associated with different tomato plant organs and a gradient of compositional similarity could be correlated to the distance of a given plant part from the soil. Unique bacterial phylotypes (at 95% identity) were associated with fruits and flowers of tomato plants. These include Microvirga, Pseudomonas, Sphingomonas, Brachybacterium, Rhizobiales, Paracocccus, Chryseomonas and Microbacterium. The most frequently observed bacterial taxa across aerial plant regions were Pseudomonas and Xanthomonas. Dominant fungal taxa that could be identified to genus with 18S amplicons included Hypocrea, Aureobasidium and Cryptococcus. No definitive presence of Salmonella could be confirmed in any of the plant samples, although 16S sequences suggested that closely related genera were present on leaves, fruits and roots.
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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
                25 March 2016
                2016
                : 11
                : 3
                : e0152126
                Affiliations
                [1 ]Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, Maryland 20892–9704, United States of America
                [2 ]Division of Epidemiology, Department of Population Health, New York University School of Medicine, 650 First Avenue, #518, New York, New York 10016, United States of America
                [3 ]Information Management Services, 6110 Executive Boulevard, Rockville, Maryland 20852,United States of America
                Singapore General Hospital, SINGAPORE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: RS JA JNS GY RBH JJG. Performed the experiments: GY XX. Analyzed the data: RS JA JNS GY XX RBH JJG. Contributed reagents/materials/analysis tools: RS JNS. Wrote the paper: RS JA JNS JS GY XX RBH JJG.

                Article
                PONE-D-15-40775
                10.1371/journal.pone.0152126
                4807824
                27015276
                20fb5a06-3dd9-4436-a8ff-179809e31436

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 15 September 2015
                : 9 March 2016
                Page count
                Figures: 2, Tables: 3, Pages: 13
                Funding
                This work was supported by the National Cancer Institute Intramural Research Program and grants R03CA159414 and R01CA159036. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Metabolites
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Colorectal Cancer
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Fusobacteria
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Fusobacteria
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Fusobacteria
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                Biochemistry
                Metabolism
                Metabolic Pathways
                Xenobiotic Metabolism
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                Microbiome
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                Genomics
                Microbial Genomics
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                Microbiology
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                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Clostridium
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Clostridium
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Clostridium
                Biology and Life Sciences
                Organisms
                Bacteria
                Actinobacteria
                Medicine and Health Sciences
                Pharmacology
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                Drug Metabolism
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