Honeysuckle-derived nanovesicles alleviate inflammatory bowel disease-associated neuropsychiatric disorders via the gut–brain axis

Rationale: Inflammatory bowel disease (IBD) is frequently accompanied by anxiety and depression, yet effective therapies targeting both intestinal inflammation and neuropsychiatric symptoms remain limited. This study aimed to investigate whether honeysuckle-derived nanovesicles (HNVs) could alleviate IBD-related affective disturbances by modulating the microbial-gut-brain axis (MGBA). Methods: A chronic colitis mouse model was established using dextran sulfate sodium (DSS). Mice were treated orally with HNVs, and anxiety- and depression-like behaviors were evaluated using behavioral assays. Intestinal barrier integrity, gut microbiota composition, systemic immune responses, proinflammatory cytokine production, hippocampal immune infiltration, 5-hydroxytryptamine (5-HT) biosynthesis and metabolism, and activation of the BDNF/TrkB/GSK3β signaling pathway were assessed using histological, microbiological, immunological, biochemical, and molecular analyses. Results: Oral administration of HNVs markedly attenuated anxiety- and depression-like behaviors in mice with chronic colitis. HNV treatment preserved intestinal barrier integrity, reshaped the gut microbial community, modulated systemic immune responses, reduced proinflammatory cytokine production and hippocampal inflammatory infiltration, and regulated 5-HT biosynthesis and metabolic pathways. These effects were associated with restoration of intestinal and neural homeostasis and activation of the BDNF/TrkB/GSK3β signaling cascade. Conclusions: HNVs alleviated IBD-related affective disturbances in experimental chronic colitis by regulating the MGBA, suppressing inflammation, modulating 5-HT metabolism, and restoring intestinal and neural homeostasis. These findings support HNVs as a potential natural nanotherapeutic strategy for the integrated management of intestinal inflammation and associated neuropsychiatric comorbidities.