Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10-5). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.

Biochemistry Department Chemistry Institute University of São Paulo São Paulo Brazil

Department CIBIO University of Trento Trento Italy

Department of Bioinformatics Biocenter University of Würzburg Würzburg Germany

Department of Biology ETH Zürich Zürich Switzerland

Department of Cancer Genome Informatics Graduate School of Medicine Faculty of Medicine Osaka University Osaka Japan

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

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

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

Division of Surgery Department of Clinical Sciences Lund Faculty of Medicine Skane University Hospital Lund Sweden

Division of Surgery Oncology and Pathology Department of Clinical Sciences Lund Faculty of Medicine Lund University Lund Sweden

Faculty of Healthy Sciences University of Southern Denmark Odense Denmark

Genome Biology Unit European Molecular Biology Laboratory Heidelberg Germany

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

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

Institute of Science and Technology for Brain Inspired Intelligence Fudan University Shanghai China

Italian Institute for Genomic Medicine Turin Italy

Laboratory of Molecular Medicine Human Genome Center The Institute of Medical Science The University of Tokyo Tokyo Japan

Max Delbrück Centre for Molecular Medicine Berlin Germany

Molecular Medicine Partnership Unit Heidelberg Germany

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medicine 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

The Jackson Laboratory for Genomic Medicine Farmington CT USA

Comment In

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

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