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

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 manner. 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). An intravenous bolus of 100-µg CRH or placebo was administered in HVs in a crossover, double-blind, randomized manner. 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 means ± SD. <i>P</i> values < 0.05 were considered significant. Twenty HVs completed the study. Mast cell or eosinophil counts were not significantly altered after CRH versus Placebo (respectively <i>P</i> = 0.31 and <i>P</i> = 0.069). Tryptase, but not chymase, significantly decreased after CRH (respectively <i>P</i> = 0.037 and <i>P</i> = 0.44) with a trend for a decrease in EDN (<i>P</i> = 0.053). Permeability was unaltered comparing both conditions. Ex vivo, transepithelial electrical resistance significantly decreased after CRH exposure compared with baseline (<i>P</i> = 0.010), which was not prevented by pretreatment with lodoxamide. In vivo CRH administration reduced tryptase levels in the supernatant of duodenal biopsies without affecting permeability, whereas ex vivo duodenal permeability increased regardless of mast 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.<b>NEW & NOTEWORTHY</b> Our investigation breaks new ground by directly examining the effects of corticotropin-release hormone (CRH) on duodenal alterations, including permeability and immune activation, in healthy subjects. Intriguingly, our findings highlight disparities between ex vivo and in vivo pathways affecting duodenal permeability, offering novel insights into the potential pathophysiology of CRH on the duodenum.