An RNA regulates iron homeostasis and host mucus colonization in Bacteroides thetaiotaomicron

Symbiotic bacteria in the human intestinal microbiota provide many pivotal functions to human health and occupy distinct biogeographic niches within the gut. Yet the molecular basis underlying niche-specific colonization remains poorly defined. To address this, we conducted a time-resolved dual RNA-seq experiment to simultaneously monitor the transcriptional co-adaptations of human commensal Bacteroides thetaiotaomicron and human gut epithelial cells in an anaerobe-epithelium co-culture system. Comparative transcriptomic analysis of mucus-associated versus supernatant Bacteroides populations unveiled small RNAs (sRNAs) that are differentially regulated between spatially segregated subpopulations. Among these, we identified IroR as a key sRNA that facilitates B. thetaiotaomicron adaptation to the mucus-rich, iron-limiting niche, partly by modulating expression of bacterial capsule genes. This work provides new insights into the spatiotemporal dynamics of gut colonization and underscores a previously underappreciated role for bacterial sRNAs in shaping mutualistic interactions between the human microbiota and the gut epithelium.