Buyang Huanwu Decoction Modulates the Gut Microbiota–C/EBPβ/AEP Axis to Ameliorate Cognitive Impairment in Alzheimer's Disease Mice

ABSTRACT Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral disturbances. Buyang Huanwu Decoction (BYHWD), a traditional Chinese herbal formulation, has demonstrated potential neuroprotective effects. This study aims to evaluate the therapeutic impact of BYHWD on cognitive impairments in 3×Tg mice and to investigate its underlying mechanism through modulation of the gut microbiota–C/EBPβ/AEP signaling pathway. Methods In two independent experiments, we assessed the effects of BYHWD and its derived fecal microbiota transplantation (FMT‐BYHWD) on behavioral performance, neuropathological alterations, and signaling pathways in 3×Tg mice. Results Treatment with BYHWD significantly improved cognitive function in 3×Tg mice and mitigated AD‐like pathological changes. By suppressing the C/EBPβ/AEP signaling pathway, BYHWD reduced pathological Aβ plaque deposition, diminished tau hyperphosphorylation, and inhibited the release of pro‐inflammatory cytokines. Further analysis revealed that BYHWD restored gut microbiota balance and suppressed the activation of the C/EBPβ/AEP pathway in the hippocampus. Moreover, transplanting FMT‐BYHWD from BYHWD‐treated mice to germ‐free 3×Tg mice also ameliorated their cognitive deficits and AD‐like pathology, suggesting that the anti‐AD effects of BYHWD are mediated through the gut–brain axis by regulating the interplay between gut microbiota and the C/EBPβ/AEP signaling pathway. Conclusion This study uncovers the mechanism by which BYHWD improves cognitive deficits and neuropathological changes in 3×Tg mice via the gut–brain axis, mediated by the modulation of the gut microbiota‐C/EBPβ/AEP signaling pathway, providing a novel therapeutic strategy for AD.