Mulberroside A Alleviates Scopolamine-Induced Cognitive Deficits by Suppressing Neuroinflammation and Oxidative Stress via the Dubosiella-Associated Microbiota–Gut–Brain Axis

Mulberroside A (MsA) possesses neuroprotective effects, but whether it alleviates Alzheimer’s disease (AD)-like cognitive impairment through the microbiota–gut–brain axis remains unclear. Using a scopolamine-induced mouse model of acute cognitive impairment (male ICR mice, n = 10/group), we demonstrated that daily administration of MsA (10, 20, and 30 mg/kg/day) for 5 weeks significantly ameliorated cognitive performance in novel object recognition and Morris water maze tests. At the optimal dose (30 mg/kg/day), MsA suppressed hippocampal microglial activation, reduced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and attenuated oxidative stress by decreasing malondialdehyde (MDA) while restoring superoxide dismutase (SOD) and glutathione (GSH) levels. MsA also strengthened intestinal barrier integrity (ZO-1, occludin) and significantly altered the gut microbiota, notably increasing the beneficial genus Dubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut–brain connection, with Dubosiella abundance positively associated with neuroprotective phospholipids and negatively with stress markers. Furthermore, fecal microbiota transplantation from MsA-treated donors successfully replicated these behavioral improvements in recipient mice, underscoring the functional involvement of the reshaped microbiome rather than a simple autonomous recovery. These results suggest that MsA alleviates AD-like cognitive impairment by reducing neuroinflammation and oxidative stress through microbiota remodeling, enhancing the intestinal barrier, and modulating the Dubosiella-associated gut–metabolite–brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits.