From intestinal permeability to dysmotility: the biobreeding rat as a model for functional gastrointestinal disorders.

Tim Vanuytsel,Shadea Salim Rasoel,Els Houben,Ricard Farré,Joran Tóth,Pieter Vanden Berghe,Hanne Vanheel,Jan Tack,Tatsuhiro Masaoka,Christophe Vanormelingen,Kristin Verbeke,Gert De Hertogh,Yvette Tache

doi:10.1371/journal.pone.0111132

Tim Vanuytsel, Shadea Salim Rasoel + Show 11 more

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https://doi.org/10.1371/journal.pone.0111132

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Abstract

BackgroundImpaired intestinal barrier function, low-grade inflammation and altered neuronal control are reported in functional gastrointestinal disorders. However, the sequence of and causal relation between these events is unclear, necessitating a spontaneous animal model. The aim of this study was to describe the natural history of intestinal permeability, mucosal and neuromuscular inflammation and nitrergic motor neuron function during the lifetime of the BioBreeding (BB) rat.MethodsNormoglycemic BB-diabetes prone (DP) and control rats were sacrificed at different ages and jejunum was harvested to characterize intestinal permeability, inflammation and neuromuscular function.ResultsBoth structural and functional evidence of increased intestinal permeability was found in young BB-DP rats from the age of 50 days. In older animals, starting in the mucosa from 70 days and in half of the animals also in the muscularis propria from 110 days, an inflammatory reaction, characterized by an influx of polymorphonuclear cells and higher myeloperoxidase activity, was observed. Finally, in animals older than 110 days, coinciding with a myenteric ganglionitis, a loss of nitrergic neurons and motor function was demonstrated.ConclusionIn the BB-rat, mucosal inflammatory cell infiltration is preceded by intestinal barrier dysfunction and followed by myenteric ganglionitis and loss of nitrergic function. This sequence supports a primary role for impaired barrier function and provides an insightful model for the pathogenesis of functional gastrointestinal disorders.

Highlights

Functional gastrointestinal disorders (FGID) like irritable bowel syndrome (IBS) and functional dyspepsia are characterized by bothersome gastrointestinal complaints in the absence of an underlying organic cause that readily explains the symptoms [1,2]
We have previously reported that the development of the inflammatory enteropathy and loss of nitrergic neurons in the BB-rat occur in BB-diabetes prone (DP) animals which do not develop diabetes [23]
Early-onset defect in small intestinal barrier function BB-DP rats showed signs of impaired intestinal barrier function from an early age, demonstrated by a lower transepithelial electrical resistance (TEER) compared to controls starting from 50 days (Fig. 1A)

Summary

Introduction

Functional gastrointestinal disorders (FGID) like irritable bowel syndrome (IBS) and functional dyspepsia are characterized by bothersome gastrointestinal complaints in the absence of an underlying organic cause that readily explains the symptoms [1,2]. Impaired intestinal barrier function [3,4,5], low-grade immune activation [4,5,6], and altered neuronal control of gastrointestinal motility [7,8], have been suggested to be involved in the pathogenesis. An attractive and often-cited disease model for FGID, and for chronic inflammatory bowel disease (IBD), is based on luminal antigen penetration through an impaired intestinal barrier leading to immune activation in the intestinal wall [9]. A spontaneous animal model sharing key intestinal characteristics of human FGID would be instrumental to separate cause from consequence and to study future treatments. Low-grade inflammation and altered neuronal control are reported in functional gastrointestinal disorders. The aim of this study was to describe the natural history of intestinal permeability, mucosal and neuromuscular inflammation and nitrergic motor neuron function during the lifetime of the BioBreeding (BB) rat

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