Ileum-Specific Transgenic Expression of Human Chimeric Intestinal Alkaline Phosphatase (IAP) Attenuates Western Diet (WD)–Induced Barrier Dysfunction and Glucose Intolerance

Abstract

Intestinal epithelial cell derived IAP dephosphorylates/detoxifies bacterial endotoxin LPS in the gut lumen. We have earlier demonstrated that improvement of intestinal barrier function was accompanied by an increase in IAP activity. Herein, we developed IAP transgenic mice where expression of human chimeric IAP is under the control of intestine specific villin promoter. As shown in Panel A, compared to non-transgenic wild type (WT) littermates, IAP expression (identified by c-myc tag) was noted in colon, ileum jejunum and duodenum of IAP-transgenic (IAPTg) mice. IAP was almost uniformly expressed along the length of the ileum (Panel B) and while IAP activity reduced from proximal P1 segment to distal P9 segment in WT mice, this activity was maintained in the IAPTg mice (Panel C). Dietary challenge with WD impaired glucose tolerance in WT mice and this intolerance was attenuated in IAPTg mice (Panels D and E). Significant decrease in fecal zonulin, a marker for intestinal barrier dysfunction, in WD fed IAPTg mice (Panel F) and a corresponding decrease in translocation of oral 4kDa FITC dextran to plasma (Panel G) suggests that IAP overexpression improves intestinal barrier function. Thus, targeted increase in IAP activity represents a novel strategy to improve WD induced intestinal dysfunction and glucose intolerance. Disclosure H. He: None. S.S. Ghosh: None. P.J. Yannie: None. J. Wang: None. S. Ghosh: None.