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


Brain. 2018;141(7):1900-1916. 

In This Article

The Intestinal Barrier

The intestinal barrier maintains homeostasis by preventing the unwanted movement of antigenic molecules and microbes from the lumen of the gastrointestinal tract, while allowing the products of digestion and water to enter the body. The intestinal barrier consists of a physical barrier provided by the inter-epithelial tight junctions, a secretory barrier that includes antimicrobial peptides, mucus and fluid and an immunological barrier, including cells and molecules of the innate and adaptive immune system. The secretory component of the epithelial barrier is regulated by neural mechanisms that integrate this component of barrier function with digestive processes in the gut. Intestinal barrier function refers to ability of the intestinal mucosa and extracellular barrier components (e.g. mucus, antimicrobial peptides) to modulate epithelial permeability and act as a physical and functional limiting step for organism-luminal interactions.

The intestinal lumen and its contents are separated from the rest of the gastrointestinal tissue (and the body) by a single layer of epithelial cells along the length of the gastrointestinal tract. These cells are being constantly renewed and thus require constant proliferation (Delgado et al., 2016). Intestinal stem cells, present in the crypts of the intestinal mucosa, differentiate into both enterocytes, and specialized secretory (Paneth cells and goblet cells) and sensory cells (enteroendocrine cells and tuft cells), a process regulated by complex transcriptional and epigenetic mechanisms (Smith et al., 2017). The intestinal barrier is permeable to water and other small molecules, a property modulated by tight junctions, located around the apical surface of adjacent epithelial cells. Tight junctions consist of a heterogeneous group of transmembrane proteins such as occludins, claudins, junctional adhesion molecules and zona occludens-1, each with specific roles (Gasbarrini and Montalto, 1999; Sturgeon and Fasano, 2016; Volynets et al., 2016; Capaldo et al., 2017; France and Turner, 2017).

The intestinal barrier (Figure 1) is continuously exposed to a number of immunological and microbiological factors. When the permeability of the intestinal barrier is breached, undesired large molecules, and commensal bacteria, may enter the lamina propria with pathological consequences (Odenwald and Turner, 2017). One of the main causes of increased permeability of the intestinal barrier is inflammation, an event thought to be essential in the pathophysiology of inflammatory bowel disease (IBD) (de Souza et al., 2017; Martini et al., 2017), coeliac disease and sepsis (Yoseph et al., 2016; Schumann et al., 2017). Inflammatory cytokines including interferons, interleukin (IL)-17 and tumour necrosis factor alpha (TNFα), as well as calcium-dependent oxidative stress, have been shown to alter the expression of tight junction proteins and lead to increased intestinal permeability (Reynolds et al., 2012; Yang et al., 2014; Al-Sadi et al., 2016; Gangwar et al., 2017).

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).

Together with intestinal epithelial cells as the first layer of the intestinal barrier are Paneth cells (Figure 1), which are specialized secretory cells derived from intestinal stem cells. Paneth cells produce antimicrobial peptides, the defensins, which are secreted into the mucus layer (Dupont et al., 2014; Yu et al., 2016; Capaldo et al., 2017). Mucus, secreted from goblet cells, is composed of heavily glycosylated oligomeric mucin proteins, water, ions and secretory IgA. This layer modulates bacterial growth in the intestinal lumen adjacent to the intestinal barrier, prevents bacterial adherence and acts as part of the innate immune response of the organism against microbial pathogens (Dupont et al., 2014).

After the mucus and the epithelial lining of the gastrointestinal tract, the next layer of the intestinal barrier is mostly immunological. Innate lymphoid cells, located in the epithelial layer, can be activated to produce a variety of inflammatory mediators, which play a defensive or a pathogenic role in mammal gut homeostasis (Bostick and Zhou, 2016). Found in close proximity to the single layer of enterocytes, intraepithelial lymphocytes are a heterogeneous population of cells that provide immune protection against pathogens and also regulate immune responses that, if unchecked, could jeopardize the integrity of the barrier (Cheroutre et al., 2011; Olivares-Villagómez and Van Kaer, 2018). The lamina propria (Figure 1) is populated by B, T and dendritic cells that can initiate and modulate a host of immunological responses (Persson et al., 2013; Gronke et al., 2017). Peyer's patches are secondary lymphoid tissues present in the intestinal mucosa. They are continuously exposed to a variety of antigens, presented to Peyer's patches by microfold epithelial cells and resident dendritic cells (Rochereau et al., 2011; Hashiguchi et al., 2015).