Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease.
In Crohn's disease (CD), inflammation is driven by luminal commensal micro-organisms; however, mechanisms of early phases of inflammation need further clarification. The earliest observable lesions of recurrent CD are microscopic erosions at the specialized follicle-associated epithelium (FAE), which lines the Peyer's patches. Therefore, our aim was to investigate the mucosal barrier to non-pathogenic bacteria in FAE of CD. The FAE of macroscopically normal ileum from patients with longstanding CD, ulcerative colitis, and controls was studied in Ussing chambers regarding electrophysiology and permeability to 51Cr-EDTA, horseradish peroxidase, and non-pathogenic E. coli strains. Transepithelial passage routes and uptake into dendritic cells were studied by confocal and electron microscopy. FAE of CD showed increased numbers of adherent bacteria, after E. coli exposure in Ussing chambers, as well as spontaneously in non-exposed archival surgical tissues. Further, we found increased uptake of fluorescent E. coli K-12 and HB101 across FAE of CD, but not in ulcerative colitis. Microscopy demonstrated intercellular and transcellular uptake of E. coli in CD, but only transcellular in controls. FAE exposed to E. coli demonstrated changes in conductance and 51Cr-EDTA permeability, suggesting that bacteria affected the paracellular pathway in CD mucosa. Following bacterial uptake, CD mucosa also demonstrated an increased percentage of E. coli co-localizing with dendritic cells, and augmented tissue release of TNF-alpha. Our data present novel insights into the pathophysiology of CD by demonstrating a previously unrecognized defect of FAE barrier to bacteria in ileal CD, leading to increased load of commensal bacteria to the inductive sites of mucosal immunity.
Keita
A V
AV
Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Sweden.
Salim
S Y
SY
Jiang
T
T
Yang
P-C
PC
Franzén
L
L
Söderkvist
P
P
Magnusson
K-E
KE
Söderholm
J D
JD
D000328:Adult; D000368:Aged; D001422:Bacterial Adhesion; D018988:Bacterial Translocation; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000276:immunology / Q000382:microbiology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D003713:Dendritic Cells / Q000382:microbiology; D004926:Escherichia coli / Q000502:physiology*; D005260:Female; D006801:Humans; D007082:Ileum; D007124:Immunoenzyme Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology*; D008221:Lymphoid Tissue / Q000382:microbiology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010581:Peyer's Patches / Q000382:microbiology; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha