Abstract
The gut microbiota may influence the occurrence and development of colorectal neuroendocrine tumors (CR-NETs), with inflammatory mediators potentially playing an important intermediary role. However, the current research evidence is insufficient to support this view. In this study, we extracted SNP data from different Genome-Wide Association Study (GWAS) summary statistics. Using bidirectional two-sample Mendelian randomization (MR), two-step MR, and multivariable Mendelian randomization (MVMR) methods, we explored the causal relationship between gut microbiota, inflammatory proteins, and CR-NETs. Our study found that five types of gut microbiota (family Acidaminococcaceae, family Porphyromonadaceae, genus Oscillospira, genus Paraprevotella, genus Ruminococcaceae NK4A214 group) and five inflammatory mediators (C-C motif chemokine Ligand 4, C-C motif chemokine Ligand 23, TNF-related apoptosis-inducing ligand, C-X-C motif chemokine Ligand 5, Monocyte chemoattractant protein 2) have a causal relationship with CR-NETs. Additionally, C-C motif chemokine Ligand 23 (CCL23) mediated the causal effect of family Porphyromonadaceae on CR-NETs (with a mediation proportion of 6.3%), while C-C motif chemokine Ligand 4 (CCL4) mediated the causal effect of genus Ruminococcaceae NK4A214 group on CR-NETs (with a mediation proportion of 4.7%). There is a causal relationship between gut microbiota and inflammatory proteins in the development of CR-NETs, with CCL23 and CCL4 possibly playing a mediating role.