Reshaping the gut microbiota: A novel oppinion of Eucommiae cortex polysaccharide alleviate learning and memory impairments in Alzheimer’s disease

• Eucommia cortex polysaccharide (EPs) alleviate learning and memory deficits in Alzheimer's disease via the gut-brain axis. • EPs ameliorate Alzheimer's disease by remodeling gut microbiota are revealed. • Expansion of short-chain fatty acid-metabolizing bacteria in the gut microbiota is associated with omprovement in Alzheimer's disease by EPs. • Short-chain fatty acids metabolized by gut microbiota modulate glutamine synthase activity as an important mediator of EPs ameliorating Alzheimer's disease. • EPs can alleviate the brain microenvironment in Alzheimer's diaease and inhibit β-amyloid formation and deposition via the gut-brain axis. Alzheimer’s disease (AD), which is a chronic neurodegenerative disorder, is marked by the progressive deteriorations in learning and memory capabilities. The microbiota-gut-brain axis has come to be regarded as a crucial element in relation to the pathogenesis as well as the treatment of AD. Eucommiae cortex polysaccharides (EPs), being among the most plentiful substances present in the Eucommiae cortex, show the potential to exert immunomodulatory and neuroprotective function. However, whether EPs are protective against AD and their mechanism of action remain to be investigated We hypothesize that EPs can regulate brain glutamine metabolism through gut microbiota and the butyric acid metabolized by them, improve oxidative stress and autophagy in the brain, and thus alleviate AD. In the present study, we used EPs (0.25 % w/w in food) and fecal microbiota transplantation, as well as butyrate supplementation (0.1 M in water), to intervene in AD mice. Multi-omics were used to determine the mechanism by which EPs improve AD-related learning and memory impairments. Our results suggest that EPs, functioning as a prebiotic, alleviated learning and memory impairments in AD mice. Mechanistically, EPs are able to reshape the gut microbiota, promote the growth of gut microbiota involved in short-chain fatty acid metabolism, particularly butyrate-producing microbes. The butyrate produced by these microbes improves the brain microenvironment by modulating oxidative stress and autophagy mediated by brain glutamate metabolism, improving learning and memory impairments in AD mice, and inhibiting the formation and deposition of beta-amyloid proteins. Fecal microbiota transplantation (FMT) and butyrate supplementation further confirm this conclusion. Our results highlighted that EPs can alleviate learning and memory impairments in AD with a gut microbiota-dependent manner and that butyric acid metabolized by butyric acid-metabolizing bacteria in the gut plays a central role in regulating brain glutamine metabolism to improve brain microenvironmental homeostasis. Meanwhile, the present study provides new insights into the treatment of AD with natural products.