Research ArticleGASTROINTESTINAL DISEASE

Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain

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Science Translational Medicine  12 Dec 2018:
Vol. 10, Issue 471, eaan0237
DOI: 10.1126/scitranslmed.aan0237

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The gut-brain conNECtion

Necrotizing enterocolitis (NEC) is a gastrointestinal disorder affecting premature infants. Newborns with NEC often develop cognitive impairments. The mechanisms leading to cognitive disabilities remain unclear. Niño et al. show that increased oxidative stress in the brain triggered NEC-associated cognitive impairments in mice. The release of the proinflammatory molecule high-mobility group box 1 from the injured intestine activated Toll-like receptor 4 on microglial cells in the brain, resulting in accumulation of reactive oxygen species. Oral administration of microglia-targeting antioxidants prevented cognitive impairments in a mouse model of NEC. The results suggest that reducing microglial activation might be a strategy to protect patients from cognitive impairments associated with NEC.

Abstract

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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