Background <p>Previous observational studies have hinted at a connection between the gut microbiota and pituitary neuroendocrine tumors, yet the causal nature of this relationship remains uncertain.</p> Methods <p>We employed a bidirectional Mendelian randomization to explore the potential impact of gut microbiota on the susceptibility to developing pituitary neuroendocrine tumors. Our analysis included weighted median estimator, simple model, weighted model, inverse variance-weighted, and the MR-Egger regression method for estimating causal effects and conducting sensitivity analyses. Additionally, reverse Mendelian randomization analysis was conducted on bacteria identified as causally linked to pituitary neuroendocrine tumors.</p> Results <p>Causal relationships were identified between genetic predisposition in the gut microbiota and pituitary neuroendocrine tumors, involving 11 distinct bacterial families and genera. Notably, no significant causal effect was detected from pituitary neuroendocrine tumors on the gut microbiota, and there were no significant heterogeneities observed in instrumental variables or horizontal pleiotropy.</p> Conclusion <p>Through two-sample Mendelian randomization analysis, we pinpointed particular gut microbiota with a causal link to both the occurrence and prognosis of pituitary neuroendocrine tumors at the genetic prognostic level. These findings hold promise for serving as valuable biomarkers for early disease detection and as potential therapeutic targets for the management of pituitary neuroendocrine tumors.</p>