Gut bacterial metabolic pathway, immune cells, and peripheral artery disease: A Mendelian randomization study

The purpose of this investigation is to determine the causal association between gut bacterial metabolic pathway and peripheral artery disease (PAD), in addition to identifying and quantifying the function of immune cells as potential mediators. Gut microbiota, gut bacterial metabolic pathway, and immune cells, and PAD were discovered using extensive genome-wide association studies summary data. We employed Mendelian randomization to study the causal links between gut microbiota, gut bacterial metabolic pathway, immune cells, and PAD. Inverse variance weighting was utilized as the major statistical approach. Moreover, we utilized 2-step Mendelian randomization to evaluate the extent of the influence of immune cell-mediated gut bacterial metabolic pathway on PAD. Genetic prediction of 3 bacterial metabolism pathways (KETOGLUCONMET-PWY, PWY-5345, and PWY-6892) was related to a reduced risk of PAD. The KETOGLUCONMET-PWY (odd ratios [OR] = 0.899, 95% CI = 0.830-0.974, P = .009), PWY-5345 (OR = 0.844, 95% CI = 0.731-0.974, P = .020), and PWY-6892 (OR = 0.855, 95% CI = 0.744-0.982, P = .027) significantly decreased the risk of PAD. We found that the traits of the following 5 immune cells were negatively related to PAD development (OR < 1, P < .05): Treg panel: CD3 on CD39+ CD4+ (OR = 0.966, 95% CI = 0.938-0.994, P = .016), CD3 on CD28+ CD4+ (OR = 0.953, 95% CI = 0.912-0.996, P = .031); Maturation stages of T cell panel: CM CD4+ %CD4+ (OR = 0.986, 95% CI = 0.974-0.999, P = .039); B cell panel: CD19 on IgD- CD38dim (OR = 0.962, 95% CI = 0.927-0.998, P = .037), CD19 on IgD+ (OR = 0.976, 95% CI = 0.955-0.996, P = .022). Mediation analysis identified immune cells as partially mediating the impact of gut bacterial metabolic pathway on PAD. This study presents genetic causality correlations between specific bacterial metabolism pathways and PAD, emphasizing the instrumental function of immune cells as mediators.