Gut microbiome-derived isoflavone metabolites may ameliorate experimental autoimmune encephalomyelitis (EAE) through estrogen receptor signaling in CD8 T-cells

Abstract 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 was validated EAE, animal model MS, where lack isoflavones (a type phytoestrogen) diet and/or lead increased severity. However, cellular molecular pathways through isoflavones/gut microbiota modulate EAE unknown. Cellular analysis periphery showed isoflavone-fed mice number CD8 T-cell colon on isoflavone-free diet. Moreover, knockout lose isoflavone-mediated protection, suggesting important role T-cells this process. Due structural similarity between isoflavone metabolites endogenous estrogen, we hypothesize induce regulatory via engagement estrogen receptors (ERs). Flow cytometric colonic had higher expression both ERα ERβ produced lower levels IFNγ, perforin, IL10. utilizing conditional KO lacking or exclusively cells determine ERs generation diet-induced T-cells. In summary, our data suggest bacterial metabolism suppression immunomodulation receptor signaling. Supported grants from NIH (1R01AI137075-01) VA (1I01CX002212)