Oral Local Budesonide Treatment Ameliorates Immune Activation and Colonic Sensitivity in a Spontaneous Model for Disorders of Gut-Brain Interaction.

Abstract

BACKGROUND: Disorders of gut-brain interaction (DGBI), such as functional dyspepsia and irritable bowel syndrome, are characterized by immune activation and increased permeability in the gastrointestinal tract. However, their role in symptom generation remains unclear. Using the normoglycemic Biobreeding diabetes-prone rat (BBDP-N) as a spontaneous model of DGBI, we aim to (1) further characterize the inflammatory infiltrate in the intestinal mucosa and (2) elucidate the relationship between immune activation, barrier function, and colonic sensitivity by studying the effect of a local anti-inflammatory corticosteroid treatment, budesonide. METHODS: Ninety-day-old BBDP-N and control rats were treated with budesonide (0.5 mg/kg/day) or vehicle for 28 days. Jejunal and colonic eosinophil and mast cell numbers and activation were assessed, as well as permeability and colonic sensitivity. KEY RESULTS: Eosinophil and mast cell numbers, as well as eosinophil but not mast cell activation were increased in BBDP-N rats. After budesonide treatment, eosinophil and mast cell infiltration decreased. Colonic sensitivity increased over time in BBDP-N rats, which was prevented when treated with budesonide, and a limited effect on permeability in budesonide-treated BBDP-N rats was also observed after treatment. CONCLUSIONS: Together, these results demonstrate that a local anti-inflammatory treatment improved intestinal permeability and visceral hypersensitivity in a preclinical, spontaneous model of DGBI. Moreover, it supports a role for intestinal inflammation in the intestinal barrier defect and symptoms, further paving the way for additional evaluation of anti-inflammatory treatments, including budesonide, in DGBI.