Toll-like receptor 4–mediated enteric glia loss is critical for the development of necrotizing enterocolitis

Mark L. Kovler, Andres J. Gonzalez Salazar, William B. Fulton, Peng Lu, Yukihiro Yamaguchi, Qinjie Zhou, Maame Sampah, Asuka Ishiyama, Thomas Prindle, Sanxia Wang, Hongpeng Jia, Peter Wipf, Chhinder P. Sodhi, David J. Hackam

Research output: Contribution to journalArticlepeer-review


Necrotizing enterocolitis (NEC) is a devastating disease of premature infants, whose pathogenesis remains incompletely understood, although activation of the Gram-negative bacterial receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium plays a critical role. Patients with NEC typically display gastrointestinal dysmotility before systemic disease is manifest, suggesting that dysmotility could drive NEC development. Both intestinal motility and inflammation are governed by the enteric nervous system, a network of enteric neurons and glia. We hypothesized here that enteric glia loss in the premature intestine could lead to dysmotility, exaggerated TLR4 signaling, and NEC development. We found that intestinal motility is reduced early in NEC in mice, preceding the onset of intestinal inflammation, whereas pharmacologic restoration of intestinal motility reduced NEC severity. Ileal samples from mouse, piglet, and human NEC revealed enteric glia depletion, and glia-deficient mice (Plp1DTR, Sox10DTR, and BdnfDTR) showed increased NEC severity compared with wild-type mice. Mice lacking TLR4 on enteric glia (Sox10-Tlr4ko) did not show NEC-induced enteric glia depletion and were protected from NEC. Mechanistically, brain-derived neurotrophic factor (BDNF) from enteric glia restrained TLR4 signaling on the intestine to prevent NEC. BDNF was reduced in mouse and human NEC, and BDNF administration reduced both TLR4 signaling and NEC severity in enteric glia–deficient mice. Last, we identified an agent (J11) that enhanced enteric glial BDNF release, inhibited intestinal TLR4, restored motility, and prevented NEC in mice. Thus, enteric glia loss might contribute to NEC through intestinal dysmotility and increased TLR4 activation, suggesting enteric glia therapies for this disorder.

Original languageEnglish (US)
Article numbereabg3459
JournalScience translational medicine
Issue number612
StatePublished - Sep 22 2021

ASJC Scopus subject areas

  • Medicine(all)


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