Docosahexaenoic acid supplementation aggravates myasthenia gravis through immune dysregulation

Myasthenia gravis (MG) is an autoimmune disorder characterized by the disruption of immune cell homeostasis and inflammatory processes. However, the impact of metabolic abnormalities on immune regulation in MG has not been well defined. The objective of this study was to identify serum metabolites causally linked to MG and to explore their role in the onset and progression of the disease. This will provide a theoretical foundation for targeted clinical interventions and therapeutic strategies. To establish the causal relationship between serum metabolites and MG, we employed Mendelian randomization. Furthermore, we conducted dietary interventions with docosahexaenoic acid (DHA) to observe its effects on the disease progression and immune cell subpopulations in experimental autoimmune myasthenia gravis (EAMG) rats. We also performed metabolomic and transcriptomic analyses of regulatory T cells (Treg) during MG progression. Our findings suggest that dysregulated lipid metabolism, particularly elevated DHA levels, is a significant risk factor for MG, influencing various markers associated with Treg cells in both MG patients and in EAMG models. The addition of 1% DHA to the diet exacerbated the severity of EAMG, enhanced B cell immune responses, and promoted antibody production. However, it also led to an increase in the proportion of Treg cells. Further in vitro experiments confirmed that DHA accumulation in Treg cells enhances their proliferation but impairs their inhibitory function, partially through the PI3K-Akt signaling pathway. These results imply that modulating lipid metabolism, especially through the PI3K-Akt pathway in Treg cells, could be critical in controlling MG.