Role of CD25hi CD45RA+ CD4 not Treg %T cell in mediating the effect of pyruvate fermentation to acetone on intrahepatic cholangiocarcinoma

This study aimed to elucidate the potential correlation between gut microbiota and intrahepatic cholangiocarcinoma (ICC) by investigating their causal relationship, while also exploring the possible role of immune cells as mediators in this association. We first identified gut microbiota based on phylum, class, order, family, and genus level information. Using summary-level data from a Genome-Wide Association Study (GWAS), we performed a 2-sample Mendelian randomization (MR) analysis of ICC and gut microbiota. Furthermore, we used 2-step MR to quantify the proportion of the effect of immune cell-mediated gut microbiota on ICC. MR analysis identified pyruvate fermentation to acetone (PFA) as predicting ICC risk reduction. There was no strong evidence that genetically predicted ICC had an effect on PFA risk. Furthermore, the proportion of genetically predicted PFA mediated by CD25hi CD45RA+ CD4 not Treg %T cell (CCCTT) was 3% (95% CI: 0.93-5.03%). In conclusion, our study established a causal relationship between PFA and ICC. We observed that a minor fraction of this effect was mediated by CCCTT, while the majority of the impact exerted by PFA on ICC remains elusive. However, further investigations are warranted to elucidate the mechanisms underlying the influence of gut microbiota on ICC development.