Microbial Adaptation in Healthy Ageing: Insights from Age-associated Structural Variation in the Human Gut Microbiome

Microbial Adaptation in Healthy Ageing: Insights from Age-associated Structural Variation in the Human Gut Microbiome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Microbial Adaptation in Healthy Ageing: Insights from Age-associated Structural Variation in the Human Gut Microbiome Jingyuan Fu, Yue Zhang, Daria Zhernakova, Ranko Gacesa, Sergio Andreu-Sánchez, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5633858/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In this metagenome-wide association study, we profiled 14,249 structural variants (SVs) in the gut microbiome of 10,215 individuals from five cohorts (four European and one African). This revealed 105 SVs that exhibited replicable associations with host chronological age across the different cohorts, with Oscillibacter sp. ER4 and Alistipes shahii emerging as key species. A comparison of 1,921 metagenome-assembled genomes (MAGs) of Oscillibacter sp. ER4 revealed a clade enriched in older individuals that was characterized by depletion of genes related to biotin and phenylalanine metabolism. When zooming in from age-associated SVs and MAGs to gene-level content, we identified 430 bacterial genes whose abundances were associated with both age and at least one of 111 health-related metrics. Focusing on the Frailty Index (FI) as a healthy ageing index, we identified association for 281 genes from age-associated SVs and 834 gene families from non-age-associated SVs. Based on their relationships with age and FI, they can be classified as displaying either a geroprotective or geropathogenic pattern. In particular, our data indicate that gut microbes are likely to acquire genes or gene families whose abundance is associated with good health, e.g. a low FI. The abundances of these genes were also positively linked to plasma concentrations of health-beneficial metabolites, including indole derivatives and thiamine. However, we observed acquisition of very few gene families whose abundance linked with poor health in older individuals. Our findings underscore the gut microbiome’s genetic adaptation and microbial functional resilience during ageing, which may confer resistance to the decline in host physiological status. Health sciences/Medical research Biological sciences/Microbiology gut microbiome structural variation metagenomic assembled genomes age healthy ageing Full Text Additional Declarations Yes there is potential Competing Interest. Competing interests RKW acted as a consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring, and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. MGN is a scientific founder of TTxD, Biotrip, Lemba and Salvina. All other authors declare no competing interests. Supplementary Files SupplementaryfiguresR1.pdf Supplementary Figures Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5633858","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":491948343,"identity":"a89d1f5c-8c51-4e33-8d20-f399fe8af1e4","order_by":0,"name":"Jingyuan 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