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 E-2 (PGE(2)), a well-known mediator of inflammation, inhibits mucosal T(regs )in a manner depending on the gut microbiota. PGE(2) through its receptor EP4 diminishes T-reg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE(2)-EP4 signaling modulates mucosal T-reg responses and exacerbates intestinal inflammation. Mechanistically, PGE(2)-modified microbiota regulates intestinal mononuclear phagocytes and type I interferon signaling. Depletion of mononuclear phagocytes or deficiency of type I interferon receptor diminishes PGE(2)-dependent T(reg )inhibition. Together, our findings provide emergent evidence that PGE(2)-mediated disruption of microbiota-T-reg communication fosters intestinal inflammation.