Liu, H.; Chen, P.; Yang, X.; Hao, F.; Tian, G.; Shan, Z.; QI, B.

Animals exist within a microbial world and are constantly challenged by pathogen infections. Microbe-mediated protection for against infection is the survival strategy for host. However, elucidating specific microbial molecules and understanding how they interact with the host\'s intracellular surveillance system for protection is difficult but highly desirable. Here, by establishing pathogen-like-bacteria screening system, we identified E. coli mutants, including ymcB, that act as pathogen-like-bacteria to defend animals against Pseudomonas aeruginosa PA14 infection by activating UPRmt. Additionally, through genetic screening, we identified neuronal transmembrane protein, MDSS-1, that is crucial for sensing ymcB and activating intestinal UPRmt. Moreover, we demonstrated that MDSS-1 functions as a receptor in ASE neurons, responsible for detecting ymcB. It then communicates microbial signals through neuropeptides, GPCR, Wnt signaling and endopeptidase inhibitors to trigger intestinal UPRmt, that defends the host animals against infections. Furthermore, Constitutionally activation of MDSS-1 in ASE neurons is sufficient to trigger intestinal UPRmt in animals, resulting in protection against infection. Our study uncovers an intriguing mechanism involving intracellular mitochondrial surveillance, where neuron-intestine crosstalk originates from ASE neurons to detect bacteria and combat pathogens. This study identifies a bacteria-sensing mechanism in neurons that regulates intestinal mitochondrial surveillance pathway for host adaptation.