The effect of corticotropin-release hormone on duodenal permeability and immune activation in healthy volunteers in a double-blind placebo-controlled study.

Introduction: In functional dyspepsia, increased gut permeability, low-grade inflammation and altered sensorimotor function have been reported. Both stress and corticotropin-release hormone(CRH) have been shown to increase small bowel permeability in a mast-cell dependent fashion. Moreover, eosinophil-derived CRH has been implicated in mast-cell activation. The aim of this study was to evaluate whether CRH administration alters duodenal permeability and immune activation in healthy volunteers(HVs). Methods: An intravenous bolus of 100μg CRH or placebo was administered in HVs in a crossover, double-blind, randomized fashion. Two hours later, a gastroscopy was performed to measure permeability in Ussing chambers and to count mast-cells and eosinophils on duodenal biopsies. Supernatant was assessed for eosinophil-derived neurotoxin(EDN), tryptase and chymase. In addition, CRH was administrated ex-vivo to baseline biopsies pretreated with or without lodoxamide. Results are described as mean±SD. p-values<0.05 were considered significant. Results: Twenty HVs completed the study. Mast-cell or eosinophil counts were not significantly altered after CRH versus placebo(respectively p=0.31 and p=0.069). Tryptase but not chymase, significantly decreased after CRH (resp. p=0.037 and p=0.44) with a trend for a decrease in EDN(p=0.053). Permeability was unaltered comparing both conditions. Ex-vivo, transepithelial electrical resistance significantly decreased after CRH exposure compared to baseline(p=0.010), which was not prevented by pre-treatment with lodoxamide. Conclusion: In-vivo CRH administration reduced tryptase levels in supernatant of duodenal biopsies without affecting permeability, whereas ex-vivo duodenal permeability increased regardless of mast51 cell stabilization. These results suggest the involvement of mast-cells in regulating gut permeability in HVs in response to CRH, possibly influenced by in-vivo compensatory mechanisms.