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

Simple SummaryAlzheimer’s disease is a progressive neurodegenerative disorder that causes memory loss, cognitive decline, and great burden on patients and families. Although many studies have focused on the brain, increasing evidence suggests that changes in the gut may also contribute to disease development. In this study, we examined whether mulberroside A, a natural compound derived from mulberry, could protect against scopolamine-induced Alzheimer’s disease-like cognitive impairment in mice. Our results showed that mulberroside A improved learning and memory, reduced inflammatory damage and oxidative stress in the brain, and protected the intestinal barrier. We also found that mulberroside A changed the composition of gut microbes, especially increasing beneficial bacteria such asDubosiella, and helped restore abnormal metabolism in the brain. Importantly, fecal microbiota transplantation from treated mice reproduced the protective effects, indicating that gut microbiota changes play a key role in the action of mulberroside A. These findings suggest that mulberroside A may improve brain health by acting through the microbiota-gut–brain axis and could be a promising natural compound for the prevention and amelioration of Alzheimer’s disease-like cognitive decline.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 genusDubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut–brain connection, withDubosiellaabundance 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 theDubosiella-associated gut–metabolite–brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits.