Pathogenic bacteria induce colonic PepT1 expression: an implication in host defense response.
OBJECTIVE
Expression of the di/tripeptide transporter PepT1 has been observed in the colon under inflammatory conditions; however, the inducing factors and underlying mechanisms remain unknown. Here, we address the effects of pathogenic bacteria on colonic PepT1 expression together with its functional consequences.


METHODS
Human colonic HT29-Cl.19A cells were infected with the attaching and effacing enteropathogenic Escherichia coli (EPEC). Wild-type and PepT1 transgenic mice or cultured colonic tissues derived from these mice were infected with Citrobacter rodentium, a murine attaching and effacing pathogen related to EPEC.


RESULTS
EPEC induced PepT1 expression and activity in HT29-Cl.19A cells by intimately attaching to host cells through lipid rafts. Induction of PepT1 expression by EPEC required the transcription factor Cdx2. PepT1 expression reduced binding of EPEC to lipid rafts, as well as activation of nuclear factor-kappaB and mitogen-activated protein kinase and production of interleukin-8. Accordingly, ex vivo and in vivo experiments revealed that C rodentium induced colonic PepT1 expression and that, compared with their wild-type counterparts, PepT1 transgenic mice infected with C rodentium exhibited decreased bacterial colonization, production of proinflammatory cytokines, and neutrophil infiltration into the colon.


CONCLUSIONS
Our findings demonstrate a molecular mechanism underlying the regulation of colonic PepT1 expression under pathologic conditions and reveal a novel role for PepT1 in host defense via its capacity to modulate bacterial-epithelial interactions and intestinal inflammation.
Nguyen
Hang Thi Thu
HT
Department of Medicine, Emory University, Atlanta, Georgia 30322, USA. hnguye9@emory.edu
Dalmasso
Guillaume
G
Powell
Kimberly R
KR
Yan
Yutao
Y
Bhatt
Shantanu
S
Kalman
Daniel
D
Sitaraman
Shanthi V
SV
Merlin
Didier
D
D000818:Animals; D001422:Bacterial Adhesion; D000071616:CDX2 Transcription Factor; D044082:Citrobacter rodentium / Q000472:pathogenicity*; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D004195:Disease Models, Animal; D054308:Enteropathogenic Escherichia coli / Q000472:pathogenicity*; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D021962:Membrane Microdomains / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D000074011:Peptide Transporter 1; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C508606:CXCL8 protein, human; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D016209:Interleukin-8; D016328:NF-kappa B; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; C082186:SLC15A1 protein, human; C489941:Slc15a1 protein, mouse; D027981:Symporters; D020928:Mitogen-Activated Protein Kinases