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Although sodium butyrate (NaB), a microbiota\u2010derived short\u2010chain fatty acid, has demonstrated anti\u2010inflammatory and barrier\u2010protective properties, the immunological mechanisms underlying its protective effects during CDI remain incompletely understood. In this study, we investigated the role of NaB in regulating macrophage polarization and epithelial repair using murine CDI models, primary bone marrow\u2010derived macrophages, THP\u20101\u2010derived macrophages, Caco\u20102 epithelial cells and macrophage\u2013epithelial co\u2010culture systems. NaB treatment significantly alleviated CDI\u2010associated weight loss, colonic shortening, histopathological injury and inflammatory cytokine production while restoring epithelial barrier integrity and tight junction protein expression. Mechanistically, NaB promoted macrophage polarization towards an anti\u2010inflammatory M2 phenotype, characterized by increased CD206 and IL\u201010 expression and reduced CD86 and IL\u20101\u03b2 expression. These immunomodulatory effects were accompanied by suppression of PI3K\/Akt\/mTOR signalling in both colonic tissues and macrophages. Pharmacological inhibition and activation studies further supported the involvement of this pathway in NaB\u2010mediated macrophage reprogramming. Importantly, conditioned medium from NaB\u2010treated macrophages enhanced epithelial viability, migration and barrier\u2010associated protein expression, whereas IL\u201010 neutralization partially abolished these protective effects, highlighting a critical role for macrophage\u2013epithelial crosstalk. Collectively, our findings demonstrate that low\u2010dose NaB protects against CDI\u2010induced intestinal injury through coordinated regulation of macrophage polarization and epithelial barrier repair, at least in part via modulation of PI3K\/Akt\/mTOR signalling. These results identify NaB as a promising host\u2010directed therapeutic strategy for CDI and provide new insights into microbiota\u2010derived metabolite\u2013immune interactions during intestinal inflammation.\n                  <\/jats:p>","DOI":"10.1111\/imm.70179","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:08:47Z","timestamp":1786435727000},"page":"594-608","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunometabolic Modulation by Low\u2010Dose Sodium Butyrate:\n                    <scp>PI3K<\/scp>\n                    \/Akt\/\n                    <scp>mTOR<\/scp>\n                    Signalling Orchestrates Macrophage Polarization to Protect Against\n                    <i>Clostridioides difficile<\/i>\n                    Colitis"],"prefix":"10.1111","volume":"179","author":[{"given":"Sisi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Infection Control Center Xiangya Hospital, Central South University  Changsha Hunan Province China"},{"name":"National Clinical Research Center for Geriatric Disorder Xiangya Hospital  Changsha Hunan China"},{"name":"Super Drug\u2010Resistant Organism Infection Prevention and Control Research Center, Xiangya Hospital, Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou","family":"Jingxiang","sequence":"additional","affiliation":[{"name":"Department of Infection Control Center Xiangya Hospital, Central South University  Changsha Hunan Province China"},{"name":"National Clinical Research Center for Geriatric Disorder Xiangya Hospital  Changsha Hunan China"},{"name":"Super Drug\u2010Resistant Organism Infection Prevention and Control Research Center, Xiangya Hospital, Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Infection Control Center Xiangya Hospital, Central South University  Changsha Hunan Province China"},{"name":"National Clinical Research Center for Geriatric Disorder Xiangya Hospital  Changsha Hunan China"},{"name":"Super Drug\u2010Resistant Organism Infection Prevention and Control Research Center, Xiangya Hospital, Central South University  Changsha Hunan Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Infection Control Center Xiangya Hospital, Central South University  Changsha Hunan Province China"},{"name":"National Clinical Research Center for Geriatric Disorder Xiangya Hospital  Changsha Hunan China"},{"name":"Super Drug\u2010Resistant Organism Infection 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