The gut microbiota as a therapeutic target in multiple sclerosis

• Autores: Laura Calvo Barreiro
• Directores de la Tesis: Carmen Espejo Ruiz (dir. tes.), Xavier Montalbán Gairín (dir. tes.), Herena Eixarch Ahufinger (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
• Idioma: español
• Tribunal Calificador de la Tesis: Joan Genescà Ferrer (presid.), Luisa María Villar Guimerans (secret.), David Otaegui Bichot (voc.)
• Programa de doctorado: Programa de Doctorado en Medicina por la Universidad Autónoma de Barcelona
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• Resumen

  • Multiple sclerosis (MS) is a chronic and degenerative disease and the most common inflammatory demyelinating disorder of the central nervous system (CNS) worldwide. Although its autoimmune aetiology is still unclear, both innate and adaptive immune responses participate in MS pathogenesis.

    Recently, the gut microbiota has emerged as a putative environmental risk factor for MS. Studies in experimental autoimmune encephalomyelitis (EAE) models have shown that the gut microbiota is an essential player in triggering autoimmune demyelination. However, experimental data support the idea that some bacterial strains, far from being harmful, have a beneficial impact on the outcome of EAE. Thus, the promotion of beneficial microorganisms via probiotics is being developed as an important therapeutic strategy involving the gut microbiota in EAE.

    In the present study, we investigated the therapeutic impact of two commercially available probiotics—Lactibiane iki and Vivomixx—on the clinical outcome of EAE. Lactibiane iki improved the clinical outcome of EAE mice in a dose-dependent manner and Vivomixx tended to ameliorate the clinical course of the experimental disease. Regarding the probiotics’ immunological effects, Lactibiane iki diminished the proinflammatory immune response in the CNS and increased immunoregulatory populations in the periphery. On the other hand, Vivomixx-treated mice showed a lower presence of costimulatory molecules in the T helper (Th) cell populations, which would be indicating an inefficient T cell activation profile in the periphery. These immunological processes may have contributed to the reduction in the demyelination and T cell infiltration in the CNS in both experimental groups. The administration of either probiotic modulated the number and phenotype of myeloid dendritic cells (mDCs) and these, in turn, could have been the responsible for the observed changes in the T cell populations in the periphery. Specifically, Lactibiane iki promoted an immature, tolerogenic phenotype of mDCs that could directly induce immune tolerance and immunoregulatory populations in the periphery, while Vivomixx decreased the percentage of mDCs expressing costimulatory molecules. Finally, it was described that both the clinical condition and disease progression altered the gut microbiome composition.

    Secondly, we studied the therapeutic effect of a previously selected mixture of human gut-derived 17 Clostridia strains on the clinical outcome of EAE. The observed clinical improvement was related to lower demyelination and astrocyte reactivity in addition to a trend to lower microglia reactivity and axonal damage in the CNS. An enhanced immunoregulatory response of regulatory T cells in the periphery was also associated to this clinical improvement. Furthermore, transcriptome studies highlighted increased antiinflammatory responses related to interferon beta in the periphery and lower activation, differentiation, and proliferation of immune cells in the CNS. Lastly, higher levels of the immunomodulatory short-chain fatty acid (SCFA) butyrate in the serum of Clostridia-treated mice might have contributed to the greater immunoregulatory response in the periphery.

    Finally, the SCFA butyrate was also tested on the chronic EAE model. This bacterial product—mainly produced from the fermentation of digestion-resistant oligosaccharides and dietary fibre—has been described as the SCFA with the largest capability to generate regulatory immune responses in vitro and in vivo. Moreover, SCFAs have been stood out as the real sources of the antiinflammatory immune responses exerted by some probiotic bacteria. Thus, the oral administration of the SCFA butyrate proved its preventive effect on CNS autoimmunity and its slight therapeutic clinical impact on EAE clinical course.

    Our results emphasise that gut microbiota can be a potential therapeutic target in MS since some microorganisms play a noticeable role in the regulation of the immune response and the processes of CNS demyelination and inflammation in this EAE model, being capable of reverting already established clinical signs.