Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis.
Goepp M., Milburn JV., Zhang B., Dong Y., Tyrrell V., Zheng X., Marshall JM., Bolsega S., Basic M., Glendinning L., Ho G-T., Satsangi J., Breyer RM., Narumiya S., McSorley HJ., Schwarze JKJ., Anderson CJ., Dockrell DH., Rossi AG., Bleich A., Lucas CD., O'Donnell VB., Mole D., Arends MJ., Zhou Y., Yao C.
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.