Alterations of intestinal permeability (IP) may contribute to the pathophysiology of immune-mediated diseases. We investigated the possible association between IP changes and multiple sclerosis (MS). We studied 22 patients with relapsing–remitting multiple sclerosis (RRMS) and 18 age- and sex-matched healthy donors (HDs), including five twin pairs (one concordant, and four discordant for disease). Measurement of lactulose (L) and mannitol (M; two non-metabolized sugars) levels in urine samples, after an oral load, allowed to quantify gut dysfunction. The proportion of participants with increased IP was significantly higher in patients than in HDs (16/22 (73%) versus 5/18 (28%); p = 0.001). Accordingly, the L/M urinary ratio showed significantly higher values in patients than in controls (p = 0.0284). Urinary mannitol concentration was significantly lower in patients than in controls (p = 0.022), suggesting a deficit of absorption from intestinal lumen. Such changes did not appear related to patients’ clinical–radiological features. The relatively high proportion of IP changes in RR-MS patients seems to confirm our work hypothesis and warrants more work to confirm the result on a larger sample, and to understand the implications for related immunological disturbances and intestinal microbiota alterations. Our finding may also have relevance for oral treatments, recently introduced in clinical practice.

Background: Most twin studies of multiple sclerosis (MS) are inconclusive regarding the impact of genes and environment on disease susceptibility. In particular, high uncertainty exists about whether shared environmental factors are aetiologically relevant. Objective: To disentangle, with a reasonable degree of confidence, the relative contributions of heritability and of shared and unique environmental components of MS susceptibility. Methods: We performed a meta-analysis of previous twin studies. After a MEDLINE search, we selected eight twin studies in France, UK, Canada, Denmark, North America, Italy, Finland and Sweden. We conducted a biometric multi-group analysis under the liability-threshold model, by taking account of the study-specific ascertainment strategies and the population-specific prevalence rates of MS. Results: The meta-analytic estimates of tetrachoric correlations were 0.71 (95% confidence interval (CI): 0.67–0.74) in monozygotic pairs and 0.46 (95% CI: 0.41–0.50) in dizygotic pairs. The biometric multi-group model provided meta-analytic estimates of 0.50 (95% CI: 0.39–0.61) for heritability, 0.21 (95% CI: 0.11–0.30) for shared environmental component and 0.29 (95% CI: 0.26–0.33) for unique environmental component. Conclusion: Our results support the continuing efforts to identify unknown genetic factors that fill the gap of ‘missing heritability’; moreover, a ‘missing environmentality’ deserves future investigations into the role of non-heritable components that act as both shared and individual-specific exposures.

The gut barrier consists of several components, including the mucus layer, made of mucins and anti-bacterial molecule, the epithelial cells, connected by tight junction proteins, and a mixed population of cells involved in the interplay with microbes, such as M cells, elongations of “antigen presenting cells” dwelling the lamina propria, intraepithelial lymphocytes and Paneth cells secreting anti-bacterial peptides. Recently, the influence of intestinal permeability (IP) changes on organs far from gut has been investigated, and IP changes in multiple sclerosis (MS) have been described. A related topic is the microbiota dysfunction that underpins the development of neuroinflammation in animal models and human diseases, including MS. It becomes now of interest to better understand the mechanisms through which IP changes contribute to pathophysiology of neuroinflammation. The following aspects seem of relevance: studies on other biomarkers of IP alterations; the relationship with known risk factors for MS development, such as vitamin D deficiency; the link between blood brain barrier and gut barrier breakdown; the effects of IP increase on microbial translocation and microglial activation; the parallel patterns of IP and neuroimmune changes in MS and neuropsychiatric disorders, that afflict a sizable proportion of patients with MS. We will also discuss the therapeutic implications of IP changes, considering the impact of MS-modifying therapies on gut barrier, as well as potential approaches to enhance or protect IP homeostasis.