A commensal bacterium secretes effector proteins to establish population heterogeneity in the gut.

The gut microbiome, comprising hundreds of individual species, is a complex and dynamic host-associated microbial community. However, how microbes interact within populations of the same species is largely unexplored. Using single-cell approaches, we discover that the human gut microbe Bacteroides thetaiotaomicron forms distinct sub-populations in the gut environment, which can be distinguished using N-hydroxysuccinimide (NHS) ester probes. This heterogeneity results from a locus encoding two secreted effector proteins and a cognate immunity factor. At the population level, this locus is among the most significantly upregulated across the B. thetaiotaomicron transcriptome in response to gut colonization; at the single-cell level, its variable expression leads to heterogeneity within the population. Sub-populations form in response to these effectors, exhibit distinct gene expression programs, and remain stable over time. Together, these findings demonstrate that prominent gut commensals establish population heterogeneity by producing and responding to secreted effector proteins.