Rehydration rescues Il22-/- mice from lethal Citrobacter rodentium infection
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Interleukin-22 (IL-22) is considered indispensable for host defence against Citrobacter rodentium, with 100% mortality of Il22 -/- mice. While IL-22 promotes epithelial barrier integrity and production of antimicrobial peptides, the precise mechanism underlying lethality remains
unclear. Here, we show that following C. rodentium infection Il22-/- mice succumb due to dehydration, rather than failure to control bacterial burden or regenerate damaged intestinal epithelium. Proteomic and gene expression analysis reveal greater enterocyte depletion in C. rodentium-infected Il22-/- mice, resulting in significant reductions in ion transporter abundances. We show that while not reducing bacterial load, improving the gut barrier integrity, or affecting immune responses, fluid therapy (FT) fully rescues Il22-/- mice by correcting systemic dehydration. Survival is associated with locally increased Reg3b, IL-17F and IL-10 levels, suggesting activation of compensatory pathways that potentially support recovery in the absence of IL-22. Recovered Il22-/- mice exhibit epithelial cell regeneration and tissue physiology similarly to C. rodentium-infected Il22+/+ mice. These findings suggest that
dehydration is the primary cause of mortality in Il22-/- mice and reveal that IL-22 prevent this outcome by preserving epithelial integrity and fluid-ion absorption. Importantly, this study underscores the necessity of incorporating supportive therapies into preclinical infection models to better reflect physiological settings and improve their relevance in modelling human disease.
unclear. Here, we show that following C. rodentium infection Il22-/- mice succumb due to dehydration, rather than failure to control bacterial burden or regenerate damaged intestinal epithelium. Proteomic and gene expression analysis reveal greater enterocyte depletion in C. rodentium-infected Il22-/- mice, resulting in significant reductions in ion transporter abundances. We show that while not reducing bacterial load, improving the gut barrier integrity, or affecting immune responses, fluid therapy (FT) fully rescues Il22-/- mice by correcting systemic dehydration. Survival is associated with locally increased Reg3b, IL-17F and IL-10 levels, suggesting activation of compensatory pathways that potentially support recovery in the absence of IL-22. Recovered Il22-/- mice exhibit epithelial cell regeneration and tissue physiology similarly to C. rodentium-infected Il22+/+ mice. These findings suggest that
dehydration is the primary cause of mortality in Il22-/- mice and reveal that IL-22 prevent this outcome by preserving epithelial integrity and fluid-ion absorption. Importantly, this study underscores the necessity of incorporating supportive therapies into preclinical infection models to better reflect physiological settings and improve their relevance in modelling human disease.
Date Issued
2026-01-09
Date Acceptance
2025-11-20
Citation
Nature Communications, 2026, 17
ISSN
2041-1723
Publisher
Nature Portfolio
Journal / Book Title
Nature Communications
Volume
17
Copyright Statement
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41467-025-67006-x
Publication Status
Published
Article Number
ARTN 306
Date Publish Online
2025-12-08