Division of Neonatology, Children's Mercy Kansas City, Kansas City, Missouri, USA; School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA.
Division of Neonatology, Children's Mercy Kansas City, Kansas City, Missouri, USA; School of Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA.
Mucosal Immunol. 2023 Apr;16(2):208-220. doi: 10.1016/j.mucimm.2023.02.002. Epub 2023 Feb 15.
A key aspect of postnatal intestinal adaptation is the establishment of symbiotic relationships with co-evolved gut microbiota. Necrotizing enterocolitis (NEC) is the most severe disease arising from failure in postnatal gut adaptation in premature infants. Although pathological activation of intestinal Toll-like receptors (TLRs) is believed to underpin NEC pathogenesis, the mechanisms are incompletely understood. We postulate that unregulated aberrant TLR activation in NEC arises from a failure in intestinal-specific mechanisms that tamponade TLR signaling (the brakes). In this review, we discussed the human and animal studies that elucidate the developmental mechanisms inhibiting TLR signaling in the postnatal intestine (establishing the brakes). We then evaluate evidence from preclinical models and human studies that point to a defect in the inhibition of TLR signaling underlying NEC. Finally, we provided a framework for the assessment of NEC risk by screening for signatures of TLR signaling and for NEC prevention by TLR-targeted therapy in premature infants.
新生儿肠道适应的一个关键方面是与共同进化的肠道微生物群建立共生关系。坏死性小肠结肠炎（NEC）是早产儿出生后肠道适应失败引起的最严重疾病。虽然肠道 Toll 样受体（TLR）的病理性激活被认为是 NEC 发病机制的基础，但这些机制尚不完全清楚。我们假设，NEC 中不受调节的异常 TLR 激活源于肠道特异性机制的失败，该机制抑制 TLR 信号（刹车）。在这篇综述中，我们讨论了阐明抑制新生儿肠道 TLR 信号发育机制的人体和动物研究（建立刹车）。然后，我们评估了来自临床前模型和人类研究的证据，这些证据表明 TLR 信号抑制缺陷是 NEC 的基础。最后，我们提供了一个通过筛选 TLR 信号特征来评估 NEC 风险的框架，并通过 TLR 靶向治疗预防早产儿 NEC。
