Microbiota-derived urolithins and cortical thickness in cognitively healthy older adults: a longitudinal MRI analysis of the WAHA trial.

Cortical thickness, assessed by magnetic resonance imaging (MRI), is a biomarker of age-related neurodegeneration. Walnut ellagitannins may influence brain structure via gut microbiota-derived urolithins. We examined whether longitudinal changes in urinary urolithins are associated with concurrent changes in cortical thickness in cognitively healthy older adults. This longitudinal MRI sub-study was conducted within the Walnuts and Healthy Aging study, a two-center (Barcelona, Spain and Loma Linda, California) randomized controlled trial testing the effects of 2-year daily walnut consumption vs. a control diet on age-related health outcomes in older individuals. A subset of participants from the Barcelona center underwent structural MRI at baseline and after 2 years. Urinary urolithin concentrations were quantified by liquid chromatography-high-resolution mass spectrometry, and their changes were related to concurrent changes in cortical thickness using multivariable-adjusted linear regression models, with analyses stratified by urolithin metabotype to account for inter-individual variability. A total of 104 participants were included. Among those allocated to the walnut diet (n = 55), greater increases in urolithin A (β = 0.023 [95% CI, 0.003-0.043] per 1-SD), urolithin C (β = 0.015 [95% CI, <0.001-0.029] per 1-SD), and its glucuronide conjugate (β = 0.017 [95% CI, 0.002-0.031] per 1-SD) were associated longitudinally with preservation of cortical thickness, predominantly in right-hemisphere regions. Associations were more pronounced among metabotype B individuals. These findings provide novel clinical evidence linking microbiota-derived (poly)phenol metabolites to brain aging and support a precision nutrition framework. Trial registration: Clinical trials.gov as NCT01634841.