A natural bacterial pathogen of uses a small RNA to induce transgenerational inheritance of learned avoidance.

Previously, we discovered that a small RNA from a clinical isolate of PA14, induces learned avoidance and its transgenerational inheritance in . is an important human pathogen, and there are other in natural habitat, but it is unclear whether ever encounters PA14-like bacteria in the wild. Thus, it is not known if small RNAs from bacteria found in natural habitat can also regulate host behavior and produce heritable behavioral effects. Here we found that a pathogenic strain isolated from the microbiota, GRb0427, like PA14, regulates worm behavior: worms learn to avoid this pathogenic bacterium following exposure to GRb0427, and this learned avoidance is inherited for four generations. The learned response is entirely mediated by bacterially-produced small RNAs, which induce avoidance and transgenerational inheritance, providing further support that such mechanisms of learning and inheritance exist in the wild. Using bacterial small RNA sequencing, we identified Pv1, a small RNA from GRb0427, that matches the sequence of . We find that Pv1 is both necessary and sufficient to induce learned avoidance of Grb0427. However, Pv1 also results in avoidance of a beneficial microbiome strain, ; this potentially maladaptive response may favor reversal of the transgenerational memory after a few generations. Our findings suggest that bacterial small RNA-mediated regulation of host behavior and its transgenerational inheritance are functional in natural environment, and that different bacterial small RNA-mediated regulation systems evolved independently but define shared molecular features of bacterial small RNAs that produce transgenerationally-inherited effects.