Nutritional Modulation of the Endogenous Antioxidant System in the Brain–Gut Axis Following Traumatic Brain Injury

<b>Background/Objectives:</b> Traumatic brain injury (TBI) disrupts both the intestinal epithelium and blood-brain barrier (BBB), contributing to oxidative stress, neuroinflammation, and behavioral impairments. <i>Vitis vinifera</i> leaf (VVL) extract possesses antioxidant and anti-inflammatory properties, but its protective effects on the brain-gut axis following TBI remain unclear. This study aimed to evaluate whether VVL supplementation preserves barrier integrity and improves neurobehavioral outcomes after TBI. <b>Methods:</b> A murine model of TBI was used, with animals receiving daily oral supplementation of the VVL extract. Neurobehavioral performance was assessed through behavioral testing, while histopathological examinations, biochemical assays, and gene expression profiling were performed to evaluate neuronal and intestinal integrity, antioxidant defense, and inflammatory responses. <b>Results:</b> VVL supplementation significantly alleviated anxiety- and depression-like behaviors and preserved the structural integrity of neuronal and intestinal tissues. Antioxidant defense mechanisms were strengthened, as shown by increased catalase and superoxide dismutase activities, together with upregulation of Nrf2 and HO-1 expression. Tight junction proteins, including ZO-1 and occludin, were upregulated in both brain and gut tissues, reflecting improved barrier integrity. Furthermore, VVL markedly reduced pro-inflammatory cytokine expression. <b>Conclusions:</b> VVL extract confers dual protection of the gut and brain barriers after TBI by enhancing endogenous antioxidant defenses, maintaining tight junction integrity, and suppressing inflammation. These findings suggest that VVL may represent a natural therapeutic strategy to mitigate oxidative stress, neuroinflammation, and behavioral dysfunctions associated with TBI.