A Novel Approach to Maintaining Gut Mucosal Integrity Using an Oral Enzyme Supplement
Sulaiman R Hamarneh*1, Sara A. Morrison*1, Tyler J. Tantillo*1, Konstantinos P. Economopoulos*1, Qingsong Tao*1, Mussa M. Mohamed*1, Kanakaraju Kaliannan*1, Sonoko Narisawa*2, José L. Millán*2, Madhu S. Malo*1, Richard A. Hodin1
1Massachusetts General Hospital, Harvard Medical School, Boston, MA;2Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA
The lack of enteral nutrition in critically-ill patients is associated with gut barrier dysfunction. We have hypothesized that intestinal alkaline phosphatase (IAP) is the key missing factor and could be used as a supplement to prevent gut-derived sepsis.
WT and IAP KO mice were used to examine gut barrier function and LPS absorption. Isolated intestinal loops were instilled with inflammatory mediators (LPS, CpG DNA, flagellin) for 2 hrs and the fluid applied to target RAW264.7 cells to determine the TNF-α response.
Serum LPS levels and permeability to 70 kD FITC-dextran were ~10-fold higher and bacterial translocation to mesenteric nodes was > 2-fold higher in the IAP KO vs WT mice (p< 0.01). qPCR revealed that the levels of the tight junction (TJ) genes (Claudin 1/3, Occludin, and Zonula Occludins (ZO) 1/2/3) were > 10-fold higher in WT vs IAP KO mice (p< 0.01). With fasting (> 48 hrs) IAP levels decreased dramatically in mice and human luminal samples. Inflammatory mediators instilled into mouse intestines induced a 2-fold greater amount of TNF-α from fasted vs fed animals. Oral IAP supplementation for 10 days improved intestinal permeability, i.e., > 50 % reduction in FITC-dextran, up-regulation of the TJ gene products, and decreased serum LPS levels.
IAP is a major regulator of the gut mucosal barrier and is able to inhibit bacterial translocation, as well as the absorption and inflammatory impact of bacterially-derived mediators. Enteral IAP supplementation may represent a novel approach to maintaining bowel integrity in critically-ill patients.
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