Multi-omics study reveals gut microbiota dysbiosis and tryptophan metabolism alterations in GH-PitNET progression

Growth hormone-secreting pituitary neuroendocrine tumors (GH-PitNETs) arise from the anterior pituitary gland and constitute 20-30% of all PitNETs, representing a significant subset of functional pituitary tumors. Despite their prevalence, the precise mechanisms underlying the development of these tumors remain elusive due to the complex pathophysiology of pituitary neoplasia. To investigate the potential role of the gut microbiome in GH-PitNETs, we conducted a comprehensive study involving 16S rRNA gene sequencing and metabolomics analysis of fecal and serum samples from 20 GH-PitNET patients and 30 healthy controls at Peking Union Medical College Hospital. Our findings revealed a distinct gut microbiota profile in GH-PitNET patients compared to healthy individuals, characterized by dysbiosis with increased abundance of Bacteroides and decreased abundance of Blautia and Bifidobacterium. Notably, alterations in specific bacterial taxa, including Intestinibacter bartlettii, Fusicatenibacter faecihominis, and Massilioclostridium, were observed in GH-PitNET patients. Concomitantly, serum metabolomics analysis identified 154 differentially abundant metabolites in GH-PitNET patients, with significant enrichment in pathways related to tryptophan metabolism. Among these metabolites, 3-indoleacetic acid (IAA) exhibited a obvious change, suggesting its potential research value for disease processing of GH-PitNETs. To further elucidate the mechanistic link between the gut microbiome and GH-PitNETs, we conducted in vitro and in vivo experiments, our results demonstrated that IAA could promote the proliferation of GH3 cells and significantly enhance growth hormone secretion by activating the cAMP pathway. These findings collectively suggest that gut microbiota dysbiosis may contribute to in the development and progression of GH-PitNETs by contributing to metabolic disturbances.