Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis

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. ORCID: https://orcid.org/0000-0003-4089-8460, Mole, Damian, Arends, Mark J., Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291 and Yao, Chengcan 2025. Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis. Cell Host & Microbe 33 (5) , pp. 671-687. 10.1016/j.chom.2025.04.014

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > Systems Immunity Research Institute (SIURI) Research Institutes & Centres > Data Innovation Research Institute (DIURI)
Publisher:	Cell Press
ISSN:	1931-3128
Date of First Compliant Deposit:	15 May 2025
Date of Acceptance:	15 April 2025
Last Modified:	20 May 2025 13:45
URI:	https://orca.cardiff.ac.uk/id/eprint/178298

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