A bidirectional brain-fat body axis for pathogen avoidance

Ingesting pathogens poses a threat to survival, driving the evolution of avoidance behaviors across species. The mechanisms linking immune detection to behavioral responses remain poorly understood. Here, we identify a bidirectional fat body-brain communication pathway that mediates pathogen avoidance in Drosophila melanogaster. Immune receptors and a specific antimicrobial peptide (AMP) are required in both the fat body and neuromodulatory neurons to suppress pathogen intake. We show that pathogen-sensing octopaminergic neurons innervate the fat body, activating calcium signaling via an octopamine receptor, thereby triggering fat body dopamine release. Dopamine then acts through Dop1R1 receptors in mushroom body output neurons to drive avoidance behavior. Two-photon calcium imaging reveals that pathogen ingestion modulates odor responses in these neurons, linking immune system activation to behavioral change. Our findings uncover a previously unrecognized immune-to-brain communication loop, illustrating how fat tissue and the innate immune system can drive behavioral adaptation to enhance survival during infection.