Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice
Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice
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DOI：
10.1152/ajpgi.00027.2011
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发表时间：
2011-06-01
影响因子：
4.5
通讯作者：
Dudeja, Pradeep K.
中科院分区：
文献类型：
--
作者：
Saksena, Seema;Goyal, Sonia;Dudeja, Pradeep K.
P-糖蛋白（P-gp）介导外源性物质和细菌毒素从肠粘膜流出到管腔中。P-gp的失调与炎症性肠病有关。某些益生菌已被证明是有效的治疗炎症性肠病。然而，益生菌对P-gp的直接影响尚不清楚。目前的研究探讨了乳酸杆菌对肠上皮细胞P-gp功能和表达的影响。利用Caco-2单层和葡聚糖硫酸钠诱导的结肠炎的小鼠模型。P-gp活性以维拉帕米敏感的[3 H]地高辛跨上皮通量测定。采用实时荧光定量PCR和免疫印迹法检测MDR 1/P-gp的表达。培养上清（CS;一曰：10或1：嗜酸乳杆菌或鼠李糖乳杆菌处理分化的Caco-2单层细胞（接种后21天）增加（接近3倍）MDR 1/P-gp mRNA和蛋白水平。L.嗜酸乳杆菌或L. rhamnosus CS通过磷酸肌醇3-激酶和ERK 1/2 MAPK途径刺激P-gp活性（接近2倍，P < 0.05）。在小鼠中，L.嗜酸乳杆菌或L.鼠李糖处理（3 × 10（9）集落形成单位）增加回肠和结肠中mdr 1a/P-gp mRNA和蛋白表达（2- 3倍）。在葡聚糖硫酸钠（DSS）诱导的结肠炎模型（3% DSS饮用水7天）中，通过组织学损伤和髓过氧化物酶活性判断的结肠炎程度被L.嗜酸乳杆菌L.嗜酸乳杆菌处理DSS处理的小鼠阻断了远端结肠中mdr 1a/P-gp mRNA和蛋白表达的减少。这些结果表明，乳酸杆菌或其可溶性因子刺激P-gp的表达和功能在正常和炎症条件下。这些数据提供了一种新的机制，涉及P-gp上调益生菌在肠道炎症性疾病的有益影响的见解。
P-glycoprotein (P-gp) mediates efflux of xenobiotics and bacterial toxins from the intestinal mucosa into the lumen. Dysregulation of P-gp has been implicated in inflammatory bowel disease. Certain probiotics have been shown to be effective in treating inflammatory bowel disease. However, direct effects of probiotics on P-gp are not known. Current studies examined the effects of Lactobacilli on P-gp function and expression in intestinal epithelial cells. Caco-2 monolayers and a mouse model of dextran sulfate sodium-induced colitis were utilized. P-gp activity was measured as verapamil-sensitive [(3)H] digoxin transepithelial flux. Multidrug resistant 1 (MDR1)/P-gp expression was measured by real-time quantitative PCR and immunoblotting. Culture supernatant (CS; 1: 10 or 1: 50, 24 h) of Lactobacillus acidophilus or Lactobacillus rhamnosus treatment of differentiated Caco-2 monolayers (21 days postplating) increased (similar to 3-fold) MDR1/P-gp mRNA and protein levels. L. acidophilus or L. rhamnosus CS stimulated P-gp activity (similar to 2-fold, P < 0.05) via phosphoinositide 3-kinase and ERK1/2 MAPK pathways. In mice, L. acidophilus or L. rhamnosus treatment (3 x 10(9) colony-forming units) increased mdr1a/P-gp mRNA and protein expression in the ileum and colon (2- to 3-fold). In the dextran sulfate sodium (DSS)-induced colitis model (3% DSS in drinking water for 7 days), the degree of colitis as judged by histological damage and myeloper-oxidase activity was reduced by L. acidophilus. L. acidophilus treatment to DSS-treated mice blocked the reduced expression of mdr1a/P-gp mRNA and protein in the distal colon. These findings suggest that Lactobacilli or their soluble factors stimulate P-gp expression and function under normal and inflammatory conditions. These data provide insights into a novel mechanism involving P-gp upregulation in beneficial effects of probiotics in intestinal inflammatory disorders.