126: Intestinal alkaline phosphatase protects the gut mucosal barrier in the context of remote trauma

Abstract

Introduction: In the setting of trauma, sepsis, and critical illness, a breakdown in the gut mucosal barrier is thought to be a major source for systemic inflammation and multi-organ failure, but the underlying mechanisms are unclear. Intestinal alkaline phosphatase (IAP) is a small intestinal brush border enzyme whose expression is lost under conditions of starvation and critical illness. Based upon reports that IAP can detoxify bacterial LPS, we hypothesized that this enzyme might play a role in the gut barrier breakdown in the context of remote trauma. Methods: IAP KO (n=7) and wild type C57/B6 mice (n=7) were banded above the greater trochanter to induce skeletal muscle ischemia for 2 hrs followed by 24 hrs of reperfusion. Sham KO and WT animals served as controls. Local (skeletal muscle) and remote (gut and lung) injury was evaluated by histology and scored. Gut barrier was assessed by measuring microbial translocation into mesenteric lymph nodes (quantitative bacterial colony growth). Groups were compared and analyzed using an unpaired student’s t-test. Results: IAP KO mice demonstrated higher levels of gut mucosal injury compared to WT animals following remote ischemia-reperfusion injury; average injury was increased 59% in IAP KO animals (2.28 ± 0.48 vs 1.04 ± 0.37, p<0.01) (figure 1). Morphologically, this was evidenced by greater sub-epithelial lifting, a higher proportion of denuded villi, and disorganization of nuclei among enterocytes. In contrast, there were no significant differences in either local hindlimb or remote lung injury between the two groups. The mesenteric lymph nodes of injured IAP KO mice demonstrated 3.8 fold more bacterial growth compared to WT, representing a significant increase in bacterial gut translocation (12,400 CFU/gm ± 3240 vs. 3783 CFU/gm ± 859, p<0.05). Conclusions: This study demonstrates that in a murine model of trauma, IAP serves an important gut barrier function, and its absence leads to an increase in mucosal injury and bacterial translocation. This protection is isolated to the gut, since there were no differences in local skeletal muscle or remote lung injury. The loss of IAP expression may explain the gut mucosal dysfunction that is seen under conditions of starvation and critical illness.