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Cited by 75Gut microbiota and healthNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

The DOI matches its Crossref record; 222 of the 222 references it cites were found in a registry or an index.

Gut microbiota-driven neuroinflammation in Alzheimer's disease: from mechanisms to therapeutic opportunities

Open access
Lei, Wenhui, Cheng, Yiwen, Liu, Xia, Gao, Jie, Zhu, Zhangcheng, Ding, Wenwen, Xu, Xiaocui, Li, Yating, Ling, Zongxin, Jiang, Ruilai, Chen, Xiaoying·2025·Frontiers in Immunology
DOI 10.3389/fimmu.2025.1582119PMC PMC12241022
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Abstract

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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Figure 1 Neuroinflammation and its feedback loops in Alzheimer’s disease. In the context of brain injury, pathological signals such as amyloid-beta (Aβ) and tau proteins can activate resting microglia and astrocytes. This activation triggers the release of pro-inflammatory cytokines and the activation of the complement system, which contributes to neuronal damage. In turn, the damaged neurons release more Aβ and tau, promoting their aggregation into amyloid plaques (NPs) and neurofibrillary tangles (NFTs). These pathological products serve as signals of neuronal injury, initiating a positive feedback loop that further exacerbates neurodegeneration.
Figure 1 Neuroinflammation and its feedback loops in Alzheimer’s disease. In the context of brain injury, pathological signals such as amyloid-beta (Aβ) and tau proteins can activate resting microglia and astrocytes. This activation triggers the release of pro-inflammatory cytokines and the activation of the complement system, which contributes to neuronal damage. In turn, the damaged neurons release more Aβ and tau, promoting their aggregation into amyloid plaques (NPs) and neurofibrillary tangles (NFTs). These pathological products serve as signals of neuronal injury, initiating a positive feedback loop that further exacerbates neurodegeneration.CC BY · PubMed Central
Figure 2 Schematic diagram illustrating the regulatory mechanism of gut dysbiosis in AD neuroinflammation. In AD, gut dysbiosis triggers immune responses and the production of harmful metabolites, including lipopolysaccharides (LPS), amyloid, Bile acids (BAs), and trimethylamine N-oxide (TMAO). These metabolites disrupt the integrity of the intestinal mucosal barrier, allowing LPS to enter systemic circulation. This, in turn, promotes systemic inflammation and activates microglia via the microbiota-gut-brain axis (MGBA). Additionally, amyloid accumulation accelerates the formation of neuronal amyloid plaques by enhancing immune system activity. Elevated levels of BAs and TMAO are associated with increased brain Aβ concentrations, while the interaction between TMAO and tau pathology may further intensify neuroinflammation, contributing to AD progression in the brain.
Figure 2 Schematic diagram illustrating the regulatory mechanism of gut dysbiosis in AD neuroinflammation. In AD, gut dysbiosis triggers immune responses and the production of harmful metabolites, including lipopolysaccharides (LPS), amyloid, Bile acids (BAs), and trimethylamine N-oxide (TMAO). These metabolites disrupt the integrity of the intestinal mucosal barrier, allowing LPS to enter systemic circulation. This, in turn, promotes systemic inflammation and activates microglia via the microbiota-gut-brain axis (MGBA). Additionally, amyloid accumulation accelerates the formation of neuronal amyloid plaques by enhancing immune system activity. Elevated levels of BAs and TMAO are associated with increased brain Aβ concentrations, while the interaction between TMAO and tau pathology may further intensify neuroinflammation, contributing to AD progression in the brain.CC BY · PubMed Central
Figure 3 Schematic diagram illustrating the therapeutic potential of gut microbiota in AD neuroinflammation. Interventions targeting gut microbiota (such as probiotics, prebiotics, synbiotics, postbiotics, and FMT) have been shown to restore the gut microbiota imbalance commonly found in AD patients. These interventions are linked to increased production of short-chain fatty acids (SCFAs), improved intestinal mucosal barrier function, reduced levels of pro-inflammatory factors, and enhanced intestinal neurotransmitters. By correcting the gut dysbiosis and modulating the gut-brain axis, these treatments have been shown to improve the neuropathological status of AD. This is reflected in enhanced cognitive function, reduced activation of neural cells, and a significant decline in amyloid-beta (Aβ) and tau protein levels, ultimately helping to alleviate AD-related neuroinflammation.
Figure 3 Schematic diagram illustrating the therapeutic potential of gut microbiota in AD neuroinflammation. Interventions targeting gut microbiota (such as probiotics, prebiotics, synbiotics, postbiotics, and FMT) have been shown to restore the gut microbiota imbalance commonly found in AD patients. These interventions are linked to increased production of short-chain fatty acids (SCFAs), improved intestinal mucosal barrier function, reduced levels of pro-inflammatory factors, and enhanced intestinal neurotransmitters. By correcting the gut dysbiosis and modulating the gut-brain axis, these treatments have been shown to improve the neuropathological status of AD. This is reflected in enhanced cognitive function, reduced activation of neural cells, and a significant decline in amyloid-beta (Aβ) and tau protein levels, ultimately helping to alleviate AD-related neuroinflammation.CC BY · PubMed Central

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Metadata

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
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2025-06-26
Volume
16
Pages
1582119-1582119
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2025.1582119
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
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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