Investigating the Role of Bile Acid Homeostasis in Multiple Sclerosis

Multiple Sclerosis (MS) is a severe neurodegenerative disease characterized by demyelination and immune cell infiltration in the central nervous system (CNS). The pathophysiology of MS is multifactorial, and gut dysbiosis has recently been identified as a contributing factor. To this end, bile acids are detergent-like compounds that are synthesized in the liver and modified in the intestine. While their primary physiological function is to aid in lipid emulsification, recent studies have shown that bile acids act as signaling molecules in a number of peripheral tissues, including the brain. However, it has not been established how the size and composition of the bile acid pool modulate the neuroinflammatory response in neurodegenerative diseases such as MS. Therefore, we utilized primary mouse astrocyte cultures to determine how bile acid treatment affected the cytokine-induced inflammatory response. Chenodeoxycholic acid (CDCA) and its conjugated form (TCDCA) elicited a modest anti-inflammatory effect in cytokine-treated astrocytes. For in vivo studies, our lab utilized the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to examine how altering the bile acid pool modulated onset and progression of disease. The overproduction of bile acids via overexpression of CYP7A1 exacerbated EAE disease severity. In contrast, depletion of the bile acid pool via 2% Cholestyramine feeding significantly reduced disease clinical score, histological damage, and markers of astrocyte activation. Elaboration on these studies could lead to novel therapeutic approaches in the treatment of MS.