Goepp Marie, Milburn Jemma V, Zhang Birong, Dong Yijia, Tyrrell Victoria, Zheng Xiaozhong, Marshall Jennifer M, Bolsega Silvia, Basic Marijana, Glendinning Laura, Ho Gwo-Tzer, Satsangi Jack, Breyer Richard M, Narumiya Shuh, McSorley Henry J, Schwarze Jürgen K J, Anderson Christopher J, Dockrell David H, Rossi Adriano G, Bleich André, Lucas Christopher D, O'Donnell Valerie B, Mole Damian, Arends Mark J, Zhou You, Yao Chengcan
Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh EH16 4UU, UK.
Systems Immunity University Research Institute and Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
Cell Host Microbe. 2025 May 14;33(5):671-687.e6. doi: 10.1016/j.chom.2025.04.014.
Aging manifests a decline of immune function, induces microbiome dysbiosis, drives organ inflammation, and impedes the resolution of inflammation. However, the mechanisms underlying age-related intestinal inflammation remain poorly described. Here, we find that the resolution of T cell-initiated intestinal inflammation is impaired with aging. This impairment is mediated by disrupting the immune-microbiota interplay, controlled by intestinal eicosanoid metabolism. Pharmacologically inhibiting eicosanoid biosynthesis, blocking the prostaglandin E receptor subtype 4 (EP4), or genetically ablating EP4 diminishes age-related impairment of intestinal inflammation resolution. Mechanistically, mononuclear phagocyte-intrinsic eicosanoid-EP4 signaling impedes the resolution of intestinal inflammation through fostering gut microbial dysbiosis and, more importantly, interrupting segmented filamentous bacterial adhesion to the intestinal epithelium. Colonization with EP4-ablated mouse microbiota or segmented filamentous bacteria improves the resolution of intestinal inflammation. These findings reveal that eicosanoid-dependent immune-microbiota interactions impair inflammation resolution in the aged intestine, highlighting potential intervention strategies for improving age-related gut health.
衰老表现为免疫功能下降，引发微生物群失调，导致器官炎症，并阻碍炎症的消退。然而，与年龄相关的肠道炎症的潜在机制仍知之甚少。在此，我们发现衰老会损害T细胞引发的肠道炎症的消退。这种损害是通过破坏由肠道类花生酸代谢控制的免疫-微生物群相互作用介导的。药理学上抑制类花生酸生物合成、阻断前列腺素E受体亚型4（EP4）或基因敲除EP4可减轻与年龄相关的肠道炎症消退障碍。从机制上讲，单核吞噬细胞内在的类花生酸-EP4信号通过促进肠道微生物群失调，更重要的是通过中断分节丝状细菌与肠上皮的粘附来阻碍肠道炎症的消退。用EP4基因敲除小鼠的微生物群或分节丝状细菌进行定植可改善肠道炎症的消退。这些发现揭示了类花生酸依赖性免疫-微生物群相互作用会损害老年肠道中的炎症消退，突出了改善与年龄相关的肠道健康的潜在干预策略。
