Regulation of spontaneous CNS autoimmunity by dietary salt

Janakiraman, Mathangi (2022): Regulation of spontaneous CNS autoimmunity by dietary salt. Dissertation, LMU München: Faculty of Medicine

Abstract

Autoimmune inflammatory diseases are on the rise in western societies. Recent research implicates the role of the gut microbiome and diet-associated factors in the development of these diseases. Research is underway to explore the metabolic and immunological aspects that are elemental to our understanding of these diseases. Indeed, a plethora of research in the last decade has focused on the concerted impact of diet and microbiota on several metabolic and autoimmune diseases like obesity, metabolic syndrome, colitis, and multiple sclerosis. To this end, a lot of attention has been given to salt, an essential component of our diet and a very dominant component in the western diet. For instance, dietary salt has been shown to influence the induction of a pro-inflammatory TH17 response in the intestine which in turn has been implicated in autoimmunity. However, data on autoimmunity is predominantly obtained in models where the disease is induced through artificial means. For understanding the role of dietary factors like salt, spontaneous disease models would serve as better tools. They are essential to study disease triggering factors and identify if dietary or microbial components contribute to disease pathogenesis. In this study, the effect of dietary salt on Experimental Autoimmune Encephalomyelitis (EAE) was explored using a spontaneous EAE model. We found that dietary salt protected mice from autoimmune disease development. On subsequent analysis of alterations due to a High Salt Diet (HSD), the alterations in the gut microbiota, particularly the increase in Enterococci and the decrease in Blautia, were prominent. The HSD-mediated disease protection was observed only in spontaneous EAE and not in an actively induced EAE model. Further analyses showed no difference between control and HSD-fed animals in functional aspects of the immune system, like T and B cell proliferation, antibody production, or antigen presentation. Analyses on the Gut Associated Lymphoid Tissue (GALT) showed that only the T cells in the intestinal GALT were altered in composition, skewing towards higher levels of IL-17+ T cells and alterations in Treg cell subsets. However, induced EAE experiments and depletion experiments showed that these differences did not have any role in protection from EAE. The expression of cell surface integrins that aid in T cell migration to the Central Nervous System (CNS) was also not altered under HSD. However, the permeability of the Blood-Brain Barrier (BBB) in vivo was significantly altered under HSD. The administration of Pertussis toxin - which is known to disrupt the BBB, was capable of reversing HSD-mediated disease protection. Further analyses on the brain endothelia showed increased levels of the tight junction proteins ZO-1 and Claudin-5 due to HSD, indicating enhanced BBB integrity. The present study has shown that HSD protects against spontaneous EAE, not via alterations in the immune system but by altering the BBB. These results suggest a broader and potentially beneficial role of salt in the pathogenesis of CNS autoimmune disease.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: CNS Autoimmunity, EAE, diet, salt, T cells, B cells, blood-brain barrier
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 5. May 2022
• 1. Referee: Krishnamoorthy, Gurumoorthy
• Signature of the printed copy: 0700/UMD 20446