Stenotrophomonas maltophilia alleviates Alzheimer’s disease model phenotype by inhibiting Aβ aggregation via autophagy

Probiotics exert neuroprotective effects against Alzheimer’s disease (AD) through modulation of gut-brain axis signaling pathways, yet disease-modifying therapies remain elusive. In this study, we demonstrate that Stenotrophomonas maltophilia ( S. maltophilia ) ameliorates AD-associated pathological and behavioral phenotypes in Caenorhabditis elegans ( C. elegans ) models, including learning deficits and paralysis. Mechanistically, S. maltophilia suppresses β-amyloid (Aβ) peptide aggregation by orchestrating the activation of conserved cellular pathways: autophagy, innate immune signaling, and unfolded protein responses in the mitochondria (UPRmt) and endoplasmic reticulum (UPRer). Specifically, S. maltophilia induces UPRmt in an atfs-1 -dependent manner and activates UPRer via the PERK kinase PEK-1. Further mechanistic analysis suggests that S. maltophilia initiates a signaling cascade: activation of ATF-7 immune pathways enhanced autophagy and subsequent clearance of Aβ aggregates. Metabolomic screening further pinpointed pizotifen as a bioactive metabolite that might inhibit Aβ aggregation through immune modulation.