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.

肠道微生物群（gut microbiota）可通过涉及调节性T细胞（regulatory T cells, Tregs）的调控途径，关键调控肠道稳态与疾病进程，但目前对介导微生物群-调节性T细胞互作的生理性环境信号仍未完全阐明。全基因组关联研究（Genome-wide association studies）表明，前列腺素E2（prostaglandin E2, PGE2）受体EP4的异常与炎症性肠病的重症表型相关，提示PGE2可能在肠道炎症中发挥有害作用，但其潜在分子机制尚不明确。本研究发现，PGE2可通过依赖肠道微生物群的方式抑制黏膜调节性T细胞，进而促进肠道炎症。PGE2-EP4信号通路可抑制产短链脂肪酸微生物群等保护性微生物，同时扩增具有促肠道炎症能力的微生物群落。将经PGE2-EP4信号通路修饰的肠道微生物群移植后，可调控黏膜调节性T细胞功能并加重肠道炎症。机制层面，经PGE2修饰的微生物群可调控肠道单核吞噬细胞（mononuclear phagocytes）与I型干扰素信号通路（type I interferon signaling）；耗竭单核吞噬细胞或敲除I型干扰素受体（type I interferon receptor），均可削弱PGE2介导的调节性T细胞抑制效应。此外，在人类结肠活检组织中，PGE2通路与调节性T细胞特征基因的表达呈负相关。综上所述，本研究结果提供了新的证据，表明PGE2介导的微生物群-调节性T细胞通讯紊乱可促进肠道炎症发生。