Associations between the gut microbiome and colorectal cancer (CRC) have been uncovered, but larger and more diverse studies are needed to assess their potential clinical use. We expanded upon 12 metagenomic datasets of patients with CRC (n = 930), adenomas (n = 210) and healthy control individuals (n = 976; total n = 2,116) with 6 new cohorts (n = 1,625) providing granular information on cancer stage and the anatomic location of tumors. We improved CRC prediction accuracy based solely on gut metagenomics (average area under the curve = 0.85) and highlighted the contribution of 19 newly profiled species and distinct Fusobacterium nucleatum clades. Specific gut species distinguish left-sided versus right-sided CRC (area under the curve = 0.66) with an enrichment of oral-typical microbes. We identified strain-specific CRC signatures with the commensal Ruminococcus bicirculans and Faecalibacterium prausnitzii showing subclades associated with late-stage CRC. Our analysis confirms that the microbiome can be a clinical target for CRC screening and characterizes it as a biomarker for CRC progression.

Biomedical Center Faculty of Medicine in Pilsen Charles University Prague Czech Republic

Candiolo Cancer Institute FPO IRCCS Candiolo Italy

Center of Clinical Investigations for In Situ Biotherapies of Cancer INSERM CIC1428 Villejuif France

Clinical and Translational Epidemiology Unit Massachusetts General Hospital Boston MA USA

Department CIBIO University of Trento Trento Italy

Department of Biophysics School of Medicine Yeditepe University Istanbul Turkey

Department of Biostatistics Harvard T H Chan School of Public Health Boston MA USA

Department of Clinical and Biological Sciences University of Torino Torino Italy

Department of Colorectal Surgery Clinica S Rita Vercelli Italy

Department of Computer Science University of Torino Torino Italy

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Medical Biology School of Medicine Yeditepe University Istanbul Turkey

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Surgery University Hospital and Faculty of Medicine in Pilsen Charles University Prague Czech Republic

Department of Translational Research and New Technologies in Medicine and Surgery University of Pisa Pisa Italy

Departments of Epidemiology and Nutrition Harvard T H Chan School of Public Health Boston MA USA

Faculté de Médecine Université Paris Saclay Kremlin Bicêtre France

Graduate School of Natural and Applied Sciences Yeditepe University Istanbul Turkey

Gustave Roussy Villejuif France

Harvard Chan Microbiome in Public Health Center Harvard T H Chan School of Public Health Boston MA USA

IEO European Institute of Oncology IRCCS Milan Italy

Infectious Disease and Microbiome Program Broad Institute of MIT and Harvard Cambridge MA USA

Institut National de la Santé Et de la Recherche Médicale U1015 Equipe Labellisée Ligue Nationale contre le Cancer Villejuif France

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague Czech Republic

Italian Institute for Genomic Medicine c o IRCCS Candiolo Candiolo Italy

Masaryk Memorial Cancer Institute Brno Czech Republic

RECETOX Faculty of Science Masaryk University Brno Czech Republic

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