Lignans redress autoimmunity and achieve curative effects on myasthenia gravis by ameliorating the gut microbiome

Myasthenia gravis (MG) is a serious inflammatory autoimmune disease characterized by continuous production of autoantibodies against targets in the neuromuscular junctions, resulting in muscle weakness. Autoimmunity has long been presumed to be irreversible. The current therapeutic regimens may alleviate the disease conditions, but curative outcomes can hardly be achieved. In this study, we assessed the curative potential of lignans on MG. Lignans, prevalent in edible plants such as flaxseed (flaxseed lignans, FL), have been shown to possess the intrinsic ability to inhibit inflammation. However, whether lignans may reverse the autoimmune state and provide curative therapies for MG is unknown.We established a C57BL/6J mouse model of experimental autoimmune myasthenia gravis (EAMG), using R97-116 peptide as the antigen, to evaluate the effects of FL on MG and investigate the molecular mechanisms of effects by multi-omics analyses. FL treatment effectively halted the progression of EAMG as reflected by the markedly alleviated muscle atrophy and significantly elevated muscle strength. The gut microbiome composition was profoundly remodeled, the gut barrier was significantly ameliorated, and the levels of the anti-R97-116 IgG autoantibody were radically lowered, all signs suggesting reversed conditions of the experimental MG by lignans. Mechanistically, the curative effects were associated with the inhibition of the Rap1gds1/Cdc42 signaling pathway. Lignans could reverse MG pathogenesis and achieve curative effects on MG by redressing the inflammatory autoimmune state through ameliorating the gut microbiome, modulating the metabolites, mitigating the gut barrier damage, and inhibiting the Rap1gds1/Cdc42 signaling pathway.