Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells.

Mehrnaz Nouri,Anders Bredberg,Björn Weström,Shahram Lavasani,Jason R Lees

doi:10.1371/journal.pone.0106335

Mehrnaz Nouri, Anders Bredberg + Show 3 more

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https://doi.org/10.1371/journal.pone.0106335

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Journal: PloS one	Publication Date: Sep 3, 2014
Citations: 172	License type: CC BY 4.0

Affiliation: Lund University, Medicon Village

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a pathogenesis involving a dysfunctional blood-brain barrier and myelin-specific, autoreactive T cells. Although the commensal microbiota seems to affect its pathogenesis, regulation of the interactions between luminal antigens and mucosal immune elements remains unclear. Herein, we investigated whether the intestinal mucosal barrier is also targeted in this disease. Experimental autoimmune encephalomyelitis (EAE), the prototypic animal model of MS, was induced either by active immunization or by adoptive transfer of autoreactive T cells isolated from these mice. We show increased intestinal permeability, overexpression of the tight junction protein zonulin and alterations in intestinal morphology (increased crypt depth and thickness of the submucosa and muscularis layers). These intestinal manifestations were seen at 7 days (i.e., preceding the onset of neurological symptoms) and at 14 days (i.e., at the stage of paralysis) after immunization. We also demonstrate an increased infiltration of proinflammatory Th1/Th17 cells and a reduced regulatory T cell number in the gut lamina propria, Peyer's patches and mesenteric lymph nodes. Adoptive transfer to healthy mice of encephalitogenic T cells, isolated from EAE-diseased animals, led to intestinal changes similar to those resulting from the immunization procedure. Our findings show that disruption of intestinal homeostasis is an early and immune-mediated event in EAE. We propose that this intestinal dysfunction may act to support disease progression, and thus represent a potential therapeutic target in MS. In particular, an increased understanding of the regulation of tight junctions at the blood-brain barrier and in the intestinal wall may be crucial for design of future innovative therapies.

Highlights

There is growing evidence for a paradigm shift in our view on the pathogenesis of autoimmune diseases
Recent observations in humans and in a variety of animal models indicate that an increased intestinal permeability (IP), often referred to as a ‘‘leaky gut’’, is playing a pathogenic role in development of gastrointestinal disorders like inflammatory bowel disease (IBD) and celiac disease, and in systemic autoimmune diseases, like type 1 diabetes (T1D) [1,2,3,4]
The effect of antibiotic treatment on the severity of an experimental colitis model for IBD, and on the experimental autoimmune encephalomyelitis (EAE) animal model of Multiple sclerosis (MS) employed in the present work, indicates a strong influence of the gut and the commensal bacteria on the immune system, suggesting that disturbances in gut physiology may contribute to development of these diseases [10,11]

Summary

Introduction

There is growing evidence for a paradigm shift in our view on the pathogenesis of autoimmune diseases. Recent observations in humans and in a variety of animal models indicate that an increased intestinal permeability (IP), often referred to as a ‘‘leaky gut’’, is playing a pathogenic role in development of gastrointestinal disorders like inflammatory bowel disease (IBD) and celiac disease, and in systemic autoimmune diseases, like type 1 diabetes (T1D) [1,2,3,4]. The effect of antibiotic treatment on the severity of an experimental colitis model for IBD, and on the experimental autoimmune encephalomyelitis (EAE) animal model of MS employed in the present work, indicates a strong influence of the gut and the commensal bacteria on the immune system, suggesting that disturbances in gut physiology may contribute to development of these diseases [10,11]

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