Quercetin glycoside-specific modulation of the gut-brain axis determines protection against colitis-associated cognitive decline.

Inflammatory bowel disease is increasingly linked to cognitive impairment. Although quercetin glycosides are known to modulate intestinal homeostasis and gut-brain interactions, their specific impact on colitis-associated cognitive dysfunction and the underlying mechanisms remain poorly understood. This study evaluated the protective effects of four quercetin glycosides (hyperoside, Gal; isoquercitrin, Glc; quercitrin, Rha; rutin, Glc-Rha) in DSS-induced colitis mice. All glycoside supplementation effectively improved the cognitive deficits and intestinal inflammation, though efficacy depended on the specific sugar moiety. Gal and Glc-Rha exhibited the most pronounced effects in repairing the intestinal barrier, suppressing neuroinflammation, and restoring synaptic proteins, whereas Rha showed limited efficacy. Mechanistically, the glycosides selectively remodeled the gut microbiota (e.g., Dubosiella enriched by Gal and Bifidobacterium by three monoglycosides) and averted the aberrant activation of indoleamine 2,3-dioxygenase 1 in both the colon and brain. This suppression halted the pathological shift of tryptophan metabolism toward the neurotoxic kynurenine pathway, thereby preserving serotonin and indole pools. Consequently, this precise metabolic modulation correlated with reduced systemic endotoxemia, suppressed glial activation. Distinct glycosylation forms drive multi-target mechanisms along the gut-brain axis, providing new insights into targeted nutritional interventions to prevent IBD-related cognitive impairment.