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 (Tregs), yet how the microbiota-Treg crosstalk is physiologically controlled is incompletely defined. Here, we report that prostaglandin E 2 (PGE 2 ), a well-known mediator of inflammation, inhibits mucosal Tregs in a manner depending on the gut microbiota. PGE 2 through its receptor EP4 diminishes Treg-favorable commensal microbiota. Transfer of the gut microbiota that was modified by PGE 2 -EP4 signaling modulates mucosal Treg 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 contracts PGE 2 -dependent Treg inhibition. Taken together, our findings provide emergent evidence that PGE 2 -mediated disruption of microbiota-Treg communication fosters intestinal inflammation.