Gene-predicted Causal Association of Immune Cell-mediated Plasma Metabolites with Acute Hepatitis B: A Mendelian Randomization Study

INTRODUCTION: Acute Hepatitis B (AHB) remains a significant global health challenge, with complex interactions between metabolic and immune responses influencing disease progression. This study aimed to investigate the causal relationships between immune cell-mediated plasma metabolites and acute hepatitis B using Mendelian Randomization (MR) analysis. METHODS: A two-sample MR analysis was conducted using genome-wide association study data from the FinnGen consortium (133 AHB cases and 451,214 controls) to examine relationships between 1,400 plasma metabolites and 731 immune cell phenotypes. Inverse variance weighting, MR-Egger regression, and weighted median analyses were employed to assess causal relationships. Mediation analysis was performed to explore the role of immune cells in metabolite-AHB associations. RESULTS: A total of 49 circulating metabolites were identified as being significantly associated with AHB risk, including 32 risk factors (e.g., 4-methylguaiacol sulfate, N-formylmethionine) and 17 protective factors (e.g., indoleacetylglutamine, beta-hydroxyisovalerate). Mediation analysis revealed 12 pairs of immune cell-metabolite relationships significantly associated with AHB. Notably, phenyllactate levels negatively regulated AHB through CD39+ secreting Treg AC (MP=- 4.83%) and B cell AC (MP=-12.1%), while 4-methylguaiacol sulfate levels positively mediated AHB through CD38 on IgD+ CD24- (MP=6.41%) and naive-mature B cells (MP=7.37%). DISCUSSION: The study's findings provide genetic evidence for causal relationships between specific plasma metabolites and acute hepatitis B risk through immune cell-mediated pathways. The identification of phenyllactate as a protective factor via CD39+ regulatory T cells and 4-methylguaiacol sulfate as a risk factor through CD38+ B cells offers insights into the immunometabolic mechanisms underlying AHB pathogenesis. CONCLUSION: This Mendelian randomization study reveals novel causal associations between plasma metabolites and acute hepatitis B mediated by specific immune cell phenotypes, providing potential biomarkers and therapeutic targets for future hepatitis B management strategies.