Probiotics-sensing mechanism in neurons that initiates gut mitochondrial surveillance for pathogen defense.

Animals constantly face microbial challenges, and microbe-mediated infection protection is crucial for host survival. Identifying specific bacteria and their interactions with host intracellular surveillance systems is important but challenging. Here, we develop a "probiotics" screening system that identifies Escherichia coli mutants, such as ΔymcB, which protect hosts from Pseudomonas aeruginosa PA14 infection by activating the mitochondrial unfolded protein response (UPR). Genetic screening reveals that MDSS-1, a neuronal transmembrane protein, is crucial for sensing ΔymcB and triggering intestinal UPR. MDSS-1 functions as a potential receptor in ASE neurons, detecting ΔymcB and transmitting signals through neuropeptides, GPCRs, Wnt signaling, and endopeptidase inhibitors to activate intestinal UPRmt and enhance protection. Constitutive activation of MDSS-1 in ASE neurons is sufficient to induce UPR and confer infection resistance. This study uncovers a neuron-intestine communication mechanism, where ASE neurons detect bacteria and modulate the intestinal mitochondrial surveillance system for host adaptation to pathogens.