Aina Vaivade: Environmental Exposures and Gut-derived Metabolites in Multiple Sclerosis: Epidemiological Analysis of Disease Risk and Disability Worsening

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and one of the leading causes of non-traumatic disability in young adults, with a higher prevalence among females. Although genetic susceptibility and several lifestyle factors contribute to MS risk, many aspects of disease susceptibility and progression remain unexplained.

This thesis investigates the role of modifiable exposures in MS, focusing on environmental contaminants and bile acid (BA) metabolism. Serum samples from people with MS (pwMS) and matched controls were analyzed using liquid chromatography-mass spectrometry to examine exposure to per- and polyfluoroalkyl substances (PFAS) and hydroxylated polychlorinated biphenyls (OH-PCBs), as well as cholesterol-derived metabolic pathways.

Exposure to environmental contaminants was associated with increased odds of MS. Several of these compounds demonstrated non-linear associations, indicating that biological effects may vary across exposure levels. Co-exposure analysis further demonstrated that PFAS and OH-PCBs were associated with increased odds of MS. In addition, a gene-environment interaction was observed, further highlighting the complexity of environmental influences on MS susceptibility.

Interestingly, while PFAS exposure was associated with increased odds of MS, higher concentrations of several PFAS were also linked to a decreased risk of disability worsening. This paradox suggests that environmental contaminants may influence different stages of MS through distinct biological mechanisms.

Altered BA metabolism was also observed in pwMS compared with controls, and several BAs, particularly conjugated BAs, were associated with an increased risk of disability worsening, suggesting that dysregulation of BA metabolism may contribute to disease progression. In addition, environmental contaminant exposures were associated with alterations in the classical BA synthesis pathway and BA metabolism, mainly in people with MS.

These findings suggest that environmental exposures and metabolic processes may interact in MS pathophysiology, potentially through mechanisms along the gut-liver-brain axis. Overall, the results also highlight a potential role for environmental contaminants in MS susceptibility and disease progression.