Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-κB signaling in the intestine
Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-κB signaling in the intestine
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DOI：
10.1152/ajpgi.00266.2011
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发表时间：
2012-03-01
影响因子：
4.5
通讯作者：
Rhoads, Jon Marc
中科院分区：
文献类型：
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作者：
Liu, Yuying;Fatheree, Nicole Y.;Rhoads, Jon Marc
Liu Y，Fatheree NY，Mangalat N，Rhoads JM.罗伊氏乳杆菌菌株通过调节肠中的TLR 4和NF-κ B信号传导降低实验性坏死性小肠结肠炎的发病率和严重程度美国生理学杂志胃肠和肝脏生理学302：G608-G617，2012年。首次发表于2011年12月29日; doi：10.1152/ajpgi.00266.2011。坏死性小肠结肠炎（NEC）是早产儿死亡和发病的主要胃肠道原因。早产儿肠道细菌定植和潜在致病微生物定植延迟。罗伊氏乳杆菌是一种益生菌，可抑制肠道感染，调节免疫系统，并可能有利于预防NEC。在以往的研究中，L. reuteri菌株DSM 17938和ATCC PTA 4659在体外差异性地调节炎症;然而，在体内新生大鼠中，这些菌株在LPS喂养诱导的回肠炎中具有等同的抗炎反应。这两种菌株在预防NEC方面的影响以前尚未研究过。新生大鼠经口胃配方饲料喂养并暴露于缺氧条件下诱发NEC。L.在配方中加入罗伊氏液以预防NEC。检查NEC评分、Toll样受体（TLR）信号传导基因、磷酸化-I κ B活性和肠道中的细胞因子水平。两种菌株均显著提高了存活率，降低了NEC的发病率和严重程度，DSM 17938的效果最佳。响应于益生菌，IL-6、TNF-α、TLR 4和NF-κ B的mRNA表达显著下调，而抗炎细胞因子IL-10的mRNA水平显著上调。与此同时，L.罗伊氏治疗导致NEC新生大鼠肠道TLR 4蛋白水平以及TNF-α和IL-1 β细胞因子水平降低。在离体研究中，两种菌株不仅显著抑制肠LPS诱导的磷酸-I κ B活性，而且还降低NEC大鼠模型肠中磷酸-I κ B的水平。牛奶配方喂养在肠道中产生了类似但更温和的促炎特征，17938也改善了这一特征。我们的研究表明，这两个L。罗伊氏菌株在我们的NEC模型和与牛奶喂养相关的肠炎中具有潜在的治疗价值。这些结果支持了L. reuteri可能是预防NEC的有价值的治疗方法。
Liu Y, Fatheree NY, Mangalat N, Rhoads JM. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF-kappa B signaling in the intestine. Am J Physiol Gastrointest Liver Physiol 302: G608-G617, 2012. First published December 29, 2011; doi:10.1152/ajpgi.00266.2011.-Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of mortality and morbidity in the premature infant. Premature infants have a delay in intestinal colonization by commensal bacteria and colonization with potentially pathogenic organisms. Lactobacillus reuteri is a probiotic that inhibits enteric infections, modulates the immune system, and may be beneficial to prevent NEC. In previous studies, L. reuteri strains DSM 17938 and ATCC PTA 4659 differentially modulated inflammation in vitro; however, the strains had equivalent anti-inflammatory responses in LPS feeding-induced ileitis in neonatal rats in vivo. The impact of these two strains in the prevention of NEC has not been previously investigated. NEC was induced in newborn rats by orogastric formula feeding and exposure to hypoxia. L. reuteri was added to the formula to prevent NEC. NEC score, Toll-like receptor (TLR)-signaling genes, phospho-I kappa B activity, and cytokine levels in the intestine were examined. Both strains significantly increased survival rate and decreased the incidence and severity of NEC, with optimal effects from DSM 17938. In response to probiotic, mRNA expression of IL-6, TNF-alpha, TLR4, and NF-kappa B was significantly downregulated, while mRNA levels of anti-inflammatory cytokine IL-10 were significantly upregulated. In parallel, L. reuteri treatment led to decrease intestinal protein levels of TLR4 and cytokine levels of TNF-alpha and IL-1 beta in newborn rats with NEC. Both strains significantly inhibited not only intestinal LPS-induced phospho-I kappa B activity in an ex vivo study but also decreased the levels of phospho-I kappa B in the intestines of NEC rat model. Cow milk formula feeding produced a similar but milder proinflammatory profile in the intestine that was also ameliorated by 17938. Our studies demonstrate that each of the two L. reuteri strains has potential therapeutic value in our NEC model and in enteritis associated with cow milk feeding. These results support the concept that L. reuteri may represent a valuable treatment to prevent NEC.