Gut bacteria-derived isoflavone metabolites ameliorate experimental autoimmune encephalomyelitis (EAE) through estrogen receptor engagement

Abstract Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system which may be influenced by gut bacteria-produced metabolites. We have shown that isoflavone-metabolizing bacteria are less abundant in MS patients as compared to healthy individuals and loss of these bacteria leads to increased disease severity in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Isoflavone metabolites can modulate the immune response through binding to estrogen receptors α and β (ERα and ERβ). Thus, we aim to investigate the role of ERα and ERβ in isoflavone-mediated disease protection in EAE by determining ER expression on immune and intestinal epithelial cells as well as receptor specificity for isoflavone-mediated protection in EAE. We hypothesize that isoflavone metabolites induce an anti-inflammatory state via engagement of ERs and that reduction/absence of these molecules may predispose patients to MS development and/or severity. To test this, we administered an isoflavone-containing diet to mice and induced EAE. Mice fed an isoflavone-containing diet developed milder disease than mice fed an isoflavone-free diet while also exhibiting higher expression of ERα, but not ERβ, in the gut. Surprisingly, there was no change in ERβ expression in splenic CD4+ or CD8+ T-cells of mice fed an isoflavone-free versus an isoflavone-containing diet. Mice administered equol also exhibited milder disease than controls. Ongoing experiments using chemical or genetic inhibition of ERα and ERβ signaling will determine the role of these receptors in EAE disease amelioration. Our results suggest that bacterial metabolism of isoflavones leads to EAE disease suppression through utilization of estrogen receptors. Supported by grants from NIH (T32AI007485, 1R01AI137075-01) and a generous gift from Margaret Heppelmann and Michael Wacek.