The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics

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.

Figure 1

The intestinal barrier and possible mechanisms of barrier dysfunction in multiple sclerosis. The normal intestinal barrier is composed of multiple layers (top). From the luminal side outwards, there is a mucus layer in close contact with the commensal microbiota, the single cell epithelial layer (woven together by tight junction proteins depicted here as green closed circles), the lamina propria and submucosa containing the immunological barrier, and finally the muscle and connective tissue layer. Changes in microbiota, mucus composition, epithelial cell death, tight junction function and immunological dysregulation could all lead to breakdown of the intestinal barrier and increased permeability (bottom).

Figure 2

An altered intestinal barrier leads to immune changes in the gut and the CNS. (1) Multiple sclerosis-associated microbiota and immune derangements lead to an altered barrier and increased permeability. (2) Microbiota diversity is reduced, as is production of SCFA’s, and some bacteria translocate to the lamina propria. (3) LPS produced by bacteria cause low-grade inflammation and endotoxaemia, and loss of SCFA signalling alters lymphocyte phenotypes. (4) LPS, microbial-associated molecular patterns (MAMPs) and reduced SCFAs alter the blood–brain barrier. (5) LPS and activated lymphocytes reach the CNS, where in absence of normal SCFA concentrations, microglia and astrocyte neuroimmune responses are affected. A = astrocytes; BBB = blood–brain barrier; M = microglia; TLR = Toll-like receptors.

Figure 3

Disease-modifying therapies can modulate the intestinal barrier. Different disease-modifying therapies in clinical use may beneficially modulate intestinal barrier function through a variety of mechanisms. (1) Oral disease-modifying therapies have antimicrobial properties, while minocycline is a tetracycline antibiotic. Dimethyl fumarate acts as a Michael acceptor and can deplete bacterial nucleophilic thiols. (2) Glatiramer acetate has been shown to increase syndecan, the most abundant heparan sulphate proteoglycan in the gastrointestinal tract. (3) Fingolimod, dimethyl fumarate and minocycline increase tight junction expression. Dimethyl fumarate increases zona occludens-1 (ZO-1) in a heme-oxygenase-1 (HO-1) dependent pathway, while S1P signalling increases E-cadherin (E-CN). (4) Most disease-modifying therapies modulate lymphocyte (LYM) populations and functions in non-neurological tissues, such as in the lamina propria. Whether any of these effects have a mechanistic relevance for their therapeutic action is unknown.