Author Identifier (ORCID)
Stephanie R. Rainey-Smith: https://orcid.org/0000-0001-7328-9624
Kevin Taddei: https://orcid.org/0000-0002-8106-7957
Ralph Martins: https://orcid.org/0000-0002-4828-9363
W. M.A.D.Binosha Fernando: https://orcid.org/0000-0002-8364-7808
Abstract
Short-chain fatty acids (SCFAs) produced by gut microbial fermentation influence host metabolism and neuroinflammatory processes implicated in Alzheimer’s disease (AD). However, the relationship between fecal SCFAs, microbial taxa, and cerebral amyloid-β (Aβ) burden in cognitively unimpaired individuals remains unclear. Fecal SCFAs were quantified using GC-MS, and microbial species were profiled by shotgun metagenomics in 87 participants. Associations between SCFAs, demographics, APOE ε4 status, and Aβ burden were tested using nonparametric statistics and multivariable regression. Microbial–SCFA links were evaluated using Spearman correlations and multivariate ordinations, with mediation analysis exploring potential indirect pathways. Acetate was the predominant SCFA and demonstrated the most robust microbial associations. Higher acetate concentrations were positively associated with Bacteroides ovatus and Faecalibacterium prausnitzii, whereas lower acetate levels were linked to species such as Bifidobacterium animalis and Lachnoclostridium scindens. Stratified analyses indicated that individuals with elevated Aβ burden exhibited more pronounced species–SCFA relationships, including a notable association between Bacteroides thetaiotaomicron and butyrate. Multivariate ordination further identified a significant overall coupling between SCFA profiles and microbial community structure. Mediation analysis suggested that an Oscillospiraceae species may represent a potential intermediary linking valerate concentrations with Aβ status. SCFA concentrations were not strongly influenced by demographic or genetic factors, but specific species demonstrated robust associations with acetate levels. Distinct SCFA–microbial interaction patterns in Aβ High individuals suggest subtle early gut microbial alterations linked to amyloid burden. These findings highlight the potential role of SCFA-related microbial pathways in preclinical AD.
Document Type
Journal Article
Date of Publication
1-1-2026
Volume
16
Issue
1
PubMed ID
41594560
Publication Title
Biomolecules
Publisher
MDPI
School
Centre of Excellence for Alzheimer's Disease Research and Care / School of Medical and Health Sciences
Funders
Delite Agro Polymers PVT–Industrial Scholarship, Alzheimer’s Research Australia, Western Australia and Edith Cowan University, Western Australia (G1005890)
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Dissanayaka, D. M. S., Jayasinghe, T. N., Sohrabi, H. R., Rainey-Smith, S. R., Taddei, K., Masters, C. L., Martins, R. N., & Fernando, W. M. A. D. B. (2025). Gut microbial composition and short-chain fatty acid metabolism in cognitively unimpaired adults stratified by amyloid-β status. Biomolecules, 16(1). https://doi.org/10.3390/biom16010018