Niño Diego F, Sodhi Chhinder P, Egan Charlotte E, Zhou Qinjie, Lin Joyce, Lu Peng, Yamaguchi Yukihiro, Jia Hongpeng, Martin Laura Y, Good Misty, Fulton William B, Prindle Thomas, Ozolek John A, Hackam David J
*Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, Maryland†Division of Newborn Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania‡Division of Pediatric Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania§Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania¶Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Shock. 2017 Jan;47(1):22-32. doi: 10.1097/SHK.0000000000000713.
Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of the premature infant. We have recently shown that NEC development occurs after an increase in proinflammatory CD4Th17 (Th17) cells and reduced anti-inflammatory forkhead box P3 regulatory T cells (Tregs) to the premature small intestine of mice and humans, which can be experimentally reversed in mice by administration of all-trans retinoic acid (ATRA). We have also shown that NEC is characterized by apoptosis of Lgr5-positive intestinal stem cells (ISCs-Lgr5 cells) within the crypts of Lieberkühn, which are subsequently essential for intestinal homeostasis. We now hypothesize that the normal lymphocyte balance within the lamina propria of the intestine can be achieved via administration of ATRA which restores mucosal integrity by preventing the loss of ISCs. Using both in vivo and in vitro strategies, we now demonstrate that Th17 recruitment and Treg depletion lead to increased apoptosis within ISC niches, significantly impairing proliferative capacity and mucosal healing. ATRA exerted its protective effects by preventing T cell imbalance, ultimately leading to the protection of the ISC pool preventing the development of NEC in mice. These findings raise the exciting possibility that dietary manipulations could prevent and treat NEC by modulating lymphocyte balance and the ISC pool within the newborn small intestine.
坏死性小肠结肠炎（NEC）是早产儿最严重的胃肠道疾病。我们最近发现，NEC的发生是在促炎性CD4 Th17（Th17）细胞增加以及抗炎性叉头框P3调节性T细胞（Tregs）减少后，出现在小鼠和人类的早产小肠中，通过给予全反式维甲酸（ATRA）在小鼠中可实验性地逆转这种情况。我们还表明，NEC的特征是利伯kühn隐窝内Lgr5阳性肠干细胞（ISCs-Lgr5细胞）的凋亡，而这些细胞随后对肠道稳态至关重要。我们现在假设，通过给予ATRA可以实现肠道固有层内正常的淋巴细胞平衡，ATRA通过防止ISCs的丢失来恢复黏膜完整性。使用体内和体外策略，我们现在证明Th17募集和Treg耗竭会导致ISC龛内凋亡增加，显著损害增殖能力和黏膜愈合。ATRA通过防止T细胞失衡发挥其保护作用，最终保护ISC池，防止小鼠发生NEC。这些发现提出了一个令人兴奋的可能性，即饮食调控可以通过调节新生儿小肠内淋巴细胞平衡和ISC池来预防和治疗NEC。
