The gut microbiota, circulating metabolites, immune cells, and pancreatitis risk: Evidence from a bidirectional two-sample Mendelian randomization study and mediation analysis

Acute pancreatitis (AP) and chronic pancreatitis (CP) are the most prominent inflammatory diseases of the pancreas that pose a significant socioeconomic burden. The goal of this study was to explore the causal interactions between gut microbiota, circulating metabolites, immune cells, and the development of pancreatitis. Summary statistics of 473 gut microbiota, 233 metabolites, 731 immune cells, AP and CP data were sourced from publicly accessible genome-wide association studies. This bidirectional 2-sample Mendelian randomization study was employed to access causal effects. To validate the Mendelian randomization findings, various sensitivity analyses were conducted. Additionally, Mediation analyses were performed to quantified the underlying pathways. We identified 36 gut microbiota, 25 metabolites, and 69 immune cell subtypes that were suggested the causal relationships with pancreatitis. Anaeromassilibacillus and Thermoprotei increase the risk of both AP and CP (AP: odds ratio [OR] = 1.25, P = .044; CP: OR = 3.49, P = .035), while Cyanobacteria reduced risk of CP (OR = 0.65, P = .011). For metabolites, intermediate density lipoprotein-free cholesterol ratios increased AP risk (OR = 1.89, P = .004), whereas ω-3 fatty acids were protected against CP (OR = 0.59, P = .015). Immune profiling implicated HLA DR + CD8 + T cells in AP progression (OR = 1.10, P < .05) and CD20 + B cells in CP protection (OR = 0.94, P < .05). Mediation analysis revealed 24 pathways. Sensitivity analysis represented no heterogeneity or pleiotropy in this study. This study supports the causal effects of gut microbiota, metabolites, and immune cells on pancreatitis. Our findings highlight therapeutic potential for targeting gut microbiota to pancreatitis interactions. These findings offer fresh perspectives on the mechanisms driving pancreatitis and may aid in advancing its prevention, diagnostic strategies, and therapeutic interventions.