Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms
Open accessAbstract
BACKGROUND: Dietary fibers are metabolized by gastrointestinal (GI) bacteria into short-chain fatty acids (SCFAs). We investigated the potential role of these SCFAs in β-amyloid (Aβ) mediated pathological processes that play key roles in Alzheimer's disease (AD) pathogenesis. RESEARCH DESIGN AND METHODS: Multiple complementary assays were used to investigate individual SCFAs for their dose-responsive effects in interfering with the assembly of Aβß1-40 and Aβ1-42 peptides into soluble neurotoxic Aβ aggregates. RESULTS: We found that several select SCFAs are capable of potently inhibiting Aβ aggregations, in vitro. CONCLUSION: Our studies support the hypothesis that intestinal microbiota may help protect against AD, in part, by supporting the generation of select SCFAs, which interfere with the formation of toxic soluble Aβ aggregates.
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The microbiota is altered in CNS diseases, which aggravates the condition, and/or its modulation might prevent or improve the development and progression of CNS pathologies.
“The central hypothesis is supported by experimental and clinical evidence that the microbiota is altered in such diseases, which aggravates the condition, and/or its modulation might prevent or improve the development and progression of CNS pathologies (17, 19, 29, 33–37).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [34]
The Introduction (page not provided) associates differences in intestinal microbiota with Alzheimer’s and Parkinson’s diseases, and the Discussion (page not provided) suggests that microbiota-derived short-chain fatty acids may protect against Alzheimer’s pathology. The paper does not establish that altered microbiota aggravates CNS diseases generally; its own experiments concern amyloid aggregation in vitro, not prevention or improvement of clinical disease. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSCFAs interfere with protein-protein interactions between amyloid-β peptides, disrupting their assembly into neurotoxic oligomers, the main toxins responsible for synapse dysfunction and cognitive deficits in AD.
“It is worth noting that SCFAs interfere with protein-protein interactions between amyloid-β peptides (Aβ), thereby disrupting their assembly into neurotoxic oligomers (34), the main toxins responsible for synapse dysfunction and cognitive deficits in AD (164).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [34]
The Discussion reports that select SCFAs—particularly valeric, butyric and propionic acids—interfered with the initial Aβ protein-protein interactions needed for oligomer assembly. Results §3.1 also reports that three other SCFAs had no observable effect, so the unqualified claim about SCFAs is broader than the findings. The later claim about synapse dysfunction and cognitive deficits is attached to a different citation and is not assessed here. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSeveral brain disorders have been linked to imbalances in the microbial composition of the gut.
“several brain disorders have been linked to imbalances in the microbial composition of the gut (17, 19, 29, 33–37)”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [34]
Key neuropathological processes underlying AD might also be modulated by SCFAs.
“Accumulating evidence has demonstrated that key neuropathological processes underlying AD might also be modulated by SCFAs (25, 34, 158, 159).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [34]
SCFAs are associated with a variety of diseases such as rectal cancer, pancreatitis, abnormal energy metabolism, constipation, blood lipid metabolism, sleep disorders and Alzheimer's disease.
“Studies have found that SCFAs are associated with a variety of diseases such as rectal cancer, 174 pancreatitis, 175 abnormal energy metabolism, 176 constipation, 177 blood lipid metabolism, 178 sleep disorders 179 and Alzheimer's disease.180”
From The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options (2021) · cites this paper as [180]
Altered short-chain fatty acid production has been demonstrated in a variety of neuropathologies.
“altered SCFA production has been demonstrated in a variety of neuropathologies (19, 21, 33–35).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [34]
The Introduction describes how gut microbes produce SCFAs and discusses their possible roles in Alzheimer’s disease and other neurodegenerative conditions. The Results test SCFAs’ effects on amyloid aggregation, not whether SCFA production is altered in neuropathologies. Searches for altered SCFA production or levels found no passage demonstrating the claimed change across multiple conditions. (LLM, conf=0.75)
Experimental — accuracy not yet measuredAltered SCFA production is demonstrated in a variety of neuropathologies.
“Altered SCFA production has also been demonstrated in a variety of neuropathologies (42, 116, 127, 130, 132, 292–295).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [294]
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References 34 · Cited by 376
- Authors
- Ho, L., Ono, K., Tsuji, M., Mazzola, P., Singh, R., & Pasinetti, G. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- SHOWA Medical University (JP)
- University of Milano-Bicocca (IT)
- Corresponding author
- Pasinetti, Giulio M.
- Venue
- Expert Review of Neurotherapeutics
- Publisher
- Informa UK Limited
- Published
- 2017-11-14
- Volume
- 18
- Issue
- 1
- Pages
- 83-90
- ISSN
- 1473-7175 (ISSN-L)
- 1744-8360
- PMC
- PMC5958896
- OpenAlex
- W2766240266
- Semantic Scholar
- de9bd8f5d0e63e55e1740ea2dafbb0adda70a8b6
- Cited by
- 376
- References
- 34
- Citations by year
- 2026: 21 · 2025: 49 · 2024: 57 · 2023: 46 · 2022: 62 · 2021: 66 · 2020: 40 · 2019: 23 · 2018: 9 · 2017: 1
- FWCI
- 14.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Expert Review of Neurotherapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- National Center for Complementary and Integrative Health (P50 AT008661-01)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- short-chain fatty acids, gut microbiota, Alzheimer's disease, amyloid-beta aggregation, dietary fiber, neuroprotection, Aβ40, amyloid-beta 42, gut-brain axis
- MeSH terms
- Gastrointestinal Microbiome, Alzheimer Disease, Animals, Dietary Fiber, Fatty Acids, Volatile, Humans, Peptide Fragments, Amyloid beta-Peptides, Probiotics
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