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While IL-22 promotes epithelial barrier integrity and production of antimicrobial peptides, the precise mechanism underlying lethality remains unclear. Here, we show that following\n                    <jats:italic>C. rodentium<\/jats:italic>\n                    infection\n                    <jats:italic>Il22<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    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\n                    <jats:italic>C. rodentium<\/jats:italic>\n                    -infected\n                    <jats:italic>Il22<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    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\n                    <jats:italic>Il22<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice by correcting systemic dehydration. Survival is associated with locally increased\n                    <jats:italic>Reg3b<\/jats:italic>\n                    , IL-17F and IL-10 levels, suggesting activation of compensatory pathways that potentially support recovery in the absence of IL-22. Recovered\n                    <jats:italic>Il22<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice exhibit epithelial cell regeneration and tissue physiology similarly to\n                    <jats:italic>C. rodentium<\/jats:italic>\n                    -infected\n                    <jats:italic>Il22<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+\/+<\/jats:italic>\n                    <\/jats:sup>\n                    mice. These findings suggest that dehydration is the primary cause of mortality in\n                    <jats:italic>Il22<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-67006-x","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T09:07:01Z","timestamp":1765184821000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rehydration rescues Il22\u2212\/\u2212 mice from lethal Citrobacter rodentium infection"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7069-4613","authenticated-orcid":false,"given":"Vishwas","family":"Mishra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuza","family":"Kozik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1932-2352","authenticated-orcid":false,"given":"Priyanka","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0881-5477","authenticated-orcid":false,"given":"Jyoti","family":"Choudhary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8437-6731","authenticated-orcid":false,"given":"Joshua L. 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