Shotgun metagenomic sequencing of the gut microbiome reveals hormone-specific taxonomic and functional shifts in PitNET patients

Background Pituitary neuroendocrine tumours (PitNETs) are common intracranial neoplasms arising from anterior pituitary hormone-secreting cells and account for 10–15% of intracranial tumours worldwide. The 2022 WHO classification stratifies PitNETs into four cell lineages — PIT1, TPIT, SF1, and lineage-undefined—that correspond to distinct hormone excess syndromes or non-functional tumours. Although surgery and first-line pharmacotherapies (somatostatin analogs for GH-, TSH-, and ACTH-secreting tumours; dopamine agonists for prolactinomas) can control hypersecretion, variable efficacy and gastrointestinal side effects highlight the need for new mechanistic insights. Emerging evidence implicates the gut microbiome in endocrine regulation via the hypothalamic–pituitary–adrenal axis, yet comprehensive metagenomic studies across PitNET subtypes are lacking. This study uses shotgun metagenomic sequencing to compare gut microbial composition and functional profiles in GH-secreting, PRL-secreting, and non-functional PitNET patients versus population controls and amongst each other. Results Alpha diversity analysis showed increased evenness in GH- and PRL-secreting tumours and greater dominance in GH and non-functional subtypes; genus-level depletion of Faecalibacterium and Bacteroides contrasted by Prevotella expansion across tumour hormonal subtypes and GH-specific Agathobacter enrichment. Species-level analysis demonstrated enrichment of mucosa-associated Prevotella species and succinate-utilizing anaerobes with depletion of niche-specific Oscillospirales, while functional shifts include GH-associated enhancement of carbohydrate catabolism, amino acid and cofactor biosynthesis, lipid remodeling, and stress-adaptation pathways. On the other hand, PRL tumours show inverse reductions in nucleotide, vitamin, and cell wall biosynthesis. We observed minimal taxonomic and functional overlap across subtypes which underscores hormone-specific gut microbiome remodeling, except for one notable species: Lawsonibacter sp900553135. Conclusions This is the first study to focus on microbiome alterations in multiple PitNET hormonal subtypes. Our results point to a highly specific hormonal hypersecretion induced microbiome disturbances both at the taxonomic and functional aspects. Lawsonibacter sp900553135 was the only species to show consistent depletion in all three PitNET hormonal subtypes, proposing a potential microbial biomarker related to PitNET-induced low-grade inflammation in the gut.