Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily marked by cognitive decline and memory loss. As one of the leading causes of dementia worldwide, AD affects millions and places a growing burden on healthcare systems. Despite decades of research, the causes and mechanisms behind AD remain incomplete, with traditional explanations focusing mainly on the buildup of beta-amyloid plaques in the brain. However, a groundbreaking shift is occurring in Alzheimer’s research, pointing to the gut microbiota as a crucial player in the disease’s development and progression.
The Role of the Gut Microbiome in Alzheimer’s Disease
The human gut is home to trillions of microorganisms, collectively known as the gut microbiota. These microbes play essential roles in digestion, immune function, and overall health. More recently, evidence has emerged suggesting that these microorganisms and their metabolites—substances produced during microbial digestion—may also influence brain health. The connection between the gut and the brain is established through what scientists call the microbiota-gut-brain (MGB) axis. Research increasingly points to a dynamic relationship between gut microbes and Alzheimer’s disease, showing how disruptions in the gut microbiome can potentially contribute to cognitive decline and AD pathogenesis.
Recent studies have uncovered that individuals with Alzheimer’s disease often have a reduced diversity of gut microbes, which may lead to a deficiency in beneficial metabolites like short-chain fatty acids (SCFAs). SCFAs are critical for maintaining the integrity of the blood-brain barrier (BBB), which protects the brain from harmful substances. The reduction of these metabolites in AD patients is linked to increased neuroinflammation and cognitive decline. The evidence suggests that the gut microbiota is far from being just a passive player in AD; instead, it may actively influence the disease’s development.
Novel Findings from Recent Research
In a recent review of over 90 studies, researchers examined various gut-derived metabolites and their roles in AD. The findings reveal several crucial insights:
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Short-Chain Fatty Acids (SCFAs): SCFAs, primarily produced by gut bacteria during the fermentation of fiber, have been shown to support BBB integrity, reduce inflammation, and enhance synaptic plasticity. However, under certain conditions, SCFAs may paradoxically increase beta-amyloid deposition, highlighting the importance of timing and dosage in therapeutic applications.
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Tryptophan-Derived Metabolites: Metabolites such as indole-3-propionic acid (IPA), produced from the amino acid tryptophan, exhibit antioxidant and anti-inflammatory effects. These metabolites help strengthen both the intestinal and cerebral barriers. Conversely, a shift in tryptophan metabolism toward neurotoxic kynurenines, which are linked to inflammation, is associated with cognitive decline in AD.
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Trimethylamine N-Oxide (TMAO): TMAO is a microbial metabolite produced from dietary choline and L-carnitine. Elevated levels of TMAO in AD patients have been consistently linked to cognitive impairment, neuroinflammation, and an increased accumulation of beta-amyloid plaques. This metabolite appears to exacerbate endothelial dysfunction, impair blood-brain barrier function, and promote neurodegeneration.
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Secondary Bile Acids and Polyphenol Derivatives: These metabolites, derived from gut bacteria and certain foods, have neuroprotective properties. Secondary bile acids help regulate energy metabolism and lipid homeostasis, while polyphenol derivatives modulate inflammation and oxidative stress, offering new avenues for therapeutic intervention.
Implications for Alzheimer’s Disease Research and Treatment
The connection between gut microbes and Alzheimer’s disease opens up a host of new research opportunities and potential therapeutic strategies. Probiotics, prebiotics, and even fecal microbiota transplantation (FMT) are being explored as methods to restore gut microbial balance and improve cognitive function in AD patients. Preliminary studies suggest that restoring SCFA levels or adjusting tryptophan metabolism through dietary interventions could offer new ways to treat or manage AD.
Moreover, manipulating harmful metabolites like TMAO may present another potential therapeutic target. Reducing TMAO levels through diet or microbial enzyme inhibitors could help alleviate neuroinflammation and slow the progression of AD. Given the growing understanding of the gut-brain connection, researchers are now focusing on harnessing microbiome-based treatments to better manage Alzheimer’s disease.
Clinical and Translational Potential
The clinical implications of these findings are vast. Researchers are now exploring microbiota-targeted interventions, such as probiotics or prebiotics, to modulate gut microbial metabolism in AD patients. Some studies have already shown modest cognitive improvements in individuals with mild cognitive impairment (MCI) and AD following interventions aimed at improving gut microbiota composition.
