A gut-brain axis for aversive interoception drives innate and anticipatory emesis in Drosophila.
Signals from the gut are increasingly recognized as modulators of brain function and behavior. However, the pathways through which the gut conveys adverse or unpleasant information to the brain are still not well understood. In this study, we identify an aversive gut-brain axis in Drosophila melanogaster that detects toxin-induced gut damage and triggers both innate and learned anticipatory emesis (vomiting). After toxin ingestion, reactive oxygen species are produced by midgut enterocytes and detected by the transient receptor potential channel TrpA1 on nearby enteroendocrine cells. This sensing stimulates the release of neuropeptides from enteroendocrine cells, likely representing the gastric malaise flies experience after eating. We show that these neuropeptides act on specific serotonergic and dopaminergic neurons in the brain. These neurons interact with each other and signal to the downstream memory-related mushroom bodies to promote emesis. This circuit not only drives an immediate emetic response but also represents a malaise-driven aversive signal. The signal manifests as the persistent activity of dopaminergic neurons, which reinforces aversive valence to odor cues in the mushroom bodies. Thus, the flies learn that a specific odor predicts the presence of a toxin in food and exhibit anticipatory emesis upon re-exposure to the same odor. Taken together, we have identified an interoceptive signaling pathway that may be conserved for detecting harmful gut conditions and for remembering how to avoid them. Our work offers a mechanistic framework for studying aversive gut-brain communication involved in feeding, metabolism, depression, brain injury, and neurodegenerative diseases.