The gut efflux pump MRP-1 exports oxidized glutathione as a danger signal that stimulates behavioral immunity and aversive learning.

Innate immune surveillance, which monitors the presence of potentially harmful microorganisms and the perturbations of host physiology that occur in response to infections, is critical to distinguish pathogens from beneficial microbes. Here, we show that multidrug resistance-associated protein-1 (MRP-1) functions in the basolateral membrane of intestinal cells to transport byproducts of cellular redox reactions to control both molecular and behavioral immunity in Caenorhabditis elegans. Pseudomonas aeruginosa infection disrupts glutathione homeostasis, leading to the excess production of the MRP-1 substrate, oxidized glutathione (GSSG). Extracellular GSSG triggers pathogen avoidance behavior and primes naïve C. elegans to induce aversive learning behavior via neural NMDA class glutamate receptor-1 (NMR-1). Our results indicate that MRP-1 transports GSSG, which acts as a danger signal capable of warning C. elegans of changes in intestinal homeostasis, thereby initiating a gut neural signal that elicits an appropriate host defense response.