Notably, a trial conducted in Italy showed that probiotic supplementation increased SCFA levels and improved cognitive function in AD patients. Similarly, fecal microbiota transplantation trials have demonstrated promise in restoring microbial diversity and improving cognitive outcomes, though more extensive studies are needed to confirm these benefits.
As research progresses, manipulating gut microbial metabolites could lead to personalized, non-invasive treatments for Alzheimer’s disease that address both the causes and symptoms of the disease.
The Path Forward
While the role of gut microbiota in AD is becoming increasingly clear, several challenges remain. Many studies rely on animal models or small-scale human trials, and their findings need to be rigorously validated in larger, more diverse populations. Moreover, the dynamic nature of the microbiota and the complexity of its interaction with the brain mean that developing standardized protocols for clinical applications will take time.
Looking ahead, researchers will need to refine multi-omics approaches, combining metabolomics, metagenomics, and transcriptomics, to better understand the interactions between gut microbes and the brain. Longitudinal studies will be crucial for identifying microbial signatures that could serve as early biomarkers of Alzheimer’s disease. With these advancements, the hope is that gut microbiota-based interventions could provide personalized treatments for AD, ultimately improving patient outcomes.
Conclusion
In conclusion, the gut microbiome and its metabolites are emerging as significant factors in the pathogenesis of Alzheimer’s disease. From influencing neuroinflammation to modulating blood-brain barrier integrity, the gut-brain axis holds untapped therapeutic potential. As research in this field progresses, microbiota-targeted interventions may offer a promising new avenue for treating and even preventing Alzheimer’s disease. The growing body of evidence underlines the importance of gut health in brain function, opening the door to innovative treatments that may one day transform the landscape of Alzheimer’s care.
The translation of the preceding English text in Chinese:
阿尔茨海默病（AD）是一种进展性的神经退行性疾病，主要表现为认知下降和记忆丧失。作为全球痴呆症的主要原因之一，阿尔茨海默病影响着数百万人，给医疗系统带来了日益增加的负担。尽管经过数十年的研究，阿尔茨海默病的病因和机制仍不完全清楚，传统的解释主要集中在大脑中β-淀粉样蛋白斑块的积累上。然而，阿尔茨海默病研究领域正在发生一场突破性的转变，研究表明肠道微生物群在该病的发展和进展中发挥着至关重要的作用。
