Authors
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.
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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 21 Aug 2026.
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