Prostaglandin E₂ promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells

The gut microbiota fundamentally regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (T_regs), yet how the microbiota-T_reg cross-talk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E₂ (PGE₂), a well-known mediator of inflammation, inhibits mucosal T_regs in a manner depending on the gut microbiota. PGE₂ through its receptor EP4 diminishes T_reg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE₂-EP4 signaling modulates mucosal T_reg responses and exacerbates intestinal inflammation. Mechanistically, PGE₂-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE₂-dependent T_reg inhibition. Together, our findings provide emergent evidence that PGE₂-mediated disruption of microbiota-T_reg communication fosters intestinal inflammation.