Gut Microbial Composition and Short-Chain Fatty Acid Metabolism in Cognitively Unimpaired Adults Stratified by Amyloid-β Status

D. M. Sithara Dissanayaka; Thilini N. Jayasinghe; Hamid R. Sohrabi; S. R. Rainey-Smith; Kevin Taddei; Colin L. Masters; Ralph N. Martins; W. M. A. D. Binosha Fernando

doi:10.3390/biom16010018

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Gut Microbial Composition and Short-Chain Fatty Acid Metabolism in Cognitively Unimpaired Adults Stratified by Amyloid-β Status

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Gut Microbial Composition and Short-Chain Fatty Acid Metabolism in Cognitively Unimpaired Adults Stratified by Amyloid-β Status

D. M. Sithara Dissanayaka, Thilini N. Jayasinghe, Hamid R. Sohrabi, S. R. Rainey-Smith, Kevin Taddei, Colin L. Masters, Ralph N. Martins and W. M. A. D. Binosha Fernando

Biomolecules (Basel, Switzerland), Vol.16(1), 18

2025

DOI: https://doi.org/10.3390/biom16010018

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Abstract

Short-chain fatty acids (SCFAs)

Gut microbiome

Amyloid-β (Aβ) pathology

Shotgun metagenomics

Preclinical Alzheimer’s disease

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.

Details

Title: Gut Microbial Composition and Short-Chain Fatty Acid Metabolism in Cognitively Unimpaired Adults Stratified by Amyloid-β Status
Authors/Creators: D. M. Sithara Dissanayaka - Edith Cowan University
Thilini N. Jayasinghe - The University of Sydney
Hamid R. Sohrabi - Murdoch University
S. R. Rainey-Smith - Murdoch University
Kevin Taddei - Australian Alzheimer’s Research Foundation
Colin L. Masters - The University of Melbourne
Ralph N. Martins - Edith Cowan University
W. M. A. D. Binosha Fernando - Edith Cowan University
Publication Details: Biomolecules (Basel, Switzerland), Vol.16(1), 18
Publisher: MDPI
Identifiers: 991005849682307891
Murdoch Affiliation: School of Psychology; Centre for Healthy Ageing; Health Futures Institute
Language: English
Resource Type: Journal article

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