Two papers published on 1 April 2019 in the Nature Medicine put in loop links betweenmicrobiome alterations and colorectal cancer (CRC). Several studies have investigated links between the gut microbiome and CRC, but questions remained about the replicability of biomarkers across cohorts and populations. New cross-study analysis defines foecal microbial species associated with CRC and multicohort analysis identifies microbial signatures of CRC in foecal microbiomes.
In first paper, a meta-analysis firmly establishes globally generalisable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics. In second paper, a combined analysis of heterogeneous CRC cohorts identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.
In first article, Manimozhiyan Arumugam of the University of Copenhagen, Copenhagen, Denmark, Peer Bork and Georg Zeller of the European Molecular Biology Laboratory, Heidelberg, Germany and study team published results of a meta-analysis of eight geographically and technically diverse foecal shotgun metagenomic studies of 768 CRC, which was controlled for several confounders. They identified a core set of 29 species significantly enriched in CRC metagenomes.
CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, the study team 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, the study team 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.
The authors concluded that through extensive validations, the meta analysis firmly establishes globally generalisable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.
In second paper, Nicola Segata of the University of Trento, Trento, Italy and colleagues report findings from performed meta analysis of five publicly available datasets and two new cohorts, they validated the findings on two additional cohorts, considering in total 969 foecal metagenomes.
Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls, 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.
Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC, identifying a relationship between microbiome choline metabolism and CRC.
The authors concluded that 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.
- Wirbel J, Pyl PT, Kartal E, et al. Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer.Nature Medicine; Published online 2019.
- Thomas AM, Manghi P, Asnicar F, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nature Medicine; Published online 1 April 2019.