The Intestinal Barrier in Multiple Sclerosis: Implications for Pathophysiology and Therapeutics

Carlos R. Camara-Lemarroy; Luanne Metz; Jonathan B. Meddings; Keith A. Sharkey; V. Wee Yong

Disclosures

Brain. 2018;141(7):1900-1916. 

In This Article

Abstract and Introduction

Abstract

Biological barriers are essential for the maintenance of homeostasis in health and disease. Breakdown of the intestinal barrier is an essential aspect of the pathophysiology of gastrointestinal inflammatory diseases, such as inflammatory bowel disease. A wealth of recent studies has shown that the intestinal microbiome, part of the brain-gut axis, could play a role in the pathophysiology of multiple sclerosis. However, an essential component of this axis, the intestinal barrier, has received much less attention. In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, and content of the intestinal microbiome entering into the circulation can impact the functions of CNS microglia. We highlight currently available studies suggesting that there is intestinal barrier dysfunction in multiple sclerosis. Finally, we address the mechanisms by which commonly used disease-modifying drugs in multiple sclerosis could alter the intestinal barrier and the microbiome, and we discuss the potential of barrier-stabilizing strategies, including probiotics and stabilization of tight junctions, as novel therapeutic avenues in multiple sclerosis.

Introduction

Biological barriers separate the internal milieu from the external environment and are essential components of maintaining homeostasis. A compromised intestinal barrier function is a prominent feature of many diseases, such as inflammatory bowel disease (Choi et al., 2017; Martini et al., 2017; Mu et al., 2017), graft versus host disease (Nalle and Turner, 2015) and coeliac disease (Schumann et al., 2017), but other biological barriers also fail in a myriad of pathological conditions (e.g. renal tubules in glomerulonephritis and lung alveoli in acute respiratory distress syndrome). The CNS is highly sensitive to homeostatic changes, and as such requires its own specialized barrier, the blood–brain barrier, for appropriate functioning. Breakdown of the blood–brain barrier is an essential hallmark of multiple sclerosis pathophysiology. Immune mediated dysregulation of the blood–brain barrier allows for migration of activated inflammatory cells into the brain, which in turn induces demyelination, axonal loss and other tissue damage (Ortiz et al., 2014; Kamphuis et al., 2015). Interestingly, many of the tight junction molecules in endothelial cells of the brain–blood barrier are identical to those in intestinal tissues, such as occludin, claudins and zona occludens-1 (Reinhold and Rittner, 2017). In this review, we examine the multiple lines of evidence, albeit mostly indirect, linking the intestinal barrier function and multiple sclerosis pathophysiology. We also discuss the possible effect of multiple sclerosis disease-modifying therapies and their association with the gut microbiome.

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