Decoding the human gut bacterial plasmids in colorectal cancer

Gut plasmids show heightened sensitivity to gut microenvironmental changes compared to their bacterial hosts. To explore their significance in colorectal cancer (CRC), we analyzed metagenomic data from 863 participants (312 CRC, 387 high-risk, 164 low-risk). Plasmid and bacterial profiles were characterized, along with trace elements and metabolites. Differential analysis, functional gene assessment (ARG, MGE, MRG, VFGB), random forest modeling, and structural equation modeling (SEM) were applied. In terms of overall abundance, plasmids in both the high-risk and CRC groups exhibited a decreasing trend. Gut plasmids significantly influenced the functional genes (ARG, MGE, MRG, VFGB) of their bacterial hosts. Six key bacterial hosts (Enterobacterales, Bucrkholderiales, Hyphomicrobiales, Lactobacillales, Bacteroidales, Campylobacterales) and 12 plasmid markers were identified. The plasmid-based model effectively predicted CRC risk. SEM revealed that trace elements (e.g., Ni), metabolites (e.g., 5-Hydroxytryptophol), and host bacteria (e.g., Campylobacterales, Enterobacterales) predominantly exerted negative effects on most plasmids, whereas Ni exhibited a positive influence on plasmids NZ_CP013564.1, NZ_CP024312.1, and NZ_CP48284.1. We characterized the composition of gut plasmids and their bacterial hosts, explored the impacts of gut plasmids on bacterial functionality, and mapped multi-omics interaction networks linking plasmids, hosts, and metabolic features.