Age-Driven Gut Microbiome Dysbiosis Modulates Tumor Proliferation in silent corticotroph adenomas

Purpose Silent corticotroph adenomas (SCAs) are aggressive pituitary neuroendocrine tumors (PitNETs), with age being a controversial prognostic factor (younger patients have higher recurrence rates). The gut microbiome (GM)’s role in SCAs remains unexplored. This study aimed to investigate how age-driven GM dysbiosis modulates SCA tumor proliferation, focusing on associations with the Ki-67 proliferation index. Methods An integrative dual-cohort design was used. A prospective cohort included 11 female SCA patients (fecal samples analyzed via metagenomic sequencing). A retrospective cohort expanded to 70 female SCA patients to validate age-Ki-67 associations. Results In the prospective cohort, younger patients (≤ 40 years) had reduced gut microbial alpha diversity (Shannon index, p = 0.0456) and distinct community structures (beta diversity, p < 0.001), with 44 differentially abundant species (OPLS-DA). Several species correlated positively with age but negatively with Ki-67 and tumor size (protective potential). The retrospective cohort confirmed younger age as an independent predictor of elevated Ki-67 (p < 0.001) after adjusting for recurrence. Conclusion Age-driven GM dysbiosis is linked to higher Ki-67 indices in SCAs, indicating microbial modulation of tumor proliferation. Younger patients have dysbiotic profiles associated with aggressive tumor biology. Key identified species may be targets for microbiome-based interventions, highlighting the need for age-specific SCA management.