Effects of intestinal alkaline phosphatase on intestinal barrier function in a cecal ligation and puncture (CLP)‐induced mouse model for sepsis

Abstract

Background Sepsis is a severe pathological condition associated with systemic inflammation, intestinal inflammation, and gastrointestinal barrier dysfunction. Intestinal alkaline phosphatase (IAP) has been demonstrated to detoxify lipopolysaccharide, an important mediator in the pathophysiology of sepsis. We investigated the effect of treatment with IAP on intestinal permeability, intestinal inflammation, and bacterial translocation. Methods OF‐1 mice were divided into 4 groups (n = 12/group), undergoing either a sham or cecal ligation and puncture (CLP) procedure to induce sepsis. Mice received IAP or a vehicle intraperitoneally 5 minutes prior to the onset of the CLP or sham procedure, which was repeated every 12 hours for two consecutive days. After two days, in vivo intestinal permeability, intestinal inflammation, and bacterial translocation were determined. Key results CLP‐induced sepsis resulted in significantly more weight loss, worse clinical disease scores, bacterial translocation, and elevated inflammatory cytokines. Intestinal permeability was increased up to 5‐fold (P < .001). IAP activity was significantly increased in septic animals. Treatment with IAP had no effect on clinical outcomes but reduced the increased permeability of the small intestine by 50% (P = .005). This reduction in permeability was accompanied by a modified gene expression of claudin‐1 (P = .025), claudin‐14 (P = .035), and interleukin 12 (P = .015). A discriminant analysis showed that treatment with IAP is linked to modified mRNA levels of several tight junction proteins and cytokines. Conclusions and inferences Treatment with IAP diminished CLP‐induced intestinal barrier disruption, associated with modified expression of several cytokines and claudins. Nevertheless, this effect did not translate into better clinical outcomes in our experimental setup.

Intestinal alkaline phosphatase modulation by food components: predictive, preventive, and personalized strategies for novel treatment options in chronic kidney disease

“…Regarding sepsis-induced acute kidney injury (AKI), it was observed in the piglet model of AKI that 25 U/kg/h of bovine IAP increased serum and renal tissue AP activity, decreased proximal tubular injury, and prevented AKI [66]. Another study showed preventive and curative effects of treatments with 1 IU/g of calf IAP, which in septic mice decreased the permeability of the small intestine by 50%, and increased mRNA expression levels of claudin-1 and claudin-14, which are main structural tight junction proteins in the intestine [67]. These studies confirmed that IAP influences both inflammatory and intestinal barriers, contributing to intestinal health [66,67].…”

Role of Intestinal Alkaline Phosphatase in Innate Immunity

“…In a mouse model of peritonitis, IAP supplementation reduced intestinal permeability and suppressed gut bacterial translocation into the blood stream, liver, and lung [ 19 ]. In another study, IAP reduced the magnitude of increased permeability in the small intestine of a cecal ligation and puncture (CLP) mouse model [ 20 ].…”

Targeting the Intestinal Barrier to Prevent Gut-Derived Inflammation and Disease: A Role for Intestinal Alkaline Phosphatase

“…In addition, peritoneal irrigation with IAP reduced the increased permeability of the small intestine induced by the cecal ligation and puncture procedure in mice by 50%. More than that, IAP also significantly enhanced survival in mice undergoing cecal ligation and puncture, likely through a reduction of local inflammation and remote organ damage [76, 77]. These findings suggest that IAP supplementation may promote the recovery of patients after abdominal surgery.…”