Background: Alterations in gut microbial composition have been consistently linked to colorectal neoplasia (CRN). However, most existing studies focus on individual taxa, while the role of community-level topological structures and microbial interaction networks in CRN development remains insufficiently understood.

Objectives: We aimed to characterize CRN-associated gut microbial network topologies, evaluate their reproducibility across populations, and assess their potential utility for noninvasive risk stratification in colorectal cancer screening.

Methods: We analyzed 3,807 newly sequenced stool metagenomes from participants enrolled in the multicenter TARGET-C screening trial, including 2,725 healthy controls, 759 non-advanced adenomas, 297 advanced adenomas, and 26 colorectal cancer cases. Microbial co-occurrence networks were constructed to identify disease-associated community structures. Findings were validated across multiple independent external cohorts. We further developed a composite topology score to quantify network imbalance and evaluated its diagnostic performance. Functional associations were explored through microbial metabolite profiling.

Results: We identified two distinct and reproducible microbial network modules: a CRN-associated network comprising 14 species (including Clostridium symbiosum) and a protective network comprising 37 species (including Roseburia and Lachnospira). These networks exhibited “seesaw-like” topological features, characterized by strong within-network co-occurrence and reciprocal exclusion between networks. Such structures were consistently validated across independent cohorts. The composite topology score effectively stratified CRN risk and demonstrated moderate-to-high diagnostic accuracy across study populations. Functionally, CRN-related network topologies were associated with alterations in microbial-derived metabolites, including indole-3-propionic acid.

Conclusions/Implications for Practice or Policy: Our study reveals that gut microbial community-level topological imbalance, rather than individual taxa alone, is closely associated with colorectal neoplasia. These findings provide novel biological insights into CRN pathogenesis and highlight the potential of microbial network-based markers for noninvasive risk stratification and precision colorectal cancer screening.