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

Marie Goepp; Jemma V. Milburn; Birong Zhang; Yijia Dong; Victoria Tyrrell; Xiaozhong Zheng; Jennifer M. Marshall; Silvia Bolsega; Marijana Basic; Laura Glendinning; Gwo Tzer Ho; Jack Satsangi; Richard M. Breyer; Shuh Narumiya; Henry J. McSorley; Jürgen K.J. Schwarze; Christopher J. Anderson; David H. Dockrell; Adriano G. Rossi; André Bleich; Christopher D. Lucas; Valerie B. O'Donnell; Damian Mole; Mark J. Arends; You Zhou; Chengcan Yao

doi:10.1016/j.chom.2025.04.014

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

Marie Goepp, Jemma V. Milburn, Birong Zhang, Yijia Dong, Victoria Tyrrell, Xiaozhong Zheng, Jennifer M. Marshall, Silvia Bolsega, Marijana Basic, Laura Glendinning, Gwo Tzer Ho, Jack Satsangi, Richard M. Breyer, Shuh Narumiya, Henry J. McSorley, Jürgen K.J. Schwarze, Christopher J. Anderson, David H. Dockrell, Adriano G. Rossi, André BleichChristopher D. Lucas, Valerie B. O'Donnell, Damian Mole, Mark J. Arends, You Zhou, Chengcan Yao (Lead / Corresponding author)

Cell Signalling and Immunology

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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.

Original language	English
Pages (from-to)	671-687.e6
Number of pages	24
Journal	Cell Host and Microbe
Volume	33
Issue number	5
DOIs	https://doi.org/10.1016/j.chom.2025.04.014
Publication status	Published - 14 May 2025

Keywords

aging
eicosanoid
EP4 receptor
gut microbiota
intestinal inflammation
mononuclear phagocyte
pathogenic T cells
prostaglandin E
resolution of inflammation
segmented filamentous bacteria

ASJC Scopus subject areas

Parasitology
Microbiology
Virology

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10.1016/j.chom.2025.04.014Licence: CC BY

Final published version
Cell Host & Microbe 33, 671–687, May 14, 2025 © 2025 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 16.5 MBLicence: CC BY

Cite this

Goepp, M., Milburn, J. V., Zhang, B., Dong, Y., Tyrrell, V., Zheng, X., Marshall, J. M., Bolsega, S., Basic, M., Glendinning, L., Ho, G. T., Satsangi, J., Breyer, R. M., Narumiya, S., McSorley, H. J., Schwarze, J. K. J., Anderson, C. J., Dockrell, D. H., Rossi, A. G., ... Yao, C. (2025). Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis. Cell Host and Microbe, 33(5), 671-687.e6. https://doi.org/10.1016/j.chom.2025.04.014

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title = "Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis",

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.",

keywords = "aging, eicosanoid, EP4 receptor, gut microbiota, intestinal inflammation, mononuclear phagocyte, pathogenic T cells, prostaglandin E, resolution of inflammation, segmented filamentous bacteria",

author = "Marie Goepp and Milburn, \{Jemma V.\} and Birong Zhang and Yijia Dong and Victoria Tyrrell and Xiaozhong Zheng and Marshall, \{Jennifer M.\} and Silvia Bolsega and Marijana Basic and Laura Glendinning and Ho, \{Gwo Tzer\} and Jack Satsangi and Breyer, \{Richard M.\} and Shuh Narumiya and McSorley, \{Henry J.\} and Schwarze, \{J{\"u}rgen K.J.\} and Anderson, \{Christopher J.\} and Dockrell, \{David H.\} and Rossi, \{Adriano G.\} and Andr{\'e} Bleich and Lucas, \{Christopher D.\} and O'Donnell, \{Valerie B.\} and Damian Mole and Arends, \{Mark J.\} and You Zhou and Chengcan Yao",

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day = "14",

doi = "10.1016/j.chom.2025.04.014",

language = "English",

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Goepp, M, Milburn, JV, Zhang, B, Dong, Y, Tyrrell, V, Zheng, X, Marshall, JM, Bolsega, S, Basic, M, Glendinning, L, Ho, GT, 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 2025, 'Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis', Cell Host and Microbe, vol. 33, no. 5, pp. 671-687.e6. https://doi.org/10.1016/j.chom.2025.04.014

TY - JOUR

T1 - Age-related impairment of intestinal inflammation resolution through an eicosanoid-immune-microbiota axis

AU - Goepp, Marie

AU - Milburn, Jemma V.

AU - Zhang, Birong

AU - Dong, Yijia

AU - Tyrrell, Victoria

AU - Zheng, Xiaozhong

AU - Marshall, Jennifer M.

AU - Bolsega, Silvia

AU - Basic, Marijana

AU - Glendinning, Laura

AU - Ho, Gwo Tzer

AU - Satsangi, Jack

AU - Breyer, Richard M.

AU - Narumiya, Shuh

AU - McSorley, Henry J.

AU - Schwarze, Jürgen K.J.

AU - Anderson, Christopher J.

AU - Dockrell, David H.

AU - Rossi, Adriano G.

AU - Bleich, André

AU - Lucas, Christopher D.

AU - O'Donnell, Valerie B.

AU - Mole, Damian

AU - Arends, Mark J.

AU - Zhou, You

AU - Yao, Chengcan

PY - 2025/5/14

Y1 - 2025/5/14

N2 - 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.

AB - 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.

KW - aging

KW - eicosanoid

KW - EP4 receptor

KW - gut microbiota

KW - intestinal inflammation

KW - mononuclear phagocyte

KW - pathogenic T cells

KW - prostaglandin E

KW - resolution of inflammation

KW - segmented filamentous bacteria

UR - https://www.scopus.com/pages/publications/105004602335

U2 - 10.1016/j.chom.2025.04.014

DO - 10.1016/j.chom.2025.04.014

M3 - Article

C2 - 40373750

AN - SCOPUS:105004602335

SN - 1931-3128

VL - 33

SP - 671-687.e6

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 5

ER -

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

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