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Archaeal Biomarkers for Colorectal Cancer Diagnosis
TAKE-HOME MESSAGE
- This multinational study investigated the contribution of gut archaea to colorectal cancer (CRC) across multiple populations using fecal metagenomic data from 10 independent cohorts. Fecal metagenomic data from patients with CRC (n = 748) and adenoma (n = 471) were compared with those from 882 healthy controls. Overall, methanogenesis-related genes and pathways were enriched in patients with CRC compared with patients with adenoma and healthy controls.
- This study suggests that biomarkers of gut archaea combined with bacterial features can potentially be used for non-invasive diagnosis of CRC. Further studies are required to confirm the findings.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBackground 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.
Additional Info
Disclosure statements are available on the authors' profiles:
A complex microbial ecosystem consisting of bacteria, viruses, fungi, and archaea inhabits the gastrointestinal tract and plays a key role in human fitness and pathogenesis of diseases like colorectal cancer (CRC). Much lesser research attention has been paid to archaea than to other microorganisms, particularly bacteria. Emerging evidence suggests that archaeal dysbiosis may be associated with CRC.1 However, large-scale surveys of archaeal association with CRC progression in geographically diverse populations are lacking. Li et al performed a meta-analysis of fecal metagenome data obtained from one in-house cohort and previously published datasets from 10 independent cohorts across the globe. This unprecedented endeavor led to the identification of novel CRC-associated archaeal features, disease-dependent co-occurring or co-excluding interactions between archaeal and bacterial groups, and a composite bacteria/archaea panel with superior CRC diagnosis power. This work greatly expands our knowledge of the links between archaea and CRC and the potential interactions between archaea and bacteria. Reminiscent of the inception of CRC bacteriome research, the study by Li et al should entail increasing research interests in understanding the cause of CRC-associated archaeal dysbiosis and establishing the contribution of specific archaeal factors or archaea–bacteria interactions to CRC etiopathogenesis. Investigating archaea community in relationship with the development of early-onset colorectal cancer may also be important. However, in contrast to bacteria, notable obstacles need to be overcome for archaea research, such as low resource availabilities concerning cultivatable clinical isolates and biological reagents, lack of tools for archaeal genetic manipulation, and controllable colonization in preclinical models. One study limitation is that data are more biased towards East Asian populations. Given the observed geographical variations, another important research direction is to validate the findings in larger cohorts with a more diverse background. Considering the advancement in CRC bacteriome research, archaeome research holds promise for discovering novel mechanisms modulating CRC development, which can facilitate the development of new preventive, diagnostic, and therapeutic approaches.
Reference
1. Saftien A, Puschhof J, Elinav E. Fungi and cancer. Gut. 2023;72(7):1410-1425. https://gut.bmj.com/content/72/7/1410.long