An atlas of colonization factors in the human gut microbiome reveals ecological strategies and inflammatory bowel disease signatures.

Long-term residence in the gut enables microbes to interact with the host and influence intestinal health. However, many microbiome studies focus on taxonomic profiles or broad metabolic pathway annotations and provide limited insight into the conserved genes that support microbial residence. Here we show that colonization factors (CFs), defined as gut-enriched genes associated with microbial residence, offer a colonization-centered functional framework for profiling the human gut microbiome. By mapping 79 CF families across 289,231 surveyed microbial genomes, we identify more than seven million CF homologs and reveal their widespread distribution, phylogenetically structured organization and functional stratification into three putative lineage-associated colonization strategies centered on metabolism, stress resistance and microbial communication. Applying this framework to 3,666 metagenomic and metatranscriptomic samples from 10 inflammatory bowel disease (IBD) cohorts, we find that disease-associated dysbiosis is accompanied by recurrent remodeling of CF repertoires. These alterations can be traced to specific colonization-associated functions and microbial carrier species, and are captured by a compact feature panel that discriminates disease status within cohorts. These results establish CF profiling as a mechanism-oriented approach for interpreting the ecological organization of the gut microbiome and prioritizing colonization-associated targets for future disease monitoring and intervention studies.