Brain health and the gut microbiome (bMicrobiome Study): a proof-of-concept, feasibility study integrating shotgun metagenomics, metrology, and multidimensional phenotyping across the cognitive aging spectrum

<h4>Background</h4>Associations between the gut microbiome and cognitive decline remain inconsistent, reflecting methodological variability, small cohorts, and limited integration of behavioral and lifestyle factors. The microbiota-gut-brain axis may influence cognition through metabolic, immune, and neuroendocrine pathways affecting mood, decision-making, and health behaviors.<h4>Methods</h4>This prospective, proof-of-concept study integrated multidimensional phenotyping with metagenomic sequencing (shotgun) in adults (50-90 y) around Washington, DC. Participants were classified as healthy controls (HC) or mild cognitive impairment (MCI) by clinical history; early Alzheimer's disease (eAD) participants were unable to complete study requirements. Longitudinal assessment used Boston Cognitive Assessment (BoCA), patient-reported outcomes (PROMIS-29), dietary intake and quality (DietID™), readiness-for-change (adapted URICA), at-home stool sample collection.<h4>Results</h4>Seventeen participants completed sufficient assessments (HC <i>n</i> = 11; MCI <i>n</i> = 6). Substantial overlap in gut microbiome composition was observed between HC and MCI. Poorly characterized or uncommon taxa drove trends; unassigned taxa were common. Assessment revealed high diet quality and variability in dietary patterns and key components (vegetables, whole grains, fat, fish). Participants demonstrated high readiness to engage in nutritional behavior change, with individuals with MCI reporting greater concern about maintaining changes and a stronger desire for external support.<h4>Conclusions</h4>Integrating multidimensional phenotyping with metagenomics is feasible in cognitive decline. Findings highlight biological and behavioral heterogeneity, limitations of species-level inference, and diet and behavioral readiness as modifiable contextual factors.