Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia, accounting for approximately 60–70% of dementia cases worldwide. It is characterized by progressive cognitive decline, memory impairment, and behavioral disturbances, placing a substantial burden on patients, caregivers, and healthcare systems. With the global prevalence of dementia expected to increase from 50 million to 131 million by 2050, identifying effective disease-modifying therapies has become a major research priority. 1,2 Although the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles remains the hallmark of AD pathology, increasing evidence suggests that oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired autophagy also play critical roles in disease progression. 2,3 Unfortunately, therapies targeting Aβ and tau have shown limited success in halting disease progression, prompting interest in alternative therapeutic strategies.4 

Recent research has highlighted the microbiota–gut–brain axis as an important regulator of brain health and neurodegeneration. Gut microbiota communicate with the central nervous system through immune, endocrine, metabolic, and neural pathways, thereby influencing cognitive function and neuroinflammation.5 Dysbiosis of the gut microbiota increases intestinal permeability and promotes the release of inflammatory mediators into the circulation, resulting in microglial activation and enhanced Aβ pathology.6 Clinical studies have reported increased abundance of Proteobacteria and reduced levels of beneficial bacteria such as Firmicutes and Bifidobacterium in patients with AD, suggesting that alterations in gut microbial composition contribute to disease development.7 Furthermore, germ-free APP/PS1 mice exhibit significantly reduced Aβ deposition, while recolonization with normal microbiota restores amyloid pathology, providing strong evidence for the involvement of gut microbes in AD progression.8 

Natural polysaccharides have attracted increasing attention because of their antioxidant, anti-inflammatory, and prebiotic properties. Among them, Eucommiae cortex polysaccharides (EPs), isolated from Eucommia ulmoides Oliver, have demonstrated considerable neuroprotective potential. Previous studies have shown that EPs improve gut microbial composition, suppress pathogenic bacteria such as Escherichia coli, reduce circulating lipopolysaccharide (LPS), and attenuate neuroinflammation.9 EPs have also been reported to regulate the kynurenine pathway, lowering hippocampal glutamate and quinolinic acid levels, thereby protecting neurons against excitotoxicity.9 In addition, EP supplementation alleviates oxidative stress and depressive-like behaviors while restoring gut microbial homeostasis in animal models, supporting its role as a natural prebiotic.10,11 

The reviewed study further expands these findings by demonstrating that EPs alleviate AD pathology through modulation of the microbiota–gut–brain axis. Dietary supplementation with EPs significantly improved learning and memory deficits in AD mice and reduced cerebral Aβ deposition. Mechanistically, EPs selectively enriched butyrate-producing gut bacteria, leading to increased production of butyrate, a short-chain fatty acid with well-established anti-inflammatory and neuroprotective functions. Butyrate regulated brain glutamate metabolism, thereby reducing glutamate-mediated excitotoxicity, decreasing oxidative stress, and promoting autophagy. These coordinated effects restored neuronal homeostasis and improved cognitive performance in AD mice. 

A major strength of the study is the use of fecal microbiota transplantation (FMT) and butyrate supplementation to validate the proposed mechanism. Transfer of microbiota from EP-treated mice reproduced many of the neuroprotective effects observed with EP supplementation, while direct butyrate administration similarly improved cognitive function. These findings demonstrate that the beneficial effects of EPs are largely mediated through gut microbiota and their metabolites rather than through direct pharmacological action alone. 

The study also emphasizes the therapeutic importance of oxidative stress and autophagy in AD. Excessive reactive oxygen species (ROS) contribute to mitochondrial dysfunction, protein aggregation, and neuronal death, whereas autophagy facilitates the clearance of damaged organelles and misfolded proteins. EP-mediated enhancement of autophagy, together with reduced oxidative stress, provides a favorable brain microenvironment that limits amyloid accumulation and neuronal degeneration.3,12 This multitarget mechanism distinguishes EPs from conventional therapies that primarily focus on single pathological pathways. 

Despite these promising findings, several limitations remain. The current evidence is derived from animal models, and the therapeutic efficacy of EPs in humans has not yet been established. Variability in human gut microbiota, dietary habits, and genetic background may influence treatment outcomes. Therefore, well-designed clinical trials are needed to evaluate the safety, optimal dosage, and long-term effectiveness of EP supplementation in patients with Alzheimer’s disease. 

In conclusion, Eucommiae cortex polysaccharides represent a promising microbiota-targeted therapeutic strategy for Alzheimer’s disease. By remodeling gut microbiota, enhancing butyrate production, regulating glutamate metabolism, reducing oxidative stress, promoting autophagy, and suppressing Aβ deposition, EPs improve cognitive function in experimental AD models. These findings strengthen the concept that modulation of the microbiota–gut–brain axis using natural polysaccharides may offer a novel, multi-targeted approach for the prevention and treatment of Alzheimer’s disease. 

References 

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