Multi-cohort analysis reveals altered archaea in colorectal cancer fecal samples across populations

Background and aim

Archaea are important components of the host microbiome, but their roles in colorectal cancer (CRC) remain largely unclear. We aimed to elucidate the contribution of gut archaea to CRC across multiple populations.

Methods

This study incorporated fecal metagenomic data from 10 independent cohorts from 7 countries and an additional in-house cohort, totaling 2101 metagenomes (748 CRC, 471 adenoma, and 882 healthy controls (HC)). Taxonomic profiling was performed using Kraken2 against the Genome Taxonomy Database. Alterations of archaeal communities and their interactions with bacteria and methanogenic functions were analyzed. Random Forest model was used to identify multicohort diagnostic microbial biomarkers in CRC.

Results

The overall archaeal alpha diversity shifted from HC, adenoma patients to CRC patients with Methanobacteriota phylum enriched while order Methanomassiliicoccales depleted. At the species level, Methanobrevibacter_A smithii and Methanobrevibacter_A sp002496065 were enriched, while 8 species, including Methanosphaera stadtmanae and Methanomassiliicoccus_A intestinalis, were depleted in CRC patients across multiple cohorts. Among them, M. stadmanae, Methanobrevibacter_A sp900314695 and Methanocorpusculum sp001940805 exhibited a progressive decrease in the HC-adenoma-CRC sequence. CRC-depleted methanogenic archaea exhibited enhanced co-occurring interactions with butyrate-producing bacteria. Consistently, methanogenesis-related genes and pathways were enriched in CRC patients. A model incorporating archaeal and bacterial biomarkers outperformed single-kingdom models in discriminating CRC patients from healthy individuals with AUC ranging from 0.744 to 0.931 in leave-one-cohort-out analysis.

Conclusions

This multicohort analysis uncovered significant alterations in gut archaea and their interactions with bacteria in healthy individuals, adenoma patients and CRC patients. Archaeal biomarkers, combined with bacterial features, have potential as non-invasive diagnostic biomarkers for CRC.