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

Treating the Diseased Intestinal Barrier

Current treatments for a diseased intestinal barrier are limited, but there are various interesting avenues of research. One of the main therapeutic targets are tight junctions. Larazotide acetate, also known as AT-1001, is a synthetic octapeptide related to the zonula occludens toxin produced by Vibrio cholera, developed as a treatment for coeliac disease. It acts locally to decrease tight junction permeability by blocking zonulin receptors and thus preventing actin rearrangement in response to stimuli, and in vitro it can stabilize tight junctions and decrease intestinal permeability (Paterson et al., 2007; Gopalakrishnan et al., 2012; Khaleghi et al., 2016). However, clinical trials in coeliac disease have yielded conflicting results, despite showing a beneficial effect over intestinal permeability (Kelly et al., 2013; Leffler et al., 2012, 2015).

Another approach in improving intestinal barrier function is enrichment of the mucus layer, a strategy being explored in IBD (Stange, 2017). Lecithin, or phosphatidylcholine, accounts for the majority of the phospholipids in the intestinal mucus layer, and is available as a delayed release oral formulation. In randomized phase II controlled studies, delayed-release lecithin was proven to be clinically and endoscopically effective in ulcerative colitis, and phase III studies are underway (Stremmel and Gauss, 2013; Stange, 2017). Recent interest has also been placed on stem cell-based therapies to regenerate the intestinal epithelium, through luminal transplantation (Holmberg et al., 2018), but these approaches are still in an experimental phase.

There has also been recent interest in the effects of vitamin D over intestinal barrier function and immune homeostasis (Dimitrov and White, 2017). In a model of experimental colitis, mice overexpressing vitamin D receptor in the intestinal epithelium show preserved intestinal permeability, reduced caspase expression and less induction of apoptosis (Liu et al., 2013). Vitamin D also attenuates TNFα-induced apoptosis in human colonic cells through reduction of NF-κB activation and mucosal IKK kinase activity, thereby preserving barrier function (see Li et al., 2015 for a review). Vitamin D signalling also preserves the mucosal barrier integrity by abrogating myosin light chain kinase dependent tight junction dysregulation during colonic inflammation through suppression of NF-κB in vitro (Du et al., 2015). Cultured colonic samples from patients with ulcerative colitis have altered expression of the tight junction claudin as well as increased pro-inflammatory cytokine expression; these changes were reversed by incubation with vitamin D (Stio et al., 2016). A recent small, randomized and placebo controlled study reported improvements in intestinal permeability [assessed by excretion of oral sugars (lactulose and mannitol were used as markers of small intestine permeability, sucrose as a marker of gastro-duodenal permeability, and sucralose as marker of combined small- and large-bowel permeability)] as well as serum immune markers in patients with IBD after vitamin D treatment (Raftery et al., 2015). Vitamin D appears to be important in the regulation of the intestinal barrier function, a mechanism not yet thoroughly evaluated in multiple sclerosis research.

Probiotics have emerged as an interesting option in regulating intestinal barrier function, fuelled by research in both in vitro and in vivo models that show that some microbiota can stabilize the intestinal barrier (Bron et al., 2017). However, small clinical studies in necrotizing enterocolitis, irritable bowel syndrome and IBD have shown only modest effects. There are no large randomized, placebo controlled studies and there is no obvious standardization of the quantities and composition of a given therapeutic probiotic 'agent', making trials difficult (Bron et al., 2017). There has been growing interest in the use of faecal microbiota transplantation (the ultimate microbiome modification) for the treatment of patients with chronic gastrointestinal infections and IBD (Smits et al., 2013), with excellent results observed in C. difficile colitis. It is also a safe procedure. Its effectiveness in autoimmune diseases and multiple sclerosis is unknown at this time. (Table 1)

There are other sources of interest in probiotics in multiple sclerosis. Probiotic administration is known to modulate the immune response in the mouse EAE model. Different formulations have been shown to reduce EAE duration (Ezendam et al., 2008), inhibit the pro-inflammatory Th1/Th17 polarization (Kwon et al., 2013), induce IL-10 producing Treg cells (Ochoa-Repáraz et al., 2010a, b; Takata et al., 2011) and enhance CD103 expression in dendritic cells (Ochoa-Repáraz et al., 2010b), all while preventing, delaying or attenuating EAE. E. coli strain Nissle 1917 has been shown to reduce EAE-induced intestinal barrier dysfunction, while also reducing disease severity and beneficially modifying T cell functions (Secher et al., 2017).

Despite these encouraging studies, few clinical trials have been performed using probiotics in multiple sclerosis. In one early trial, investigators used the non-pathogenic helminth Trichuris suis (Fleming et al., 2011). Five newly diagnosed patients with relapsing-remitting multiple sclerosis were given T. suis orally for 3 months, and favourable trends were seen in MRI outcomes (reduction in enhancing lesions from baseline) and immunological assessments (increased IL-10). A recent double-blind, placebo-controlled trial randomized 60 multiple sclerosis patients to receive a probiotic capsule or placebo for 12 weeks (Kouchaki et al., 2017). Probiotic treatment mildly improved Expanded Disability Status Scale (an absolute 0.4-point difference) and depression and anxiety symptoms, reduced high-sensitivity C-reactive protein and improved other metabolic measures such as insulin sensitivity and high-density lipoprotein-cholesterol levels. Probiotics also downregulated the gene expression of some pro-inflammatory cytokines in patients' peripheral blood-derived mononuclear cells (Tamtaji et al., 2017). In these studies, the treatment was safe and tolerable, but follow-up was too short to show any meaningful benefit in radiological or clinical outcome measures. Nonetheless, the encouraging results seen in the EAE model will surely promote further clinical trial development.

SCFAs are bacterial fermentation products from indigestible diet components. The most common SCFAs are acetate, propionate and butyrate. SCFAs could have a beneficial effect over the intestinal barrier. Butyrate was shown to be able to accelerate tight junction protein assembly and preserve permeability in a single enterocyte layer in vitro model, a process mediated by AMP-activated protein kinase activity (Peng et al., 2009). SCFAs could also increase prostaglandin-dependent mucin expression in intestinal epithelial cells, enhancing their mucoprotective properties (Willemsen et al., 2003). In an EAE model, dietary SCFA ameliorated the course of EAE through expanded Treg cell populations in the lamina propria, through suppression of the JNK1 and p38 pathway (Haghikia et al., 2015). CD44 knockout mice that show attenuated EAE also have increased microbiota diversity and SCFA production in the gut (Chitrala et al., 2017).

Dietary interventions that increase the availability of SCFAs and reduce other types of fatty acids could be an interesting therapy in improving the intestinal barrier function in multiple sclerosis, with the additional possibility of beneficial immunological effects. However, evidence showing a benefit for any kind of dietary interventions in multiple sclerosis is scarce, despite widespread acceptance that a 'healthy' diet is probably best (Altowaijri et al., 2017; Esposito et al., 2017). Some probiotic species are also rich sources of SCFAs, suggesting the possibility of a combination approach.

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