A Novel Approach to Maintain Gut Mucosal Integrity Using an Oral Enzyme Supplement

Abstract

Objective To determine the role of intestinal alkaline phosphatase (IAP) in enteral starvation-induced gut barrier dysfunction and to study its therapeutic effect as a supplement to prevent gut-derived sepsis. Background Critically ill patients are at increased risk for systemic sepsis and, in some cases, multi-organ failure leading to death. Years ago, the gut was identified as a major source for this systemic sepsis syndrome. Previously, we have shown that IAP detoxifies bacterial toxins, prevents endotoxemia, and preserves intestinal microbiotal homeostasis. Methods WT and IAP- KO mice were used to examine gut barrier function and tight junction protein levels during 48 h starvation and fed states. Human ileal fluid samples were collected from 20 patients post ileostomy and IAP levels were compared between fasted and fed states. To study the effect of IAP supplementation on starvation-induced gut barrier dysfunction, WT mice were fasted for 48 h +/− IAP supplementation in the drinking water. Results The loss of IAP expression is associated with decreased expression of intestinal junctional proteins and impaired barrier function. For the first time, we demonstrate that IAP expression is also decreased in humans who are deprived of enteral feeding. Finally, our data demonstrates that IAP supplementation reverses the gut barrier dysfunction and tight junction protein losses due to a lack of enteral feeding. Conclusions IAP is a major regulator of gut mucosal permeability and is able to ameliorate starvation-induced gut barrier dysfunction. Enteral IAP supplementation may represent a novel approach to maintain bowel integrity in critically-ill patients.

Intestinal Alkaline Phosphatase Attenuates Alcohol-Induced Hepatosteatosis in Mice

“…Furthermore, we have shown the beneficial effects of exogenous IAP in the context of a variety of gut barrier dysfunction conditions [25,33]. We therefore sought to determine the effect of exogenous IAP supplementation on gut barrier function in the context of alcohol exposure.…”

“…Our findings suggest that oral supplementation of IAP can prevent liver injury due to alcohol intake in mice. Alcohol induced liver cell damage results in elevated levels of serum ALT levels in human and rodents [32] and in clinical settings ALT levels are proportional to the degree of liver injury [33]. Both pre- and simultaneous IAP treatment with alcohol significantly lowered the serum ALT levels, while giving the IAP after the alcohol failed to block the elevations in ALT.…”

Mechanisms of Intestinal Barrier Dysfunction in Sepsis

“…Further, although alterations in the tight junction can mediate barrier function, the experiments performed cannot prove that the alterations seen in tight junction following sepsis are mechanistically responsible for hyperpermeability, nor can they determine the relative contributions of the claudin-2, claudin-5, JAM-A, occludin and ZO-1. The experiments also do not examine the role of nutrition in intestinal hyperpermeability, since starvation, in and of itself, induces gut barrier dysfunction which can be ameliorated via intestinal alkaline phosphatase (35). While all animals in this study had free access to food and water throughout, it is possible that oral intake was decreased after the onset of sepsis.…”

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis

“…IAP mRNA levels are reduced in patients with UC [55]. IAP also promotes growth of intestinal commensal bacteria, preserving homeostasis of the gut microbiota [53,56]. As a naturally occurring enzyme, IAP has a low risk profile [57,58].…”

“…The gut brush border enzyme intestinal alkaline phosphatase (IAP) functions as an anti-inflammatory epithelial defense factor that detoxifies a variety of proinflammatory byproducts such as lipopolysaccharides and CpG-DNA and promotes the gut barrier function [51,52,53,54]. IAP mRNA levels are reduced in patients with UC [55].…”