Presented by: Yan Yan
View Abstract
Changes in the gut microbiota have been associated with colorectal cancer (CRC), but neither the causal mechanisms nor the underlying microbial strains and molecular products needed to understand mechanistic connections have been elucidated. To identify these, we extended a previous meta-analysis to include stool metagenomic profiles of 600 CRC patients, 143 with precancerous adenomas, and 662 healthy controls from nine recently published CRC microbiome studies. We developed a method called MMUPHin to jointly normalise these datasets and identify specific microbial species and strains significantly correlated with the presence and/or severity of CRC neoplasia. Our approach uncovered novel CRC biomarkers, including several strains typical of the oral cavity, as well as enrichment in encoded metabolic pathways underlying the production of butyrate, lysine, acetate, and several tumor-promoting metabolites, such as ammonia and polyamines. These metabolic capabilities were carried predominantly by prevalent species of Bacteroides, Alistipes, or facultative anaerobes Escherichia and Klebsiella. Interestingly, we identified instances where the gene carriage was significantly different among strains of the same species in CRC patients compared to control individuals, indicating strain-specific functional distinctions in the CRC microbiome that would be invisible in taxonomically-focused analyses. We also found a group of genes unique to subsets of E. coli pan-genome associated with CRC phenotypes, comprising encoded pathways for lysine degradation, adhesion, and flagellar motility. We are currently testing whether these strain associations are phylogenetically enriched. Our work thus uncovers specific microbial strains, gene products, and pathways with potential bioactivity in CRC, providing new leads for future mechanistic studies that will advance our understanding of the microbiome’s role in CRC initiation and development.