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^mt). Genetic screening reveals that MDSS-1, a neuronal transmembrane protein, is crucial for sensing ΔymcB and triggering intestinal UPR^mt. 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^mt 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.