Dissecting the immune-metabolic axis in appendicitis: A Mendelian randomization mediation study

Area of Science:

• Immunology
• Metabolomics
• Gastroenterology

Background:

• Appendicitis development is linked to immune and metabolic dysregulation.
• Causal pathways connecting immune and metabolic factors to appendicitis remain unclear.

Purpose of the Study:

• To investigate the causal effect of immune cell traits on appendicitis risk.
• To assess the mediating role of plasma metabolites in this relationship.

Main Methods:

• Mendelian randomization (MR) analysis using genome-wide association study summary statistics from European cohorts.
• Included 731 immune cell traits, 1400 plasma metabolites, and appendicitis data.
• Employed inverse variance weighted method, mediation analysis, and reverse MR.

Main Results:

• Initially, three immune cell traits and 12 plasma metabolites showed significant associations with appendicitis risk.
• CD86+ plasmacytoid dendritic cells showed a protective effect; CD28+ T cells and CD27 on IgD+ memory B cells were linked to increased risk.
• 13-HODE + 9-HODE levels partially mediated the effect of CD28+ T cells on appendicitis (17.7% mediation).
• Sensitivity analyses found no evidence of heterogeneity, pleiotropy, or reverse causation.
• However, after FDR adjustment, no associations remained significant, indicating exploratory findings.

Conclusions:

• The study provides exploratory evidence for an immune-metabolic axis in appendicitis pathogenesis.
• Identified potential causal pathways and mediators warranting further investigation.
• Results are hypothesis-generating and require validation in independent datasets before clinical application.