Necrotizing enterocolitis induces T lymphocyte–mediated injury in the developing mammalian brain

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Science Translational Medicine  06 Jan 2021:
Vol. 13, Issue 575, eaay6621
DOI: 10.1126/scitranslmed.aay6621

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Elucidating the gut-brain connection in necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by acute intestinal necrosis and long-term neurological dysfunction, through mechanisms that are poorly understood. In new work, Zhou et al. study a neonatal mouse model of NEC, human brain autopsy specimens from infants with and without NEC, and human and mouse brain organoids. They report that CD4+ T lymphocytes, partially of intestinal origin, damage the developing brain of neonatal mice in the setting of NEC through the release of IFN-γ. These findings suggest that early management of intestinal injury, or control of the lymphocyte response, could improve neurological impairment in children with NEC.


Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4+ T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intracerebroventricular delivery of gut T lymphocytes from mice with NEC into Rag1−/− recipient mice lacking CD4+ T cells resulted in brain injury. Brain organoids derived from mice with or without NEC and from human neuronal progenitor cells revealed that IFN-γ release by CD4+ T lymphocytes induced microglial activation and myelin loss in the organoids. IFN-γ knockdown in CD4+ T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1−/− recipient mice. T cell receptor sequencing revealed that NEC mouse brain-derived T lymphocytes shared homology with gut T lymphocytes from NEC mice. Intraperitoneal injection of NEC gut-derived CD4+ T lymphocytes into naïve Rag1−/− recipient mice induced brain injury, suggesting that gut-derived T lymphocytes could mediate neuroinflammation in NEC. These findings indicate that NEC-associated brain injury may be induced by gut-derived IFN-γ–releasing CD4+ T cells, suggesting that early management of intestinal inflammation in children with NEC could improve neurological outcomes.

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