Summary The bacterium Segatella copri is a prevalent member of the human gut microbiota associated with both health and disease states, but intrinsic factors that determine its ability to effectively colonize the gut are not understood. By extensive transcriptome mapping of S. copri and examining human-derived samples, we discover a previously unknown small RNA named here Segatella RNA colonization factor (SrcF). We show that SrcF is essential for S. copri gut colonization in a gnotobiotic mouse model. SrcF regulates genes involved in nutrient acquisition, and its own expression is controlled by complex carbohydrates, particularly fructans. Furthermore, SrcF expression is strongly influenced by human microbiome composition and by the breakdown of fructans by cohabitating commensals, suggesting that the breakdown of complex carbohydrates mediates inter-species signaling among commensals beyond its established function in generating energy. Together, this study highlights the contribution of a small RNA as a key regulator in gut colonization.

The RNA landscape of the human commensal Segatella copri reveals a small RNA essential for gut colonization