Altered Expression and Function of P-Glycoprotein in Dextran Sodium Sulfate-Induced Colitis in Mice

Iizasa, Hisashi; Genda, Naomi; Kitano, Tomohide; Tomita, Mikio; Nishihara, Kenji; Hayashi, Masahiro; Nakamura, Kazuhide; Kobayashi, Shizuko; Nakashima, Emi

doi:10.1002/jps.10326

Cited by 41 publications

(25 citation statements)

References 18 publications

(17 reference statements)

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“…We, therefore, evaluated the effects of L. acidophilus on mdr1/P-gp expression in a murine model of DSS colitis. In agreement with previous findings (19), our results showed that DSS caused a significant decrease in mdr1a/P-gp mRNA and protein expression. However, L. acidophilus significantly attenuated the inhibitory effects of DSS on mdr1a/P-gp mRNA and protein expression.…”

Section: Discussionsupporting

confidence: 93%

“…Although several studies have implicated a decrease in P-gp function and expression in the pathogenesis of intestinal inflammation (2,19,22,30), no studies directly link the protective effects of probiotics in maintaining epithelial integrity to increased mdr1a/P-gp expression. We, therefore, evaluated the effects of L. acidophilus on mdr1/P-gp expression in a murine model of DSS colitis.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms in the human MDR1 gene have been associated with reduced intestinal P-gp expression in patients with ulcerative colitis (UC) and Crohn's disease (1,28). Furthermore, a decrease in function and expression of P-gp has been shown in an experimental mouse model of dextran sulfate sodium (DSS)-induced colitis (19) and T cell receptor (TCR␣) knockout (30) mice. Since P-gp plays an important role in maintaining intestinal epithelial integrity, it is essential to understand the cellular and molecular mechanism(s) regulating P-gp in the intestine.…”

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confidence: 99%

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Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice

Saksena

Goyal²,

Raheja³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice. Am J Physiol Gastrointest Liver Physiol 300: G1115-G1123, 2011. First published February 24, 2011 doi:10.1152/ajpgi.00027.2011.-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 (ϳ3-fold) MDR1/P-gp mRNA and protein levels. L. acidophilus or L. rhamnosus CS stimulated P-gp activity (ϳ2-fold, P Ͻ 0.05) via phosphoinositide 3-kinase and ERK1/2 MAPK pathways. In mice, L. acidophilus or L. rhamnosus treatment (3 ϫ 10 9 colonyforming 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 myeloperoxidase 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. multidrug resistance 1; Lactobacillus species; phosphoinositide 3-kinase; ERK1/2 kinase; dextran sulfate sodium-induced colitis; intestinal inflammation

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice

Saksena

Goyal²,

Raheja³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…35 P-gp dysregulation preceded in the large intestine before intense inammatory symptoms appeared in DSS-induced colitis mice model, 36 indicating that P-gp downregulation is one of the early events in colitis progression. In the present study, a diminished P-gp expression in colon tissues of rats with DSS-induced colitis was consolidated, which was in agreement with the nding in DSS-induced colitis mice model 36 and TNBS-induced colitis rat in rats.…”

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confidence: 99%

Mori Cortex regulates P-glycoprotein in Caco-2 cells and colons from rats with experimental colitis via direct and gut microbiota-mediated mechanisms

et al. 2017

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ac P-Glycoprotein dysregulation and microbial imbalance have been implicated in inflammatory bowel diseases. Here we found that oral dosing of Mori Cortex, the root bark of Morus alba L. markedly alleviated inflammatory responses, reinstated microbial balance, and enhanced P-glycoprotein (P-gp) expression in rat colitis (UC) induced by oral administration of dextran sulfate sodium. The effects of Mori Cortex extract (MCE) on colon P-gp were examined using Caco-2 cells which revealed a timedependent regulatory profile. The distinct effects on P-gp by individual main components may account for the direct biphasic effects of MCE. The involvement of gut microbiota in P-gp regulation by MCE was assessed by incubating the culture supernatant (CS) of fecal bacteria from normal, UC or MCE pretreated rats with Caco-2 cells. Interestingly, compared to normal CS, UC CS but not MCE CS diminished P-gp expression in Caco-2 cells, and this down-regulation could be reversed by pretreatment of Caco-2 cells with MCE. Moreover, MCE CS treated Caco-2 cells generated proinflammatory IL-1b and IL-8 comparable to that of the normal group and lower than the UC group, whereas, the anti-inflammatory IL-10 stimulated by MCE CS was significantly higher than the UC CS. In conclusion, MCE alleviated colitis-like symptoms and enhanced the intestinal epithelial integrity (P-gp up-regulation) in experimental colitis. The mechanisms involve both a direct effect and a gut microbiota-mediated pathway.

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“…Pgp expression was shown to be reduced in the colon and ileum of patients with active ulcerative colitis and refractory Crohn's disease (4). Further evidence in support of the strong relationship between decreased Pgp/MDR1 expression or activity and IBD susceptibility has been reported in other experimental mouse models of IBD, including dextran sulfate sodium (DSS)-induced colitis (DSS-colitis) (24), IL-10 knockout (6), and T cell receptor-␣ knockout (36) mice, where Pgp expression/activity is significantly decreased.…”

mentioning

confidence: 88%

Lactobacillus acidophilusstimulates intestinal P-glycoprotein expression via a c-Fos/c-Jun-dependent mechanism in intestinal epithelial cells

Priyamvada

Anbazhagan

Kumar

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Altered Expression and Function of P-Glycoprotein in Dextran Sodium Sulfate-Induced Colitis in Mice

Cited by 41 publications

References 18 publications

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

Mori Cortex regulates P-glycoprotein in Caco-2 cells and colons from rats with experimental colitis via direct and gut microbiota-mediated mechanisms

Lactobacillus acidophilusstimulates intestinal P-glycoprotein expression via a c-Fos/c-Jun-dependent mechanism in intestinal epithelial cells

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