Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.

Biochemistry Department Chemistry Institute University of São Paulo São Paulo Brazil

Biocomplexity Institute of Virginia Tech Blacksburg VA USA

Department CIBIO University of Trento Trento Italy

Department of Bioinformatics Biocenter University of Würzburg Würzburg Germany

Department of Cancer Genome Informatics Osaka University Osaka Japan

Department of Colorectal Surgery Clinica S Rita Vercelli Italy

Department of Computer Science University of Turin Turin Italy

Department of Medical Sciences University of Turin Turin Italy

Department of Molecular Biology of Cancer Institute of Experimental Medicine Prague Czech Republic

Department of Surgical and Medical Sciences University of Catanzaro Catanzaro Italy

Division of Cancer Genomics National Cancer Center Research Institute Tokyo Japan

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Preventive Oncology National Center for Tumor Diseases and German Cancer Research Center Heidelberg Germany

Faculty of Healthy Sciences University of Southern Denmark Odense Denmark

German Cancer Consortium German Cancer Research Center Heidelberg Germany

Graduate School of Public Health and Health Policy City University of New York New York NY USA

Human Genome Center The Institute of Medical Science The University of Tokyo Tokyo Japan

Huntsman Cancer Institute and Department of Population Health Sciences University of Utah Salt Lake City UT USA

IEO European Institute of Oncology IRCCS Milan Italy

Institute for Implementation Science in Population Health City University of New York New York NY USA

Italian Institute for Genomic Medicine Turin Italy

Laboratory of Neurosciences Institute of Psychiatry University of São Paulo São Paulo Brazil

Max Delbrück Centre for Molecular Medicine Berlin Germany

Medical Genomics Laboratory CIPE A C Camargo Cancer Center São Paulo Brazil

Molecular Medicine Partnership Unit Heidelberg Germany

Mucosal Immunology and Microbiota Unit Humanitas Research Hospital Milan Italy

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

PRESTO Japan Science and Technology Agency Saitama Japan

Research Fellow of Japan Society for the Promotion of Science Tokyo Japan

School of Life Science and Technology Tokyo Institute of Technology Tokyo Japan

Structural and Computational Biology Unit European Molecular Biology Laboratory Heidelberg Germany

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Nat Rev Genet. 2019 Jun;20(6):318-319. doi: 10.1038/s41576-019-0126-2. PubMed

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Nat Med. 2019 Dec;25(12):1948. doi: 10.1038/s41591-019-0663-4. PubMed

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