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Niño, Diego F; Zhou, Qinjie; Yamaguchi, Yukihiro; Martin, Laura Y; Wang, Sanxia; Fulton, William B; Jia, Hongpeng; Lu, Peng; Prindle, Jr, Thomas; Zhang, Fan; Crawford, Joshua; Hou, Zhipeng; Mori, Susumu; Chen, Liam L; Guajardo, Andrew; Fatemi, Ali; Pletnikov, Mikhail; Kannan, Rangaramanujam M; Kannan, Sujatha; Sodhi, Chhinder P; Hackam, David J
Science translational medicine, 12/2018, Letnik: 10, Številka: 471Journal Article
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 of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.
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in: SICRIS
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