Longitudinal changes in the gut microbiome following a multidomain lifestyle intervention in older adults at risk of dementia: an exploratory sub-study of the SUPERBRAIN trial

Multidomain lifestyle interventions may improve cognitive function in older adults at risk of dementia, but their effects on the gut microbiome remain unclear. We investigated longitudinal changes in the gut microbiome following a multidomain lifestyle intervention, examined their associations with clinical outcomes, and evaluated whether baseline microbiome features could predict intervention responsiveness in an exploratory sub-study of the 24-week SUPERBRAIN (SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at-risk elderly people) trial. A total of 130 older adults aged 60–79 years with at least one modifiable dementia risk factor and without overt dementia were included (91 in the multidomain intervention [MI] group and 39 controls). Participants in the MI group underwent a 24-week multidomain lifestyle intervention. Stool samples collected at baseline and week 24 underwent 16S rRNA gene sequencing. Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Longitudinal changes in gut microbiome composition and predicted microbial functional profiles were evaluated, and their associations with clinical outcomes were examined. Baseline microbiome and clinical features were also assessed for their ability to predict intervention responsiveness, defined as ΔRBANS > 0. Compared with controls, the MI group showed greater improvement in RBANS Total Scale Index scores ( P < 0.001). Observed amplicon sequence variant (ASV) richness and inverse Simpson diversity decreased from baseline to week 24 within the MI group ( P = 0.027 and P = 0.039, respectively), but not within the control group ( P = 0.464 and P = 0.812, respectively). Weighted UniFrac beta diversity showed a significant longitudinal shift within the MI group ( P < 0.001), but not within the control group ( P = 0.193). The dysbiosis index also decreased within the MI group (P < 0.001), consistent with a shift toward the healthy reference microbiome configuration, whereas no significant change was observed in the control group (P = 0.372). Integrated analyses identified 19 genera showing directionally consistent changes in the MI group, including enrichment of short-chain fatty acid (SCFA)-producing genera (e.g., Faecalibacterium and Butyrivibrio ) and reductions in members of the Enterobacteriaceae family. Longitudinal changes in several microbial genera were associated with changes in clinical outcomes. An exploratory machine-learning model combining baseline microbiome and clinical features achieved an area under the receiver operating characteristic curve (AUC) of 0.83 for predicting intervention responsiveness, with baseline Short Physical Performance Battery (SPPB) score and Eubacterium abundance emerging as the strongest contributors. Multidomain lifestyle intervention was associated with longitudinal remodeling of the gut microbiome in older adults at risk of cognitive decline. Baseline microbiome composition also showed potential as an exploratory predictor of intervention responsiveness. Larger studies incorporating multi-omics approaches and independent validation cohorts are warranted to confirm these findings and clarify the biological mechanisms underlying these associations. ClinicalTrials.gov, NCT03980392. Registered 10 June 2019.