Regulating gut-brain homeostasis by vitamin B12 to resist stroke

Ischemic stroke is one of the leading causes of death in the United States and is a major culprit for eliciting critical disability in veterans whereby the subsequent ailments can result in traumatic brain injury, potentially manifesting in severe neurodegenerations. No efficacious therapy is currently available to translate into clinical settings. We conspicuously demonstrated that stroke-induced inflammation deteriorated ileal epithelium homeostasis and gut dysbiosis. Stroke also critically reduced regulatory T cells (Tregs) and significantly recruited pathogenic IL17 gd T cells implicated in tissue damage. Intriguingly, vitamin B12 (VB12) functionally sustained ileal epithelia cells (iECs), Tregs and microglia to synergistically protect against pathological inflammation. Thus, controlling stroke-induced inflammation through VB12-dependent intervention may constitute a critical therapeutic regimen to mitigate toxic inflammation and improve the host recovery. To investigate these dovetailing lines of inquiry, the objective of the proposed studies is to mechanistically elucidate VB12 interplay in functionally rewiring iECs, Tregs and the microbiome to synergistically control stroke-associated intestinal and neuroinflammation, potentially improving host neurobehavior poststroke. The hypothesis is that VB12 molecularly coordinates the intestinal and cerebral cellular homeostasis to crucially limit stroke-associated inflammation and significantly contributes to swift host recovery. The specific aims are: 1) Elucidate VB12- dependent regulation of iECs during stroke-induced inflammation, 2) Delineate VB12 significance in functionally sustaining ileal Tregs to control gut homeostatic response to induced stroke, and 3) Elaborate on VB12 interplay in supporting brain Tregs to limit stroke-associated neuroinflammation and improve the host recovery thereafter. The predicted outcomes of these preclinical studies will underscore VB12-dependet mechanisms involved in alleviating and improving the host recovery post stroke. Project Number: 1I01BX006310-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Mansour Zadeh | Institution: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM, SAN ANTONIO, TX | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 GAST-L (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/10916839