Gut Microbiome-Derived Isoflavone Metabolites May Ameliorate Experimental Autoimmune Encephalomyelitis (EAE) Through Estrogen Receptor Signaling in CD8 T-cells

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS which may be influenced by diet- and gut bacteria-produced metabolites. We have shown that phytoestrogen-metabolizing bacteria are reduced in MS patients compared to healthy individuals. The importance of phytoestrogen-metabolizing bacteria was validated in EAE, an animal model of MS, where lack of isoflavones (a type of phytoestrogen) in the diet and/or lack of phytoestrogen-metabolizing bacteria lead to increased disease severity. However, the cellular and molecular pathways through which isoflavones/gut microbiota modulate EAE is unknown. Cellular analysis of the gut and periphery showed that isoflavone-fed mice have an increased number of CD8 T-cell in the colon compared to mice on an isoflavone-free diet. Moreover, CD8 T-cell knockout mice lose isoflavone-mediated disease protection, suggesting an important role of CD8 T-cells in this process. Due to the structural similarity between isoflavone metabolites and endogenous estrogen, we hypothesize that isoflavone metabolites may induce regulatory CD8 T-cells via engagement of estrogen receptors (ERs). Flow cytometric analysis of colonic CD8 T-cells showed that isoflavone-fed mice had higher expression of both ERα and ERβ and produced lower levels of IFNγ, perforin, and IL10. We are utilizing conditional KO mice lacking ERα or ERβ exclusively in CD8 cells to determine the importance of ERs in the generation of diet-induced CD8 T-cells. In summary, our data suggest that bacterial metabolism of isoflavones may lead to EAE disease suppression through immunomodulation of CD8 T-cells via estrogen receptor signaling. Supported by grants from NIH (1R01AI137075-01) and VA (1I01CX002212)