Abstract INTRODUCTION Individuals with similar white matter hyperintensities (WMH) burden show heterogeneous cognitive outcomes, yet the biological mechanisms underlying this variability remain incompletely understood. METHODS We integrated 16S rDNA sequencing, untargeted metabolomics, and multi‐modal magnetic resonance imaging (MRI) to comprehensively characterize gut microbiome, plasma metabolome, and brain glymphatic function in 56 healthy controls, 40 WMH with normal cognition (WMH‐NC), and 49 WMH with cognitive impairment (WMH‐CI). RESULTS Group comparisons revealed differences in six bacterial genera, three plasma metabolites, and five glymphatic markers across three groups, with Acetivibrio , 1,5‐naphthalenediamine, beta‐uridine, free water fraction within the white matter, and index of diffusivity along the perivascular spaces (ALPS index) showing differences between WMH‐CI and WMH‐NC. Correlation and mediation analyses demonstrated associations between microbiota and cognition, mediated by tetradecyldiethanolamine and ALPS index. DISCUSSION These findings provide preliminary insights into plausible microbiota‐metabolites‐glymphatic function‐cognition associations in WMH, potentially informing more targeted interventions for vascular cognitive impairment.
Xu et al. (Sun,) studied this question.