[Research Articles] Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain
Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential ...
Source: Science Translational Medicine - Category: Biomedical Science Authors: Nino, D. F., Zhou, Q., Yamaguchi, Y., Martin, L. Y., Wang, S., Fulton, W. B., Jia, H., Lu, P., Prindle, T., Zhang, F., Crawford, J., Hou, Z., Mori, S., Chen, L. L., Guajardo, A., Fatemi, A., Pletnikov, M., Kannan, R. M., Kannan, S., Sodhi, C. P., Hackam, Tags: Research Articles Source Type: research
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