The Contribution of Gut Barrier Changes to Multiple Sclerosis Pathophysiology

Abstract

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.

Histone H3K9 methylation regulates chronic stress and IL‐6–induced colon epithelial permeability and visceral pain

“…Occludin is a structural and regulatory protein that modulates epithelial barrier function together with paracellular pore‐forming protein claudins 49 . Decreased expression in TJ proteins could disrupt TJ pores resulting in increased permeability to macromolecules and ions, which is linked to a variety of local and systemic diseases 49‐52 . The observation that application of IL‐6 increased paracellular permeability further confirmed the linkage of pro‐inflammatory cytokines and intestinal barrier dysfunction.…”

“…49 Decreased expression in TJ proteins could disrupt TJ pores resulting in increased permeability to macromolecules and ions, which is linked to a variety of local and systemic diseases. [49][50][51][52] The observation that application of IL-6 in- in females. 60,61 It is noteworthy that IBS is commonly observed in military personnel exposed to combat conditions, a predominately male population.…”

The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders

“…Multiple studies in patients with multiple sclerosis have found increased abundance of mucosal bacteria including Akkermansia muciniphila, Methanobrevibacter, and Acinetobacter calcoaceticus and decreased abundance of Butyricimonas, Faecalibacterium, and Parabacteroides distasonis (Cantarel et al, 2015;Jangi et al, 2016;Berer et al, 2017;Cekanaviciute et al, 2017). Such alterations in the mucosal microbiome potentially favor the growth of pathogenic bacteria that alter the composition of the mucus layer and therefore may exacerbate core symptoms of these disorders (Camara-Lemarroy et al, 2018;Buscarinu et al, 2019) CONCLUSION In summary, multiple pathways relevant to mucus homeostasis may be impacted by nervous system impairments in neurological disease. Furthermore, altered mucus properties could contribute to the widespread observations of microbial dysbiosis in autism, Parkinson's Disease, Alzheimer's Disease, and multiple sclerosis, and potentially exacerbate core symptoms.…”

COVID-19: dealing with a potential risk factor for chronic neurological disorders

“…COVID-19 may indeed trigger MS or its clinical manifestation also through other mechanisms. In MS, intestinal dysbiosis and changes in intestinal permeability are increasingly recognized as modulators of neuroinflammatory mechanisms through the so-called gut–brain axis [ 57 ]. Therefore, the alteration of the intestinal barrier and microbiota induced by SARS-CoV2 may enhance autoreactive response (as previously mentioned).…”