PRJNA564944
Prostaglandin E2 promotes intestinal inflammation via inhibiting microbiota-dependent regulatory T cells
The gut microbiota critically regulates intestinal homeostasis and disease partially through mechanisms that involve modulation of regulatory T cells (Tregs), yet the environmental cues that exert physiological control over microbiota-Treg crosstalk are incompletely defined. Genome-wide association studies demonstrate that alterations in the prostaglandin E2 (PGE2) receptor EP4 are associated with a more severe disease phenotype in inflammatory bowel disease, indicating potentially deleterious functions of PGE2 on intestinal inflammation, but the underlying mechanisms are unclear. Here, we report that PGE2 promotes intestinal inflammation by inhibiting mucosal Tregs in a manner depending on the gut microbiota. PGE2-EP4 signaling represses protective microbes like short chain fatty acid-producing microbiota while expands the microbes with capacity to promote intestinal inflammation. Transfer of the gut microbiota that are modified by PGE2-EP4 signaling modulates mucosal Treg functions 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 Treg inhibition. Furthermore, the PGE2 pathway negatively correlates with Treg signature gene expression in human colon biopsies. Taken together, our findings provide emergent evidence that PGE2-mediated disruption of microbiota-Treg communication promotes intestinal inflammation.