Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation
Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation
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DOI：
10.1152/ajpgi.00142.2012
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发表时间：
2013-01-01
影响因子：
4.5
通讯作者：
Nanthakumar, Nanda
中科院分区：
文献类型：
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作者：
Ganguli, Kriston;Meng, Di;Nanthakumar, Nanda
甘古丽K，孟丁，劳塔瓦S，鲁L，沃克瓦，南库玛N。益生菌通过调节调节先天免疫介导的炎症的肠道细胞基因来预防坏死性小肠结肠炎。Am J Physiol Gasterintest肝脏Physiol 304：G132-G141,2013。2012年11月8日首次出版；doi：10.1152/ajpgi.00142.2012。-坏死性小肠结肠炎(NEC)是早产儿的一种广泛的肠道炎症性疾病，部分原因是由于先天免疫反应基因的不成熟表达，对初始细菌定植产生了过度的炎症反应。在一项随机的安慰剂对照临床试验中，给极低出生体重儿补充益生菌显著降低了NEC的发生率。本研究的主要目的是确定这两个临床有效的益生菌菌株-婴儿双歧杆菌和嗜酸乳杆菌的分泌产物是否通过加速肠道固有免疫反应基因的成熟来预防NEC，以及这两种菌株是否为这一作用所必需的。用益生菌条件培养液(PCM)培养未成熟的人肠上皮细胞、人未成熟的异种肠上皮细胞和NEC原代培养的肠上皮细胞(NEC-IEC)，检测IL-8和IL-6对炎症刺激的反应。后两种模型还检测了先天免疫反应基因的表达。在未成熟的异种移植中，PCM暴露可显著降低内毒素和IL-1β诱导的IL-8和IL-6的表达，降低TLR2和TLR4mRNA的表达，并增加特异性炎症负性调节因子SIGIRR和Tollip的mRNA水平。在NEC-IEC中，PCM降低了TLR2依赖的IL-8和IL-6的诱导，增加了SIGIRR和Tollip的表达。Tollip siRNA介导的基因敲除可逆转PCM减弱的炎症反应。抗炎分泌因子是一种5-10 kDa的分子，可抵抗DNA酶、核糖核酸酶、蛋白酶、热应激和酸暴露。婴儿条件培养液在未成熟的人肠上皮细胞中显示出比嗜酸乳杆菌更好的抗炎特性，这表明这种作用具有菌株特异性。结论：PCM促进先天免疫反应基因表达成熟，可能解释了益生菌在临床NEC中的保护作用。
Ganguli K, Meng D, Rautava S, Lu L, Walker WA, Nanthakumar N. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am J Physiol Gastrointest Liver Physiol 304: G132-G141, 2013. First published November 8, 2012; doi:10.1152/ajpgi.00142.2012.-Necrotizing enterocolitis (NEC), an extensive intestinal inflammatory disease of premature infants, is caused, in part, by an excessive inflammatory response to initial bacterial colonization due to the immature expression of innate immune response genes. In a randomized placebo-controlled clinical trial, supplementation of very low birth weight infants with probiotics significantly reduced the incidence of NEC. The primary goal of this study was to determine whether secreted products of these two clinically effective probiotic strains, Bifidobacterium infantis and Lactobacillus acidophilus, prevented NEC by accelerating the maturation of intestinal innate immune response genes and whether both strains are required for this effect. After exposure to probiotic conditioned media (PCM), immature human enterocytes, immature human intestinal xenografts, and primary enterocyte cultures of NEC tissue (NEC-IEC) were assayed for an IL-8 and IL-6 response to inflammatory stimuli. The latter two models were also assayed for innate immune response gene expression. In the immature xenograft, PCM exposure significantly attenuated LPS and IL-1 beta-induced IL-8 and IL-6 expression, decreased TLR2 mRNA and TLR4 mRNA, and increased mRNA levels of specific negative regulators of inflammation, SIGIRR and Tollip. In NEC-IEC, PCM decreased TLR2-dependent IL-8 and IL-6 induction and increased SIGIRR and Tollip expression. The attenuated inflammatory response with PCM was reversed with Tollip siRNA-mediated knockdown. The anti-inflammatory secreted factor is a 5- to 10-kDa molecule resistant to DNase, RNase, protease, heat stress, and acid exposure. B. infantis-conditioned media showed superior anti-inflammatory properties to that of L. acidophilus in immature human enterocytes, suggesting a strain specificity to this effect. We conclude that PCM promotes maturation of innate immune response gene expression, potentially explaining the protective effects of probiotics in clinical NEC.