Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee 37232-0696, USA.
J Clin Invest. 2011 Jun;121(6):2242-53. doi: 10.1172/JCI44031. Epub 2011 May 23.
Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria-derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40's effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation.
益生菌可能对多种肠道疾病的临床病程有有益的影响，但我们对益生菌作用的理解是有限的。我们从鼠李糖乳杆菌 GG（LGG）中鉴定出一种益生菌衍生的可溶性蛋白 p40，它可以防止肠道上皮细胞中的细胞因子诱导的细胞凋亡。在本研究中，我们使用小鼠模型分析了 p40 调节肠道上皮细胞中细胞反应的机制以及 p40 对实验性结肠炎的影响。我们表明，重组 p40 蛋白激活了表皮生长因子受体（EGFR），导致 Akt 激活。p40 通过 EGFR 的激活对于体外和离体抑制细胞因子诱导的肠道上皮细胞凋亡是必需的。此外，我们开发了一种果胶/玉米醇溶蛋白水凝胶珠系统，专门将 p40 递送到小鼠结肠，在结肠上皮细胞中激活 EGFR。含有 p40 的珠粒的给药以 EGFR 依赖性方式减少了肠上皮细胞凋亡和结肠上皮细胞屏障功能的破坏，从而预防和治疗 DSS 诱导的肠道损伤和急性结肠炎。此外，p40 激活 EGFR 对于改善 oxazolone 诱导的结肠炎中的结肠上皮细胞凋亡和慢性炎症是必需的。这些数据定义了我们认为是益生菌衍生的可溶性蛋白保护肠道免受损伤和炎症的一种以前未被认识的机制。
