P-302 Villous Length Does Not Explain Decreased Expression of Xenobiotic Genes in the Small Intestine of Children with Crohn's Disease

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Abstract

Background:

Previous studies have demonstrated decreased expression of genes important to xenobiotic and drug metabolism (e.g., PXR, villin, CYP3A4) in inflamed versus non-inflamed intestinal tissue in patients with Crohn's disease. Interpretation of these results is confounded by lack of knowledge regarding the influence of decreased epithelial mass versus inflammation/disease, per se, on intestinal gene expression. The aim of this prospective investigation was to assess the relationship between PXR, villin, and CYP3A4 intestinal gene expression and intestinal villous length in inflamed versus non-inflamed small bowel tissue in children with and without Crohn's disease.

Methods:

In addition to standard-of-medical-care clinical and histopathology review, fresh flash frozen duodenal and terminal ileal (TI) mucosal biopsy tissues from 22 treatment-naïve children with Crohn's disease, and 20 age-, sex-matched controls without inflammatory bowel disease, were assessed for inflammation extent and villous length by 2 independent experienced pediatric pathologists. Villous length (n = 42 children) and mRNA expression of PXR, villin, and CYP3A4, run in triplicate (RT-qPCR), normalized to GAPDH, were compared in inflamed and non-inflamed tissues of high mRNA integrity (Experion) in a subset of children (n = 29; 10 CD, 19 Control). Independent student t-test and ANOVA were used to compare differences in villous length and gene expression in the duodenum and TI, and the relationships to disease state and inflammation extent explored via Spearman's correlation (rs); JMP v12, α < 0.05.

Results:

Villous length was statistically shorter in inflamed versus non-inflamed mucosal biopsies in both the duodenum (352.42 ± 41.47 versus 505.78 ± 13.12 µm; P < 0.0001) and TI (290.88 ± 179.42 versus 480.00 ± 72.70 µm; P = 0.001). Villous length was not associated with changes in mRNA expression of PXR in duodenum (rs = −0.02) or TI (rs = −0.12), villin in duodenum (rs = −0.05) or TI (rs = −0.1), nor CYP3A4 in duodenum (rs = 0.09) or TI (rs = −0.06). mRNA expression of PXR and villin were positively correlated in both the duodenum (rs = 0.93, P < 0.0001) and TI (rs = 0.88, P < 0.0001) across all samples.

Conclusions:

The changes in mRNA expression of PXR, villin, and CYP3A4 in the small intestine of children with Crohn's disease cannot be attributed to the changes in villous length, observed in this patient population. Independent of intestinal villous length, mRNA expression of villin appears closely correlated with expression of the xenobiotic receptor and transcriptional regulator, PXR, in duodenal and terminal ileal mucosal biopsies from children with and without Crohn's disease. Current studies are further investigating the nature of the relationship between villin and genes involved in xenobiotic and drug metabolism in the human intestine.

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