Exploring the role of succinyl carnitine in the association between CD39⁺ CD4⁺ T cell and ulcerative colitis: A Mendelian randomization study

TL;DR

This study finds that CD39⁺ CD4⁺ T cells may increase the risk of ulcerative colitis, partly through the metabolite succinyl carnitine, suggesting a new immunometabolic pathway.

Contribution

The study identifies a novel causal link between CD39⁺ CD4⁺ T cells and UC, partially mediated by succinyl carnitine, using Mendelian randomization.

Findings

CD39⁺ CD4⁺ T cells have a statistically significant positive causal effect on ulcerative colitis risk.

Succinyl carnitine partially mediates the effect of CD39⁺ CD4⁺ T cells on UC with a 3.3% mediation proportion.

The relationship is unidirectional, as UC does not causally affect CD39⁺ CD4⁺ T cell levels.

Abstract

This study aimed to investigate the potential causal relationship between immune cell and the risk of ulcerative colitis (UC), and to explore whether serum metabolites may mediate this association, thereby suggesting potential biomarkers or therapeutic targets.

We conducted a Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies to evaluate both the direct effects and potential mediating roles of 731 immune cells and 1,400 serum metabolites in relation to UC. Instrumental variables were rigorously selected based on genome-wide significance and linkage disequilibrium thresholds. The primary analytical method was inverse variance weighted, supplemented by MR-Egger regression and weighted median methods to ensure robustness. Cochran’s Q test, MR-Egger intercept, and leave-one-out analysis were employed to evaluate heterogeneity and pleiotropy. Mediation MR analysis was conducted to examine potential metabolite-mediated pathways.

We identified a statistically significant positive causal effect of CD39⁺ CD4⁺ T cell on UC risk (OR = 1.05, 95% CI = 1.03–1.08, beta_all = 0.05). Sensitivity analyses confirmed the robustness of this association, and reverse MR analysis indicated no causal effect of UC on CD39⁺ CD4⁺ T cell, suggesting a unidirectional relationship. Mediation analysis further revealed that succinyl carnitine (C4DC) partially mediated the effect of CD39⁺ CD4⁺ T cell on UC, with a mediation proportion of 3.3%.

Our findings suggest that CD39⁺ CD4⁺ T cell may increase the risk of UC, potentially by modulating the levels of succinyl carnitine (C4DC). These results indicate a potential immunometabolic pathway in UC pathogenesis and highlight CD39⁺ CD4⁺ T cell and C4DC as promising targets for further research. However, additional experimental validation is required to confirm these findings and assess their clinical relevance.

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