肠道微生物群在阿尔茨海默病中的作用
人类肠道是数万亿微生物的家园，这些微生物统称为肠道微生物群。它们在消化、免疫功能和整体健康中发挥着至关重要的作用。最近的证据表明，这些微生物及其代谢产物——即微生物在消化过程中产生的物质——也可能对大脑健康产生影响。肠道与大脑之间的联系通过科学家所称的微生物群-肠道-大脑（MGB）轴建立起来。研究逐渐表明，肠道微生物与阿尔茨海默病之间存在一种动态关系，揭示了肠道微生物群的失调如何可能促使认知下降和阿尔茨海默病的发病机制。
最近的研究发现，阿尔茨海默病患者通常具有较低的肠道微生物多样性，这可能导致有益代谢物（如短链脂肪酸（SCFAs）的缺乏）。SCFAs对维持血脑屏障（BBB）的完整性至关重要，血脑屏障保护大脑免受有害物质的侵害。阿尔茨海默病患者这些代谢物的减少与神经炎症的增加和认知下降相关联。证据表明，肠道微生物群远非阿尔茨海默病中的被动参与者；相反，它可能在该病的发展中起着积极作用。
最近研究中的新发现
在最近对90多项研究的回顾中，研究人员考察了各种肠道衍生代谢物及其在阿尔茨海默病中的作用。研究结果揭示了几个关键的见解：
短链脂肪酸（SCFAs）： SCFAs主要由肠道细菌在发酵纤维过程中产生，已被证明有助于维持血脑屏障的完整性，减少炎症，并增强突触可塑性。然而，在某些情况下，SCFAs可能会悖论地增加β-淀粉样蛋白的沉积，这突显了治疗应用中时机和剂量的重要性。
色氨酸衍生代谢物： 色氨酸产生的代谢物如吲哚-3-丙酸（IPA）具有抗氧化和抗炎作用。这些代谢物有助于增强肠道和大脑屏障。相反，色氨酸代谢向神经毒性犬尿喹啉酸转变，这与阿尔茨海默病中的炎症和认知下降相关联。
三甲胺-N-氧化物（TMAO）： TMAO是从膳食胆碱和L-肉碱中产生的微生物代谢物。阿尔茨海默病患者中TMAO的水平升高与认知障碍、神经炎症和β-淀粉样蛋白斑块积累增加密切相关。这个代谢物似乎加剧了内皮功能障碍，损害血脑屏障功能，并促进神经退行性变。
二级胆汁酸和多酚衍生物： 这些代谢物来源于肠道细菌和某些食物，具有神经保护作用。二级胆汁酸有助于调节能量代谢和脂质稳态，而多酚衍生物则调节炎症和氧化应激，提供了治疗干预的新途径。
阿尔茨海默病研究与治疗的启示
肠道微生物与阿尔茨海默病之间的联系为新的研究机会和潜在的治疗策略打开了大门。益生菌、益生元，甚至粪菌移植（FMT）正被探索作为恢复肠道微生物平衡和改善阿尔茨海默病患者认知功能的方法。初步研究表明，通过饮食干预恢复SCFA水平或调整色氨酸代谢可能为治疗或管理阿尔茨海默病提供新的方式。
此外，调节有害代谢物如TMAO可能成为另一个潜在的治疗靶点。通过饮食或微生物酶抑制剂减少TMAO水平，可能有助于缓解神经炎症并减缓阿尔茨海默病的进展。随着对肠脑连接的理解不断深入，研究人员现在正着眼于利用微生物群基础的治疗方法更好地管理阿尔茨海默病。
临床和转化潜力
这些发现的临床意义巨大。研究人员现在正在探索针对微生物群的干预措施，如益生菌或益生元，以调节阿尔茨海默病患者肠道微生物代谢。一些研究已经显示，在针对改善肠道微生物组成的干预后，轻度认知障碍（MCI）和阿尔茨海默病患者的认知功能有所改善。
值得注意的是，在意大利进行的一项试验表明，益生菌补充剂可以提高SCFA水平并改善阿尔茨海默病患者的认知功能。同样，粪菌移植试验也在恢复微生物多样性和改善认知结果方面显示出希望，尽管仍需要更大规模的研究来确认这些好处。
随着研究的进展，调节肠道微生物代谢物可能会导致个性化、非侵入性的阿尔茨海默病治疗，既能解决疾病的根本原因，又能缓解其症状。
前进的道路
尽管肠道微生物群在阿尔茨海默病中的作用日益清晰，但仍然存在一些挑战。许多研究依赖于动物模型或小规模的人类试验，其结果需要在更大、更多样化的人群中进行严格验证。此外，微生物群的动态性质及其与大脑的相互作用的复杂性意味着，制定临床应用的标准化协议还需要时间。
展望未来，研究人员将需要精炼多组学方法，结合代谢组学、宏基因组学和转录组学，更好地理解肠道微生物与大脑之间的相互作用。纵向研究对于确定能够作为阿尔茨海默病早期生物标志物的微生物特征至关重要。随着这些进展的实现，人们希望基于肠道微生物群的干预能够为阿尔茨海默病提供个性化的治疗，最终改善患者的预后。
结论
总之，肠道微生物群及其代谢物正成为阿尔茨海默病发病机制中的重要因素。从影响神经炎症到调节血脑屏障的完整性，肠脑轴具有尚未开发的治疗潜力。随着这一领域研究的深入，针对微生物群的干预可能为治疗甚至预防阿尔茨海默病提供有前途的新途径。越来越多的证据突显了肠道健康在大脑功能中的重要性，为未来可能改变阿尔茨海默病护理格局的创新治疗方法打开了大门。
Reference:
Xinchen Ji, Jian Wang, Tianye Lan, Dexi Zhao, Peng Xu
Gut microbial metabolites and the brain–gut axis in Alzheimer’s disease: A review.
Biomol Biomed [Internet]. 2025 Aug. 11 [cited 2025 Dec. 4];26(2):240–250.
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12921
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