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

CNS Demyelination and Intestinal Barrier Breakdown in Gastrointestinal Disorders: An Important Link?

An association between multiple sclerosis and IBD has been suggested because of common epidemiological, immunological and genetic patterns (Barcellos et al., 2006). IBD patients have an increased risk for cerebrovascular disease, peripheral neuropathy and demyelinating disease (Casella et al., 2014; Ferro et al., 2014; Morís, 2014), and anti-TNF therapies that are widely used in IBD have also been associated with CNS demyelination (Katsanos and Katsanos, 2014). Indeed, a recent meta-analysis of 10 case-control studies including over 1 million patients found a risk ratio of 1.54 for multiple sclerosis/IBD comorbidity, with no difference between Crohn's disease and ulcerative colitis (Kosmidou et al., 2017). Certain authors propose that IBD can be conceived as a disorder of the intestinal epithelial barrier, and barrier breakdown is known to be an essential step in the pathophysiology of both Crohn's and ulcerative colitis (for reviews see Jäger et al., 2013; Antoni et al., 2014; Goll and van Beelen Granlund, 2015). Evidence showing white matter involvement in IBD could also provide a link between intestinal barrier breakdown and CNS demyelination.

In an early study, investigators found a 3-fold increase of white matter hyperintensities in the MRIs of patients with IBD (Geissler et al., 1995). A recent estimate suggested that over half of all IBD patients will have white matter hyperintensities in a routine MRI (Ferro et al., 2014). Other findings in IBD include decreased grey matter volume and decreased axial diffusivity in major white matter tracts (Zikou et al., 2014). The aetiology of the white matter lesions found in patients with IBD is uncertain, and some authors suggest that ischaemia and vasculitis might be responsible (Zikou et al., 2014). However, in a report of five cases of patients with Crohn's disease with symptomatic acute white matter lesions suggestive of demyelination, systemic infection, coagulation disorders, or vasculitis were ruled out (de Lau et al., 2009). Additionally, other studies have attempted to describe white matter lesions in patients with Crohn's disease with more detail. White matter lesions suggestive of demyelination were found in 72% of 54 patients compared to 34% in age- and sex-matched controls (Chen et al., 2012). The role of anti-TNF therapy is also debated, and some observational studies have not found an association between therapy and presence of white matter hyperintensities (Chen et al., 2012). In a retrospective analysis of 9095 patients with IBD, anti-TNF therapy was not found to increase the risk of confirmed inflammatory demyelinating CNS lesions (de Felice et al., 2015).

Other gastrointestinal diseases where the intestinal barrier is impaired have also been associated with CNS demyelination. In patients with multiple sclerosis, serological and histological markers of coeliac disease are more frequent than in healthy controls (Rodrigo et al., 2011), although other studies have found inconsistent results (Salvatore et al., 2004). Cases of comorbid coeliac disease and multiple sclerosis are abundant in the literature (Batur-Caglayan et al., 2013; Casella et al., 2016), as are cases of coeliac disease with white matter lesions mimicking multiple sclerosis or other CNS demyelinating diseases (Mirabella et al., 2006; Finsterer and Leutmezer, 2014; Krom et al., 2017). MRI studies in patients with coeliac disease have also shown higher proportion of white matter lesions and grey matter atrophy (Bilgic et al., 2013).

Although a causal link between intestinal barrier breakdown and CNS demyelination cannot be concluded with certainty in these cases, there appears to be an association not solely explained by their shared epidemiological and immunological characteristics. The association between these entities is certainly complex and in need of further study.