Open Collections

Abstract

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease caused by autoreactive T cells that invade the central nervous system (CNS). The cause of MS remains unknown, and particularly the environmental components of disease susceptibility remain poorly understood. Perturbations of the intestinal environment, whether through infection or by an altered gut microbiome, have demonstrated striking abilities to modulate MS-like disease in animal models, either in protective or pathogenic capacities. Here, we investigate three distinct modalities by which modulation of the intestinal ecosystem alters disease course of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Dietary fibres are potent modulators of immune responses that can restrain inflammation in multiple disease contexts. I demonstrate a potent ability of the dietary fibre guar gum to delay disease and neuroinflammation in EAE. These findings reveal specificity in the host response to fibre sources and define a pathway of fibre-induced immunomodulation that protects against pathologic neuroinflammation. Both people of advanced age and people with MS exhibit alterations in the gut microbiome and its associated metabolites; however, the relationship between these observations is poorly characterized. Here, I establish an age-dependent mouse model of progressive MS, and adapt this model to test the effects of an age-associated microbiota on disease progression. These findings provide a framework for metabolite discovery associated with EAE disease chronicity and severity. The immune response to helminths is diametrically opposed to the immune response generated during inflammatory autoimmune diseases, which has provoked investigation into harnessing helminths as immunotherapy in MS. Here, I describe the ability of the helminth Trichinella spiralis to ameliorate EAE, both prophylactically and therapeutically. These findings highlight the therapeutic potential of helminth-evoked immune responses to reduce neuroinflammation in people with MS. Collectively, these findings highlight the diversity of mechanisms by which the immune system and development of neuroinflammatory disease can be altered by the intestinal environment. Each of the modalities evaluated here identify novel mechanisms that could be harnessed for therapeutic benefit in people with MS.