Proton signaling links epithelial sensing to neural control of host defense in C. elegans

Effective host defense against pathogens requires coordinated behavioral and immune responses, yet the mechanisms that couple epithelial sensing to these systemic defenses remain poorly understood. Here, we identify a proton-mediated gut-to-neuron signaling pathway that orchestrates host defense in C. elegans. Intestinal pathogens stimulate mechanosensitive Ca²⁺ influx into intestinal epithelial cells (IECs) through the TRP channel GON-2, activating the Na⁺/H⁺ exchanger NHX-6 via the calmodulin CMD-1 to drive basolateral proton release. These protons activate cholinergic motor neurons through the acid-sensing ion channel ASIC-1, enhancing cholinergic transmission to promote both pathogen avoidance and intestinal innate immunity. Notably, mouse NHE1 and ASIC1a can functionally substitute for their nematode counterparts. Together, these findings demonstrate a role for proton signaling in gut-to-neuron communication, revealing a potentially conserved mechanism that links epithelial sensing to neuroimmune defense.