Ruolo del microbiota intestinale nella Sclerosi Multipla come potenziale biomarker e target terapeutico

Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the brain and spinal cord that causes physical disability in young adults, especially women. The relapsing-remitting is the most common form of MS: relapses match with focal inflammation and demyelination of the central nervous system (CNS). The disease is considered of autoimmune origins, because of self-reactive lymphocytes that give aberrant responses against self-antigens of the CNS due to an imbalance between inflammatory and regulatory cells. However, the exact cause of MS is still unknown. In last decade, a correlation between gut microbiota (GM) dysbiosis and immune response was discovered in MS. Among the different alteration identified in several studies, a common pattern was the reduction of short-chain fatty acids (SCFAs) produced by specific taxa. The aim of my thesis is to present the involvement of some products coming from the GM as biomarkers and immunomodulators. IgA, a key regulator at the mucosal interface of the gut, was found to have a role in MS. IgA plasma cell clones originated from antigen-specific B cell responses to intestinal bacterial surface antigens in the gut were able to migrate through the blood into the CNS during active MS. The frequency of GM-reactive IgA in the cerebrospinal fluid (CSF) of MS patients was elevated during relapsing compared to remission suggesting that GM-specific-IgA can be a reliable biomarkers of MS active phases. SCFA, bioactive metabolites produced by GM during fibre fermentation, have been implicated in the development of MS. When amount of SCFAs and circulating T cells and B cells were analysed in MS patients and healthy controls, a positive correlation of the frequency of T follicular regulatory (Tfr) cells was found with low levels of propionate and of total B-cells with serum levels of butyrate; while frequencies of class-switched memory B cells were negatively correlated with butyrate levels. These data point out for a role of SCFA in the immunomodulation of MS supporting the idea that increasing beneficial SCFA trough probiotic supplementation could be beneficial in restoring immune balance. As a proof of concept, the immunomodulatory effects of two probiotics, Lactobacillus plantarum and Lactobacillus paracasei were analysed on PBMC derived from patients with MS. The treatment with cell-free supernatant of Lactobacilli was shown to shift CD4+ T cells of MS patients toward an anti-inflammatory phenotype through inhibition of Th1 and Th17 cells and decreasing their cytokines. In conclusion, these results corroborate the role of GM in MS disease and suggest GM as a therapeutic target; in detail, GM derived products such as GM-specific IgA and SCFA have the potential to be novel biomarkers for disease activity. The manipulation of MS patients’ GM by Lactobacilli probiotic administration may induce immunoregulation that could attenuate the severity of the disease.