Oxidative Stress-Microbiota-Epigenetics Crosstalk: A Missing Link Between Cognition and Social Behavior in Metabolic and Neuropsychiatric Disorders.

Oxidative stress (OS) reflects a pathologic imbalance between excessive production of reactive oxygen species (ROS) and insufficient antioxidant defenses. Growing evidence indicates that a healthy gut microbiota (GM) is essential for regulating redox homeostasis, whereas gut dysbiosis contributes to elevated ROS levels and oxidative damage in DNA, lipids, and proteins. This redox disequilibrium initiates a cascade of cellular disturbances-including synaptic dysfunction, altered receptor activity, excitotoxicity, mitochondrial disruption, and chronic neuroinflammation-that can, in turn, impair cognitive and social functioning in metabolic and neuropsychiatric disorders via epigenetic mechanisms. In this review, we synthesize current knowledge on (1) how OS contributes to cognitive and social deficits through epigenetic dysregulation; (2) the role of disrupted one-carbon metabolism in epigenetically mediated neurological dysfunction; and (3) mechanistic links between leaky gut, OS, altered GM composition, and GM-derived epigenetic metabolites. We also highlight emerging microbiota-based therapeutic strategies capable of mitigating epigenetic abnormalities and improving cognitive and social outcomes. Understanding the OS-microbiota-epigenetic interplay may uncover new targetable pathways for therapies aimed at restoring brain and behavioral health.