CD8+ T Cell-Derived Perforin Exacerbates Dysbiosis and Inflammatory Bowel Disease via β-Hydroxybutyrate Suppression in Mouse Colonic Epithelium
Shiyang Huang,1,2,* Lehan Pan,3– 5,* Mingyang Li,1,2 Shu Pang,4– 7 Yue Tian,8 Wen Shi,1,2 Ye Zong,4– 6 Dong Zhang,8– 10 Dan Tian3– 5 1Immunology Research Center for Oral and Systemic Health, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical Uni...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2025-05-01
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| Series: | Journal of Inflammation Research |
| Subjects: | |
| Online Access: | https://www.dovepress.com/cd8-t-cell-derived-perforin-exacerbates-dysbiosis-and-inflammatory-bow-peer-reviewed-fulltext-article-JIR |
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| Summary: | Shiyang Huang,1,2,* Lehan Pan,3– 5,* Mingyang Li,1,2 Shu Pang,4– 7 Yue Tian,8 Wen Shi,1,2 Ye Zong,4– 6 Dong Zhang,8– 10 Dan Tian3– 5 1Immunology Research Center for Oral and Systemic Health, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 4National Clinical Research Center for Digestive Diseases, Beijing, People’s Republic of China; 5State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 6Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 7Department of General Practice, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 8Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 9Beijing Institute of Brain Disorders, Capital Medical University, Beijing, People’s Republic of China; 10Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dan Tian, Email tiand@ccmu.edu.cn Dong Zhang, Email zhangd@ccmu.edu.cnBackground: The etiology and pathogenesis of inflammatory bowel disease (IBD) are generally thought to be related to immune dysfunction and intestinal microbiota dysbiosis. However, the exact mechanisms remain unclear.Methods: We applied a DSS-induced colitis model in wild-type and perforin-deficient (Prf1−/−) mice. Adoptive transfer experiments and metabolic profiling were conducted, and 16S rRNA gene sequencing analyzed gut microbiota. The impact of a 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) inhibitor on inflammation and dysbiosis was also assessed.Results: In this study, we demonstrated that perforin production in CD8+ T cells was significantly increased in both patients with IBD and mice with colitis. Moreover, compared with wild-type mice, perforin deficiency (Prf1−/−) mice exhibited mitigated inflammation in a DSS-induced colitis model. The CD8+ T cell adoptive transfer model indicated that perforin produced by CD8+ T cells directly induced colitis. Prf1−/− mice with colitis exhibited activation of the fatty acid metabolic process, highlighted by increased expression of Hmgcs2 and pyruvate dehydrogenase kinase isoform 4 (Pdk4) in the colon and accumulation of the related metabolite β-hydroxybutyrate. The absence of perforin partly reversed the imbalance in the gut microbiota composition caused by DSS, including increases in Alloprevotella and Parabacteroides. However, the HMGCS2 inhibitor exacerbated intestinal inflammation and dysbiosis in Prf1−/− mice.Conclusion: CD8+ T cell-derived perforin promoted colitis by disrupting gut microbiota composition through the suppression of β-hydroxybutyrate production. This study provides novel targets for therapeutic strategies of IBD.Keywords: perforin, CD8+ T cells, inflammatory bowel disease, microbiomes, β-hydroxybutyrate |
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| ISSN: | 1178-7031 |