Journal
NATURE MEDICINE
Volume 25, Issue 4, Pages 667-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-019-0405-7
Keywords
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Funding
- Lega Italiana per La Lotta contro i Tumori
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [16/23527-2]
- Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, Brazil)
- FAPESP [14/26897-0]
- Associacao Beneficente Alzira Denise Hertzog Silva (ABADHS, Brazil)
- PRONON/SIPAR
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior -Brazil (CAPES) [001]
- Italian Institute for Genomic Medicine (IIGM)
- Compagnia di San Paolo Torino
- Fondazione Umberto Veronesi
- Grant Agency of the Czech Republic [17-16857S]
- Fondazione Umberto Veronesi [FUV-14-SG-GANDINI]
- European Union [707345]
- European Research Council (ERC-STG project MetaPG)
- MIUR 'Futuro in Ricerca' [RBFR13EWWI_001]
- European Union
- National Cancer Institute [U24CA180996, R01 CA189184, R01 CA207371, U01 CA206110, P30 CA042014]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [1R21AI121784-01]
- Fulbright Research Scholarship
- EMBL
- DKFZ
- Huntsman Cancer Foundation
- Intramural Research Program of the National Cancer Institute
- ETH Zurich
- European Research Council [ERC-2010-AdG_20100317, ERC-AdG-669830]
- Novo Nordisk Foundation [NNF10CC1016515]
- Danish Diabetes Academy - Novo Nordisk Foundation
- TARGET research initiative (Danish Strategic Research Council) [0603-00484B]
- Matthias-Lackas Foundation
- BMBF [031A537B]
- ERA-NET TRANSCAN project [01KT1503]
- Helmut Horten Foundation
- National Cancer Center Research and Development Fund [25-A-4, 28-A-4, 29-A-6]
- Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) [JP18ek0109187]
- JST (Japan Science and Technology Agency)-PRESTO [JPMJPR1507]
- Japan Society for the Promotion of Science KAKENHI [16J10135, 142558, 221S0002]
- Joint Research Project of the Institute of Medical Science
- University of Tokyo
- Takeda Science Foundation
- Suzuken Memorial Foundation
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [14/26897-0, 16/23527-2] Funding Source: FAPESP
- Grants-in-Aid for Scientific Research [16J10135] Funding Source: KAKEN
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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 trimethylaminelyase 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.
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