Four dietary flavonoids differentially modulate the gut microbiota–barrier interaction against colitis-driven cognitive deficits

Accumulating evidence links inflammatory bowel disease (IBD) to cognitive impairment driven by gut barrier disruption and dysbiosis via the gut-brain axis. Currently, the impact of dietary flavonoids on IBD-related cognitive deficits remains unclear. This study found that the selected flavonoids (quercetin, kaempferol, luteolin, apigenin) could ameliorate colitis severity in mice, with kaempferol and quercetin being most effective in rescuing cognitive impairments in novel object recognition and Y-maze tests. They suppressed microglial activation (apigenin uniquely reversed astrocyte overactivation) and quercetin/apigenin elevated hippocampal synaptic proteins. Mechanistically, flavonoids enhanced intestinal barrier function: apigenin and luteolin upregulated tight junction proteins, and quercetin reduced intestinal permeability as reflected by notably decreased FITC-dextran flux ( p < 0.05). Flavonoid treatments reshaped gut microbiota composition. Kaempferol optimally restored α-diversity (Shannon index, p < 0.001), while quercetin/kaempferol enriched beneficial Bifidobacterium and Lactobacillus . Redundancy analysis confirmed correlations between intestinal barrier integrity, microbiota composition, and cognitive performance. Overall, these findings reveal distinct yet complementary regulatory roles of four structurally similar flavonoids along the gut–brain axis—targeting gut microbiota, intestinal barrier, or brain neuroinflammation—highlighting their potential as a multi-targeted dietary strategy for preventing colitis-driven cognitive impairment.