Gut microbiota-driven neuroinflammation in Alzheimer's disease: from mechanisms to therapeutic opportunities
Open accessAbstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, tau hyperphosphorylation, and chronic neuroinflammation. While neuroinflammation—mediated by microglial and astrocyte activation—has long been considered a secondary response to Aβ pathology, emerging evidence positions it as a primary driver of cognitive decline. Notably, the gut microbiota, through the microbiota-gut-brain axis (MGBA), is crucial in modulating neuroinflammation. Dysbiosis disrupts gut barrier integrity, promotes systemic inflammation, and exacerbates neuroinflammatory responses, thereby accelerating AD progression. Recent advances reveal that gut microbiota-derived metabolites (e.g., short-chain fatty acids, lipopolysaccharides) directly influence microglial activation and Aβ aggregation. These findings have opened new therapeutic possibilities, with microbiota-targeted approaches such as probiotics, prebiotics, and fecal microbiota transplantation demonstrating promising neuroprotective effects in preclinical studies by reducing neuroinflammation and preserving cognitive function. However, translating these findings into clinical applications requires further validation through randomized controlled trials. This review summarizes the current understanding of gut microbiota-driven neuroinflammation in AD, from molecular mechanisms to potential therapeutic strategies. Targeting the MGBA represents a paradigm shift in AD management, emphasizing the modulation of neuroinflammation and pathological progression through gut microbiota interventions. The discussion also addresses existing research challenges and outlines future directions to advance this promising field.
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Gut microbes regulate blood-brain barrier integrity.
“Germ-free mice have higher BBB permeability, which is restored by normal microbiota, indicating that gut microbes regulate BBB integrity.”
From Progress on the correlation between sepsis and gut microbiota: a narrative review (2026) · cites this paper as Lei et al., 2025
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- Authors
- Lei, W., Cheng, Y., Liu, X., Gao, J., Zhu, Z., Ding, W., Xu, X., Li, Y., Ling, Z., Jiang, R., & Chen, X.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Wenzhou Medical University (CN)
- Nantong University (CN)
- Corresponding author
- Ling, Zongxin
- Jiang, Ruilai
- Chen, Xiaoying
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2025-06-26
- Volume
- 16
- Pages
- 1582119-1582119
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC12241022
- OpenAlex
- W4411664782
- Cited by
- 68
- References
- 222
- Citations by year
- 2026: 60 · 2025: 8
- FWCI
- 6.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases
- Fundamental Research Funds for the Central Universities (2022ZFJH003)
- Natural Science Foundation of Zhejiang Province (LQ24H090005)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, gut microbiota, neuroinflammation, microbiota-gut-brain axis, dysbiosis, intestinal barrier integrity, short-chain fatty acids, lipopolysaccharide, microglial activation, amyloid-beta aggregation, tau hyperphosphorylation, probiotics, prebiotics, fecal microbiota transplantation, cognitive decline
- MeSH terms
- Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Brain-Gut Axis, Neuroinflammatory Diseases, Alzheimer Disease, Animals, Brain, Humans, Probiotics, Dysbiosis
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