Brain-gut crosstalk associated with brain ageing in young and mid-life adults: a multicohort cross-sectional study

Kanhao Zhao and colleagues evaluated a functional-connectivity brain-aging index in three cohorts. The discovery cohort included 674 adults, the replication cohort 444, and an independent multi-omics cohort 344. The index was the age-bias-corrected difference between predicted and chronological brain age. Higher brain-age deviation was consistently associated with connectivity patterns involving the posterior cingulate, precuneus, and medial frontal regions. It was also associated with poorer working memory and executive function and with more depressive symptoms. In the independent cohort, stool metagenomic and metabolomic profiles were integrated with the brain-age measure. Ceramides, 24-hydroxycholesterol, dicarboxylic acids, and other features were linked to the index. Pathway enrichment pointed to neuroimmune, vascular, synaptic, and mitochondrial biology. This is a useful biomarker and mechanism-generating study. It is not a probiotic trial, a dietary intervention, or evidence that changing gut metabolites will reverse brain aging. The cohorts were cross-sectional, so reverse causation and residual confounding are possible. Brain-age models can also encode technical and population biases. Any longevity claim requires longitudinal and randomized intervention studies with cognitive and functional endpoints.

These findings suggest that BAI captures individual variability associated with brain health-related phenotypes and support the potential association of peripheral brain-gut biological pathways in early brain ageing.