Division of Gastroenterology, Department of Pediatrics, The University of Texas Health Science Center at Houston McGovern Medical School , Houston, Texas.
Am J Physiol Gastrointest Liver Physiol. 2018 Aug 1;315(2):G231-G240. doi: 10.1152/ajpgi.00084.2017. Epub 2018 Apr 12.
Lactobacillus reuteri DSM 17938 (LR 17938) has been shown to reduce the incidence and severity of necrotizing enterocolitis (NEC). It is unclear if preventing NEC by LR 17938 is mediated by Toll-like receptor 2 (TLR2), which is known to mediate proinflammatory responses to bacterial cell wall components. NEC was induced in newborn TLR2 or wild-type (WT) mice by the combination of gavage-feeding cow milk-based formula and exposure to hypoxia and cold stress. Treatment groups were administered formula supplemented with LR 17938 or placebo (deMan-Rogosa-Sharpe media). We observed that LR 17938 significantly reduced the incidence of NEC and reduced the percentage of activated effector CD4T cells, while increasing Foxp3 regulatory T cells in the intestinal mucosa of WT mice with NEC, but not in TLR2 mice. Dendritic cell (DC) activation by LR 17938 was mediated by TLR2. The percentage of tolerogenic DC in the intestine of WT mice was increased by LR 17938 treatment during NEC, a finding not observed in TLR2 mice. Furthermore, gut levels of proinflammatory cytokines IL-1β and IFN-γ were decreased after treatment with LR 17938 in WT mice but not in TLR2 mice. In conclusion, the combined in vivo and in vitro findings suggest that TLR2 receptors are involved in DC recognition and DC-priming of T cells to protect against NEC after oral administration of LR 17938. Our studies further clarify a major mechanism of probiotic LR 17938 action in preventing NEC by showing that neonatal immune modulation of LR 17938 is mediated by a mechanism requiring TLR2. NEW & NOTEWORTHY Lactobacillus reuteri DSM 17938 (LR 17938) has been shown to protect against necrotizing enterocolitis (NEC) in neonates and in neonatal animal models. The role of Toll-like receptor 2 (TLR2) as a sensor for gram-positive probiotics, activating downstream anti-inflammatory responses is unclear. Our current studies examined TLR2 mice subjected to experimental NEC and demonstrated that the anti-inflammatory effects of LR 17938 are mediated via a mechanism requiring TLR2.
罗特氏乳杆菌 DSM 17938（LR 17938）已被证明可降低坏死性小肠结肠炎（NEC）的发病率和严重程度。目前尚不清楚 LR 17938 是否通过 Toll 样受体 2（TLR2）介导来预防 NEC，TLR2 已知可介导对细菌细胞壁成分的促炎反应。通过管饲喂养牛基配方奶粉并暴露于低氧和冷应激，在新生 TLR2 或野生型（WT）小鼠中诱导 NEC。治疗组给予添加 LR 17938 或安慰剂（德曼-罗戈萨-夏普培养基）的配方奶。我们观察到，LR 17938 可显著降低 WT 小鼠 NEC 的发病率，并降低活化效应性 CD4T 细胞的百分比，同时增加肠道黏膜中的 Foxp3 调节性 T 细胞，但在 TLR2 小鼠中则不然。LR 17938 对树突状细胞（DC）的激活作用是通过 TLR2 介导的。在 WT 小鼠 NEC 期间，LR 17938 治疗可增加肠道中耐受型 DC 的百分比，而在 TLR2 小鼠中则未观察到这种情况。此外，在 WT 小鼠中，LR 17938 治疗后肠道中促炎细胞因子 IL-1β 和 IFN-γ 的水平降低，但在 TLR2 小鼠中则不然。总之，体内和体外的综合研究结果表明，TLR2 受体参与了 DC 的识别和 DC 对 T 细胞的致敏，以在口服 LR 17938 后防止 NEC。我们的研究进一步阐明了益生菌 LR 17938 预防 NEC 的主要作用机制，表明新生儿对 LR 17938 的免疫调节是通过一种需要 TLR2 的机制介导的。新的和值得注意的是，罗特氏乳杆菌 DSM 17938（LR 17938）已被证明可预防新生儿和新生动物模型中的坏死性小肠结肠炎（NEC）。Toll 样受体 2（TLR2）作为革兰氏阳性益生菌的传感器，激活下游抗炎反应的作用尚不清楚。我们目前的研究检查了 TLR2 敲除小鼠的实验性 NEC，并表明 LR 17938 的抗炎作用是通过一种需要 TLR2 的机制介导的。
