Immunometabolic Modulation by Low‐Dose Sodium Butyrate: PI3K/Akt/mTOR Signalling Orchestrates Macrophage Polarization to Protect Against Clostridioides difficile Colitis
- 1Department of Infection Control Center Xiangya Hospital, Central South University Changsha Hunan Province China
- 2National Clinical Research Center for Geriatric Disorder Xiangya Hospital Changsha Hunan China
- 3Super Drug‐Resistant Organism Infection Prevention and Control Research Center, Xiangya Hospital, Central South University Changsha Hunan Province China
Abstract
Clostridioides difficile infection (CDI) remains a major cause of antibiotic‐associated colitis and is characterized by excessive intestinal inflammation, epithelial barrier disruption and impaired mucosal repair. Although sodium butyrate (NaB), a microbiota‐derived short‐chain fatty acid, has demonstrated anti‐inflammatory and barrier‐protective 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‐derived macrophages, THP‐1‐derived macrophages, Caco‐2 epithelial cells and macrophage–epithelial co‐culture systems. NaB treatment significantly alleviated CDI‐associated 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‐inflammatory M2 phenotype, characterized by increased CD206 and IL‐10 expression and reduced CD86 and IL‐1β 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‐mediated macrophage reprogramming. Importantly, conditioned medium from NaB‐treated macrophages enhanced epithelial viability, migration and barrier‐associated protein expression, whereas IL‐10 neutralization partially abolished these protective effects, highlighting a critical role for macrophage–epithelial crosstalk. Collectively, our findings demonstrate that low‐dose NaB protects against CDI‐induced 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‐directed therapeutic strategy for CDI and provide new insights into microbiota‐derived metabolite–immune interactions during intestinal inflammation.
Related
- p38α orchestrates BRAFV600E-melanoma progression and immunotherapy response via tumor fitness and immune microenvironment modulation.
- Nanotherapeutic macrophage reprogramming through immunometabolic and microbial modulation for sepsis treatment.
- Overexpression of TUBA1A suppresses bladder cancer progression with potential modulation of autophagic activity and macrophage polarization
- Epidemiology, risk factors and outcomes of Clostridioides difficile infection in a UK district general hospital: a retrospective cohort study
- Comparative Efficacy of Vancomycin and Fidaxomicin Regimens for the Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials
BibTeX
@article{zhang2026immunometabolic,
title = {{Immunometabolic Modulation by Low‐Dose Sodium Butyrate: PI3K/Akt/mTOR Signalling Orchestrates Macrophage Polarization to Protect Against Clostridioides difficile Colitis}},
author = {Sisi Zhang and Zhou Jingxiang and Caixia Tan and Yuanyuan Xiao and Ju Zou and Biyue Tian and Anhua Wu and Chunhui Li},
journal = {Immunology},
year = {2026},
month = aug,
doi = {10.1111/imm.70179},
url = {https://doi.org/10.1111/imm.70179},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immunometabolic Modulation by Low‐Dose Sodium Butyrate: PI3K/Akt/mTOR Signalling Orchestrates Macrophage Polarization to Protect Against Clostridioides difficile Colitis
AU - Sisi Zhang
AU - Zhou Jingxiang
AU - Caixia Tan
AU - Yuanyuan Xiao
AU - Ju Zou
AU - Biyue Tian
AU - Anhua Wu
AU - Chunhui Li
PY - 2026
DA - 2026/08/11
JO - Immunology
DO - 10.1111/imm.70179
UR - https://doi.org/10.1111/imm.70179
AB - Clostridioides difficile infection (CDI) remains a major cause of antibiotic‐associated colitis and is characterized by excessive intestinal inflammation, epithelial barrier disruption and impaired mucosal repair. Although sodium butyrate (NaB), a microbiota‐derived short‐chain fatty acid, has demonstrated anti‐inflammatory and barrier‐protective 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‐derived macrophages, THP‐1‐derived macrophages, Caco‐2 epithelial cells and macrophage–epithelial co‐culture systems. NaB treatment significantly alleviated CDI‐associated 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‐inflammatory M2 phenotype, characterized by increased CD206 and IL‐10 expression and reduced CD86 and IL‐1β 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‐mediated macrophage reprogramming. Importantly, conditioned medium from NaB‐treated macrophages enhanced epithelial viability, migration and barrier‐associated protein expression, whereas IL‐10 neutralization partially abolished these protective effects, highlighting a critical role for macrophage–epithelial crosstalk. Collectively, our findings demonstrate that low‐dose NaB protects against CDI‐induced 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‐directed therapeutic strategy for CDI and provide new insights into microbiota‐derived metabolite–immune interactions during intestinal inflammation.
SN - 0019-2805
SN - 1365-2567
ER -