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P003. Vitamin D deficiency enhances adherent invasive Escherichia coli induced barrier dysfunction and experimental colonic injury

A. Assa1, L. Pinnell2, J. Rautava2, L. Vong2, K. Johnson-Henry2, P. Sherman2, 1Tel Aviv University, Gastroenterology, Petach Tikvah, Israel, 2University of Toronto, Cell Biology, Toronto, Canada

Background

Adherent-invasive Escherichia coli (AIEC) colonization, has been strongly implicated to be involved in crohn's disease and was found to be associated with ileal mucosa of Crohn's disease patients. The aim of this study was to investigate the effects of 1,25(OH)2D3, the active form of vitamin D, on AIEC-induced changes in intestinal epithelial barrier function in vitro, as well as to determine its effect on AIEC colonization, pathogenicity, and disease severity during dextran sodium sulfate (DSS)-induced colitis, in vivo.

Methods

Polarized epithelial Caco2-bbe cells were grown in medium with or without vitamin D and then challenged with AIEC serotype LF-82. Barrier function was assessed by measuring transepithelial electrical resistance (TER), fluorescein isothiocyanate dextran (10 kilodalton), paracellular permeability, and the expression and distribution of the intercellular tight junction proteins zonula occludens (ZO)-1 and claudin-1. Weaned female C57BL/6 mice were fed either a vitamin D sufficient or deficient diet for 5 weeks and then infected with AIEC in the absence or presence of 2% DSS pre-treatment. Disease severity was assessed by histology to determine colonic epithelial hyperplasia, an in vivo gut permeability assay, and analysis of fecal microbioata composition. Presence of invasive bacteria was assessed by transmission electron microscopy.

Results

We demonstrate that 1,25(OH)2D3 protects against AIEC-induced disruption of transepithelial resistance, paracellular permeability and tight junction protein distribution. Moreover, mice fed a vitamin D-deficient diet for 5 weeks exhibited pronounced epithelial barrier dysfunction, and were more susceptible to LF82 colonization and invasion as well as worsened colonic injury when infected following a 7-day course of 2% DSS. Vitamin D deficiency also resulted in an altered composition of the fecal microbiota both in the absence and presence of AIEC infection.

Conclusion

Our data shows that vitamin D is able to mitigate the deleterious effects of AIEC on the intestinal mucosa, by protecting against AIEC-induced disruption of intestinal permeability and preserving tight junction architecture. Vitamin D deficiency also predisposes to AIEC-induced colonic injury in an experimental colitis model. This highlights the possible association between vitamin D status, dysbiosis and Crohn's disease in humans, and suggests that vitamin D may be beneficial as an adjunctive therapeutic modality in inflammatory bowel diseases.