CD8+ T Cell-Derived Perforin Exacerbates Dysbiosis and Inflammatory Bowel Disease via β-Hydroxybutyrate Suppression in Mouse Colonic Epithelium

作者：Shiyang Huang, Lehan Pan, Mingyang Li, Shu Pang, Yue Tian, Wen Shi, Ye Zong, Dong Zhang, Dan Tian · 发表于：Journal of Inflammation Research · 年份：2025 · DOI：10.2147/jir.s509875 · 被引用次数：4 · 研究领域：Clinical Nutrition and Gastroenterology、Microscopic Colitis

Background: 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−/−...