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 [HCs]). 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. A Random Forest model was used to identify multicohort diagnostic microbial biomarkers in CRC.

Results: The overall archaeal alpha diversity shifted from HCs, patients with adenoma, to patients with CRC with the Methanobacteriota phylum enriched while the order Methanomassiliicoccales depleted. At the species level, Methanobrevibacter_A smithii and Methanobrevibacter_A sp002496065 were enriched, whereas 8 species, including Methanosphaera stadtmanae and Methanomassiliicoccus_A intestinalis, were depleted in patients with CRC across multiple cohorts. Among them, M stadtmanae, 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 patients with CRC. A model incorporating archaeal and bacterial biomarkers outperformed single-kingdom models in discriminating patients with CRC from healthy individuals with the area under the curve 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, patients with adenoma, and patients with CRC. Archaeal biomarkers, combined with bacterial features, have potential as noninvasive diagnostic biomarkers for CRC.