Neuronal PRDX-2-Mediated ROS Signaling Regulates Food Digestion via peripheral UPRmt Activation

All organisms depend on food digestion for survival, yet the brain-gut signaling mechanisms that regulate this process are not fully understood. Here, using an established C. elegans digestion model, we uncover a pathway in which neuronal ROS (free radicals) signal the intestine to suppress digestion. Genetic screening reveals that reducing genes responsible for maintaining ROS balance increases free radicals and decreases digestion. PRDX-2 knockout in olfactory neurons (AWC) elevates ROS and reduces digestive capacity, mediated by the neuropeptide NLP-1 and activation of the mitochondrial unfolded protein response (UPR mt ) in the intestine. Additionally, over-expressing nlp-1 or ablating AWC neurons both trigger UPR mt and inhibit digestion. These findings reveal a brain-gut connection in which neuronal PRDX-2-mediated ROS signaling modulates food digestion, highlighting a critical role of free radicals in shutting down digestion to alleviate stress and reduce food consumption. Neuronal PRDX-2-mediated reactive oxygen species (ROS) signaling in C. elegans AWC neurons triggers intestinal mitochondrial stress response, halting digestion to reduce cellular stress. This discovery reveals a brain-gut pathway regulating food intake via ROS signaling.