{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:38:59Z","timestamp":1792795139683,"version":"4.5.0"},"reference-count":55,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Delite Agro Polymers PVT\u2013Industrial scholarship, Alzheimer\u2019s Research Australia, Western Australia and Edith Cowan University, Western Australia","award":["G1005890"],"award-info":[{"award-number":["G1005890"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Short-chain fatty acids (SCFAs) produced by gut microbial fermentation influence host metabolism and neuroinflammatory processes implicated in Alzheimer\u2019s disease (AD). However, the relationship between fecal SCFAs, microbial taxa, and cerebral amyloid-\u03b2 (A\u03b2) 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 \u03b54 status, and A\u03b2 burden were tested using nonparametric statistics and multivariable regression. Microbial\u2013SCFA 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 A\u03b2 burden exhibited more pronounced species\u2013SCFA 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 A\u03b2 status. SCFA concentrations were not strongly influenced by demographic or genetic factors, but specific species demonstrated robust associations with acetate levels. Distinct SCFA\u2013microbial interaction patterns in A\u03b2 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.<\/jats:p>","DOI":"10.3390\/biom16010018","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:30:18Z","timestamp":1766489418000},"page":"18","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Gut Microbial Composition and Short-Chain Fatty Acid Metabolism in Cognitively Unimpaired Adults Stratified by Amyloid-\u03b2 Status"],"prefix":"10.3390","volume":"16","author":[{"given":"D. M. Sithara","family":"Dissanayaka","sequence":"first","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3374-0916","authenticated-orcid":false,"given":"Thilini N.","family":"Jayasinghe","sequence":"additional","affiliation":[{"name":"The Charles Perkins Centre, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid R.","family":"Sohrabi","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"},{"name":"Centre for Healthy Ageing, Murdoch University, Murdoch, WA 6150, Australia"},{"name":"Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. R.","family":"Rainey-Smith","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"},{"name":"Centre for Healthy Ageing, Murdoch University, Murdoch, WA 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8106-7957","authenticated-orcid":false,"given":"Kevin","family":"Taddei","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3072-7940","authenticated-orcid":false,"given":"Colin L.","family":"Masters","sequence":"additional","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph N.","family":"Martins","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"},{"name":"Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW 2109, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. M. A. D. Binosha","family":"Fernando","sequence":"additional","affiliation":[{"name":"Centre of Excellence for Alzheimer\u2019s Disease Research & Care, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia"},{"name":"Alzheimer\u2019s Research Australia, Ralph and Patricia Sarich Neuroscience Research Institute, Nedlands, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","first-page":"331","article-title":"The potential role of gut-derived inflammation in multiple system atrophy","volume":"7","author":"Engen","year":"2017","journal-title":"J. Park. 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