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

The Intestinal Barrier in Multiple Sclerosis: Consequences of a Leaky gut

Recent attention in the brain-gut connection in multiple sclerosis research has been focused on the role of the commensal gut microbiome while largely ignoring the interface of the microbiome with the organism, i.e. the intestinal barrier. Therefore, actual evidence for an alteration of the intestinal barrier in multiple sclerosis is limited. In a study of 12 jejunal biopsies from multiple sclerosis patients, Lange and Shiner (1976) found subtle histological changes, such as two cases of villous atrophy, as well as some cases of intestinal inflammatory cell infiltration. A later study found similar infiltrates, and also evidence of intestinal malabsorption in close to 20 of 52 patients with multiple sclerosis (Gupta et al., 1977).

In 1996, Yacyshyn et al. (1996) showed that 5 of 20 patients with multiple sclerosis had an altered lactulose/mannitol permeability test, suggesting increased intestinal permeability, a finding also associated with peripheral expression of CD45RO on CD20+ B cells. In the most recent study to date, the lactulose/mannitol permeability test was again used to evaluate intestinal permeability in 22 patients with multiple sclerosis and compared with age- and sex-matched controls (Buscarinu et al., 2017). Investigators found abnormal permeability in 73% of cases versus 28% in controls, but no association between permeability and brain MRI lesion load.

Similar findings have been recently described in the EAE model, the prototypic inflammatory animal model of multiple sclerosis. Investigators have found altered intestinal permeability, reduced submucosa thickness and altered tight junction expression in intestinal epithelial cells (Nouri et al., 2014). These alterations could also be induced in mice by adoptive transfer of pathogenic T cells. Furthermore, a recent study showed that the degree of intestinal permeability disturbance is closely associated with EAE severity (Secher et al., 2017). Treatment with Escherichia coli strain Nissle 1917, a probiotic known to improve intestinal barrier function, preserved tight junction expression and decreased intestinal permeability, leading to reduced EAE severity and decreased secretion of pro-inflammatory cytokines and an increased production of the anti-inflammatory cytokine IL-10 (Secher et al., 2017). This reduction of intestinal permeability led to a reduction of the migration of inflammatory T cells to the CNS, suggesting an impact on blood–brain barrier permeability as well (Secher et al., 2017).

The above studies suggest that there is indeed an alteration in the intestinal barrier in patients with multiple sclerosis and that these changes are at least partly due to an altered intestinal immune response (Buscarinu et al., 2017). The clinical relevance of these findings is unclear, but several possibilities arise. Intestinal barrier dysfunction has been associated with susceptibility to systemic infections (König et al., 2016), and both CNS and systemic infections are a common complication in patients with multiple sclerosis (Venkatesan, 2015). Another possibility is that the intestinal barrier's interplay with commensal microbiota could modulate the immune response pathologically. Finally, alterations in intestinal permeability may modulate or perpetuate neuroimmune dysregulation by increased transmucosal passage of injurious or immunogenic antigens.

The essential role of the commensal microbiome in the regulation of intestinal immunity is beginning to be recognized, and several recent reviews have been published on this subject (Haak and Wiersinga, 2017; Shi et al., 2017). Commensal bacteria are able to strengthen the gut barrier and regulate intestinal permeability (Lin and Zhang, 2017). A healthy microbiota also preserves intestinal epithelial cell integrity through the production of SCFAs that increase tight junction expression and through toll-like receptor activation (Wells et al., 2017). Intestinal commensal bacteria are recognized by toll-like receptors, a process leading to protection of intestinal epithelium against injury and barrier disruption (Rakoff-Nahoum et al., 2004). Toll-like receptor signalling also promotes epithelial cell proliferation, IgA secretion and expression of antimicrobial peptides in Paneth cells (Abreu, 2010; Wells et al., 2011).

Alterations in the gut homeostatic mechanisms in multiple sclerosis could have as one of its consequences increased bacterial translocation through an impaired intestinal barrier. One recent study found elevated levels of endotoxin [lipopolysaccharide (LPS)] in plasma of patients with multiple sclerosis, and endotoxin concentrations were related to in vivo IL-6 production and increased in vitro T-helper 17 (Th17)-like responses (Teixeira et al., 2013). Circulating endotoxin was also correlated with the Expanded Disability Status Scale, a measure of clinical disability in multiple sclerosis. In another study, LPS and LPS-binding protein were found to be elevated in the serum of EAE-induced mice; investigators also found increased LPS-binding protein levels in the serum of multiple sclerosis patients compared to healthy controls (Escribano et al., 2017). These studies are evidence of a low-grade endotoxaemia that could be present in patients with multiple sclerosis, possibly due to bacterial translocation in the setting of an altered intestinal barrier.

Besides LPS, enteric bacteria also produce microbial-associated molecular patterns (MAMPs) such as bacterial lipoproteins and double-stranded RNA that can enter the systemic circulation and act through toll-like receptors to modulate the immune system (Patten and Collett, 2013). Toll-like receptors are known to be expressed in microglia and to modulate initiation and severity of EAE in experimental models (Miranda-Hernandez and Baxter, 2013). LPS is a well-known stimulant of microglial responses and is able to disrupt the blood–brain barrier by increasing microglial production of matrix metalloproteinases (Frister et al., 2014). LPS and other MAMPs could constitute another pathway by which an altered intestinal barrier could affect neuroimmune responses in multiple sclerosis.

Finally, the use of oral disease-modifying therapies and/or symptomatic drugs in multiple sclerosis also constitute a concern, as the intestinal barrier is essential in drug absorption (Sánchez-Navarro et al., 2016). On the other hand, there are no currently marketed therapies to improve intestinal barrier function; nutritional, microbial-derived and probiotic agents are being investigated. In the next section, we will discuss the possible effects of currently used disease-modifying therapies on the intestinal barrier as well as other pathophysiological considerations.

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