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

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.

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.

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.

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.

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.