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  3. Gasdermin-D-mediated epithelial-immune circuit synchronizes nutrient absorption and host defense in the small intestine

Gasdermin-D-mediated epithelial-immune circuit synchronizes nutrient absorption and host defense in the small intestine

  • Immunity. 2025 Sep 9;58(9):2226-2240.e7. doi: 10.1016/j.immuni.2025.06.019.
Qianzhou Yu 1,  Danlu Jiang 1,  Tianming Zhao 1,  Yuelin Guan 2,  Jian Zhang 3,  Dehang Yang 1,  Ruya Sun 1,  Weiwei Yu 4,  Zhen Wang 1,  Sheng Chen 4,  Mobai Li 1,  Tianyi Hu 1,  Qiqi Deng 1,  Xiaoyang Lu 1,  Yidong Yang 1,  Mengfei Chang 1,  Liheng Du 1,  Xue Zhang 5,  Zhexu Chi 6,  Di Wang 7
Affiliations

Affiliations

  • 1 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 2 National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310052, P.R. China.
  • 3 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, P.R. China.
  • 4 Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 5 Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 6 International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang, P.R. China. Electronic address: ralf@zju.edu.cn.
  • 7 Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, P.R. China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. Electronic address: diwang@zju.edu.cn.
PMID: 40712560 DOI: 10.1016/j.immuni.2025.06.019
Abstract

The small intestine (SI) absorbs nutrients and acts as a barrier against pathogens. Diet enables the absorptive function of the SI while maintaining immune homeostasis. But how the SI transmits nutritional signals to the immune response and adapts to dietary intake remains unclear. Here, we demonstrated that epithelial gasdermin D (GSDMD) in the SI facilitated the absorptive function of enterocytes, subsequently empowering an epithelial-immune cooperation to modulate host defense. Unlike its pyroptotic function, GSDMD determines the absorptive versus the defensive zonation of enterocytes and promotes brush border assembly. This diet-induced, GSDMD-mediated adaptation promoted lipid absorption and subsequently rewired enterocyte metabolism to support intraepithelial γδ T lymphocytes (γδ T-IELs), thereby enhancing barrier function. Impairment of this GSDMD-mediated circuit exacerbated barrier-dysfunction-associated enteritis. Our results reveal how epithelial cells and lymphocytes co-adapt to nutrient signals in the SI, thereby adjusting the equilibrium between nutrient uptake and host defense in response to environmental change.

Keywords

GSDMD; brush border assembly; enteritis; enterocyte; feeding pattern; host defense; intraepithelial γδ T lymphocytes; nutrient absorption; nutritional imbalance; the small intestine.

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