Quercetin Enhances Innate Immunity in Caenorhabditis elegans Against Pseudomonas aeruginosa via Redox Homeostasis and Immune Signaling.

BACKGROUND: Quercetin (Que) is widely recognized for its antioxidant and cytoprotective activities, yet its host-directed immunomodulatory mechanisms during Pseudomonas aeruginosa strain UCBPP-PA14 (PA14) infection in the Caenorhabditis elegans model remains insufficiently defined. PURPOSE: This study examined the protective effects of Que against PA14 and aimed to uncover previously uncharacterized metabolic and signaling mechanisms that contribute to enhanced host defense and epithelial homeostasis. METHODS: Survival, pharyngeal pumping, intestinal permeability, and PA14 intestinal colonization were assessed, accompanied by antioxidant enzyme profiling, targeted metabolomics of central carbon and glutathione metabolism, and immune-related transcriptional analyses. In vitro antibacterial and antibiofilm activities were also systematically evaluated to distinguish host- from pathogen-directed effects. RESULTS: Que significantly improved survival, restored pharyngeal pumping, maintained epithelial barrier integrity, and reduced PA14 colonization, whereas only sub-MIC antibiofilm activity with negligible effects on planktonic growth was observed in vitro, indicating a primarily host-centric mode of action. A key innovation of this work is the identification of dose-dependent redox rewiring, characterized by pentose phosphate pathway-glutathione remodeling, elevated NADP⁺, and disrupted GSH/GSSG and NADPH/NADP⁺ ratios. Additionally, Que induced glycolytic redistribution independently of total glucose levels. Transcriptionally, Que suppressed insulin/insulin-like signaling components (daf-2, age-1, pdk-1) and activated daf-16, alongside enhanced sek-1, skn-1, lys-7, and spp-1 expression. CONCLUSION: These findings reveal a previously unrecognized metabolic-signaling axis through which Que evokes controlled redox perturbation to attenuate IIS, stabilize epithelial physiology, and strengthen antimicrobial defense independently of direct bactericidal effects.