Gut-immune signaling drives blood-brain barrier damage in pediatric allogeneic stem cell transplant

Davies, M. R.; Cross, C. B.; Ryan, F. R.; Yu, L.; Dorraki, M.; Greenberg, Z.; Salter, A.; Williams, C. M.; Li, A.; Zannettino, A. C.; Bonder, C. S.; Bardy, C.; Wardill, H. R.

doi:10.64898/2026.08.17.745172

bioRxiv · 10.64898/2026.08.17.745172

Gut-immune signaling drives blood-brain barrier damage in pediatric allogeneic stem cell transplant

Davies, M. R.·Cross, C. B.·Ryan, F. R.·Yu, L.·Dorraki, M.·Greenberg, Z.·Salter, A.·Williams, C. M.·Li, A.·Zannettino, A. C.·Bonder, C. S.·Bardy, C.·Wardill, H. R.

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Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving therapy for children with high-risk hematological diseases. However, allo-HSCT also confers the risk of long-term neurocognitive dysfunction, particularly in pediatric recipients, and the mechanisms underlying this remain poorly understood. While gastrointestinal toxicities and immune responses following allo-HSCT have been well characterized, their contribution to central nervous system toxicities is unknown. Here, using clinical biomarker analysis, we show evidence of blood-brain barrier (BBB) dysfunction in pediatric allo-HSCT, associated with IL-6 signaling and reduced levels of brain-derived neurotrophic factor. Pre-transplant gastrointestinal mucosal barrier injury was associated with post-transplant BBB leakage, implicating disrupted gut-brain-axis signaling. In vitro, gut damage-associated immune activation induced apoptosis and remodeling of brain microvascular endothelial cells (BMECs), with surviving cells exhibiting tight junction disruption and cytoskeletal reorganization. Plasma from allo-HSCT recipients similarly induced BMEC apoptosis. Notably, both immune signaling- and patient plasma-induced BMEC apoptosis were prevented by IL-6 inhibition or supplementation with the gut microbiota-derived metabolite propionate. Together, these findings identify immune signaling as a correlate of BBB damage clinically and a causative driver in vitro in pediatric allo-HSCT.

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Davies, M. R., Cross, C. B., Ryan, F. R., Yu, L., Dorraki, M., Greenberg, Z., Salter, A., Williams, C. M., Li, A., Zannettino, A. C., Bonder, C. S., Bardy, C., Wardill, H. R.. 2026-08-20. Gut-immune signaling drives blood-brain barrier damage in pediatric allogeneic stem cell transplant. https://doi.org/10.64898/2026.08.17.745172

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