title: Upregulation of P-glycoprotein by probiotics in intestinal epithelial cells and in the dextran sulfate sodium model of colitis in mice.
abstract: 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 (∼3-fold) MDR1/P-gp mRNA and protein levels. L. acidophilus or L. rhamnosus CS stimulated P-gp activity (∼2-fold, P < 0.05) via phosphoinositide 3-kinase and ERK1/2 MAPK pathways. In mice, L. acidophilus or L. rhamnosus treatment (3 × 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 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.
authors.affiliation: Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago, Jesse Brown Veterans Affairs Medical Center, 60612, USA. saksena@uic.edu
authors.forename: Seema
authors.initials: S
authors.lastname: Saksena
authors.forename: Sonia
authors.initials: S
authors.lastname: Goyal
authors.forename: Geetu
authors.initials: G
authors.lastname: Raheja
authors.forename: Varsha
authors.initials: V
authors.lastname: Singh
authors.forename: Maria
authors.initials: M
authors.lastname: Akhtar
authors.forename: Talat M
authors.initials: TM
authors.lastname: Nazir
authors.forename: Waddah A
authors.initials: WA
authors.lastname: Alrefai
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Gill
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D003106:Colon / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D007778:Lactobacillus / Q000254:growth & development*; D007779:Lactobacillus acidophilus / Q000254:growth & development; D052201:Lacticaseibacillus rhamnosus / Q000254:growth & development; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019936:Probiotics / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D016264:Dextran Sulfate; C095122:multidrug resistance protein 3; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3