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Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit

Cellular & Molecular Immunology volume 20, pages 119–130 (2023)Cite this article

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Abstract

Mannose is a naturally occurring sugar widely consumed in the daily diet; however, mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking. Herein, we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery. Macrophage-secreted inflammatory cytokines, particularly TNF-α, induced pathological endoplasmic reticulum stress (ERS) in intestinal epithelial cells (IECs), which was prevented by mannose via normalization of protein N-glycosylation. By preserving epithelial integrity, mannose reduced the inflammatory activation of colonic macrophages. On the other hand, mannose directly suppressed macrophage TNF-α production translationally by reducing the glyceraldehyde 3-phosphate level, thus promoting GAPDH binding to TNF-α mRNA. Additionally, we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease. Finally, we revealed that activating PMM2 activity with epalrestat, a clinically approved drug for the treatment of diabetic neuropathy, elicited further sensitization to the therapeutic effect of mannose. Therefore, mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages, thereby normalizing aberrant immunometabolism in the gut.

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All data associated with this study are presented in the paper or Supplementary Materials and are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (82271862 and 81873418 to YK, 82171730 to PX, 81970484 to QC), the Zhejiang Provincial Ten Thousand Program for Leading Talents of Science and Technology Innovation (2021R52015 to YK), and the Natural Science Foundation of Zhejiang Province (LY20H160032 to PX, LQ21H090064 to TP).

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Author notes

  1. These authors contributed equally: Peng Xiao, Ziwei Hu.

Authors and Affiliations

  1. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Peng Xiao, Ke Guo, Manlu Shen & Qian Cao

  2. Department of Pathology and Pathophysiology, and Department of Gastroenterology at Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Peng Xiao & Yuehai Ke

  3. Immunological Disease Research Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Peng Xiao, Ke Guo, Manlu Shen & Qian Cao

  4. Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China

    Peng Xiao

  5. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China

    Ziwei Hu, Jiaheng Lang, Huilun Zhang, Hongqiang Cheng, Xue Zhang & Yuehai Ke

  6. Department of General Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Tianyuan Pan

  7. Department of Immunology, Harvard Medical School, Boston, MA, USA

    Randall Tyler Mertens

  8. Zhejiang Laboratory for Systems and Precision Medicine, Zhejiang University Medical Center, Hangzhou, China

    Yuehai Ke

Authors
  1. Peng Xiao
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  11. Qian Cao
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Contributions

Conceptualization: PX, YK. Methodology: QC, ZH, HZ, PX, YK, HC, XZ. Investigation: ZH, HZ, JL, TP, RTM, KG, MS, PX. Visualization: ZH, HZ, JL, PX. Funding acquisition: TP, PX, QC, YK. Project administration: PX, YK, XZ, HC, QC. Supervision: PX, YK, XZ, QC. Writing—original draft: ZH, JL, PX, RTM, YK. Writing—review and editing: ZH, JL, PX, RTM, YK.

Corresponding authors

Correspondence to Peng Xiao, Qian Cao or Yuehai Ke.

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Xiao, P., Hu, Z., Lang, J. et al. Mannose metabolism normalizes gut homeostasis by blocking the TNF-α-mediated proinflammatory circuit. Cell Mol Immunol 20, 119–130 (2023). https://doi.org/10.1038/s41423-022-00955-1

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