Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation

Andrew Maltez Thomas, Paolo Manghi, Francesco Asnicar, Edoardo Pasolli, Federica Armanini, Moreno Zolfo, Francesco Beghini, Serena Manara, Nicolai Karcher, Chiara Pozzi, Sara Gandini, Davide Serrano, Sonia Tarallo, Antonio Francavilla, Gaetano Gallo, Mario Trompetto, Giulio Ferrero, Sayaka Mizutani, Hirotsugu Shiroma, Satoshi ShibaTatsuhiro Shibata, Shinichi Yachida, Takuji Yamada, Jakob Wirbel, Petra Schrotz-King, Cornelia M Ulrich, Hermann Brenner, Manimozhiyan Arumugam, Peer Bork, Georg Zeller, Francesca Cordero, Emmanuel Dias-Neto, João Carlos Setubal, Adrian Tett, Barbara Pardini, Maria Rescigno, Levi Waldron, Alessio Naccarati, Nicola Segata

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)667-678
Number of pages12
JournalNature Medicine
Volume25
Issue number4
DOIs
Publication statusPublished - Apr 2019

Keywords

  • Biomarkers, Tumor/metabolism
  • Choline/metabolism
  • Cohort Studies
  • Colorectal Neoplasms/diagnosis
  • Databases, Genetic
  • Gastrointestinal Microbiome
  • Humans
  • Lyases/genetics
  • Metagenomics
  • Species Specificity

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  • Cite this

    Thomas, A. M., Manghi, P., Asnicar, F., Pasolli, E., Armanini, F., Zolfo, M., Beghini, F., Manara, S., Karcher, N., Pozzi, C., Gandini, S., Serrano, D., Tarallo, S., Francavilla, A., Gallo, G., Trompetto, M., Ferrero, G., Mizutani, S., Shiroma, H., ... Segata, N. (2019). Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nature Medicine, 25(4), 667-678. https://doi.org/10.1038/s41591-019-0405-7