Gut Microbial Topology and Metabolic Signatures Associated With Colorectal Neoplasia

ABSTRACT

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.