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 (Plp1^ΔDTR, Sox10^ΔDTR, and Bdnf^ΔDTR) showed increased NEC severity compared with wild-type mice. Mice lacking TLR4 on enteric glia (Sox10-Tlr4^ko) 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.

中文翻译：

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Toll 样受体 4 介导的肠神经胶质细胞丢失对于坏死性小肠结肠炎的发展至关重要

坏死性小肠结肠炎 (NEC) 是早产儿的一种毁灭性疾病，尽管肠上皮上革兰氏阴性细菌受体 Toll 样受体 4 (TLR4) 的激活发挥着关键作用，但其发病机制仍不完全清楚。NEC 患者通常在全身性疾病出现之前表现出胃肠动力障碍，这表明胃肠动力障碍可能会促进 NEC 的发展。肠道蠕动和炎症均由肠神经系统（肠神经元和神经胶质细胞网络）控制。我们在此假设，过早肠道中肠神经胶质细胞的丢失可能导致运动障碍、TLR4 信号传导过度和 NEC 发育。我们发现，在小鼠 NEC 早期，即肠道炎症发生之前，肠道动力减弱，而肠道动力的药物恢复则降低了 NEC 的严重程度。来自小鼠、仔猪和人类 NEC 的回肠样本显示肠神经胶质细胞耗竭，而神经胶质细胞缺陷小鼠（Plp1 ^ΔDTR 、 Sox10 ^ΔDTR和Bdnf ^ΔDTR）与野生型小鼠相比，NEC 严重程度增加。肠神经胶质细胞上缺乏 TLR4 的小鼠 ( Sox10-Tlr4 ^ko ) 没有表现出 NEC 诱导的肠神经胶质细胞耗竭，并且免受 NEC 的影响。从机制上讲，来自肠胶质细胞的脑源性神经营养因子 (BDNF) 抑制肠道上的 TLR4 信号传导，从而预防 NEC。小鼠和人类 NEC 中的 BDNF 减少，并且 BDNF 给药可降低肠神经胶质细胞缺陷小鼠的 TLR4 信号传导和 NEC 严重程度。最后，我们鉴定了一种药物 (J11)，它可以增强小鼠肠道胶质细胞 BDNF 的释放、抑制肠道 TLR4、恢复肠道蠕动并预防 NEC。因此，肠神经胶质细胞的丢失可能通过肠道运动障碍和 TLR4 激活增加导致 NEC，这表明肠神经胶质细胞可以治疗这种疾病。