Abstract
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-/- 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.