Microbial phenolic metabolites at the neurovascular interface: a precision-nutrition framework for brain aging

Brain aging is increasingly recognized as a neurovascular and inflammatory process involving blood-brain barrier dysfunction, endothelial activation, pericyte impairment, astrocyte-microglia reactivity, oxidative stress, white matter vulnerability, and cognitive decline. Although polyphenol-rich diets are widely associated with brain-health benefits, many parent polyphenols have limited systemic bioavailability, suggesting that gut microbiota-derived microbial phenolic metabolites may represent more biologically relevant circulating exposures. However, systemic MPM exposure is also conditioned by intestinal barrier integrity, which may change with aging and determine the magnitude, timing, and inflammatory context of metabolite entry into the circulation. This Mini Review examines microbial phenolic metabolites as proximate mediators at the blood-brain barrier and neurovascular unit, rather than as indirect extensions of parent dietary polyphenols. We synthesize human and translational evidence linking urinary and plasma microbial phenolic metabolites, including phenyl-γ-valerolactones, urolithins, enterolignans, phenolic acids, and conjugated metabolites, with exposure assessment, brain-adjacent detection, and cognitive aging phenotypes. We also review mechanistic evidence showing that low-molecular-weight phenolic metabolites can cross blood-brain barrier models, modify endothelial barrier integrity, influence tight-junction and adherens-junction organization, and attenuate inflammatory signaling in endothelial and microglial systems. Building on this evidence, we propose a hypothesis-generating gut-barrier-MPM-BBB/NVU response modelmodel in which diet-derived MPMs may be linked to brain-aging resilience through candidate effects on blood-brain barrier preservation, endothelial inflammatory restraint, pericyte and glial support, and downstream cognitive outcomes. Finally, we outline a pathology-informed precision-nutrition framework integrating dietary assessment, urine/plasma metabolomics, fecal microbial enzyme capacity, intestinal permeability markers, neurovascular biomarkers, imaging readouts, and cognitive testing to identify potential neurovascular responder metabotypes.