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

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.