Gut Microbial Topology and Metabolic Signatures Associated With Colorectal Neoplasia

Alterations of gut microbial communities impact health. However, the structure and function of community-level topologies related to colorectal neoplasia (CRN) remain unclear. We analyzed 3807 newly sequenced stool metagenomes from participants (2725 healthy controls, 759 non-advanced adenomas, 297 advanced adenomas, and 26 colorectal cancers) in a multicenter TARGET-C screening trial and validated our findings in multiple independent cohorts. We identified a CRN-associated network (14 species, including Clostridium symbiosum) and a negatively associated network (37 species, including Roseburia and Lachnospira), forming a "seesaw-like" microbial association pattern characterized by within-group co-occurrence and between-group co-exclusion. The structures were stable across the independent datasets. A composite score derived from the microbial topology stratified CRN risk, and diagnostic models based solely on the presence/absence status of the topological species achieved moderate accuracy across the cohorts (area under the curve ranging from 0.66 to 0.87). Functionally, changes in CRN-related microbial association patterns were associated with microbe-derived metabolites. Our findings provide novel insights into the microbial topology associated with CRN and support its potential application in non-invasive risk stratification. However, the utility of these topological features in colorectal cancer remains exploratory and requires further validation in larger colorectal cancer cohorts.