DRD2 Deficiency Underlies Pituitary Adenoma Dependent on Escherichia coli Translocation from the Gut

ABSTRACT Pituitary adenoma (PA) are common intracranial tumor types that have harmful effects on human health. However, the pathogenesis of PA remains unclear yet. The intratumoral microbiome has been reported playing an important impact on the occurrence, metastasis, immune monitoring, and drug resistance of various tumors. While normal dopamine receptor D2 (DRD2) expression is enriched in the apical junction of pituitary epithelium and colonic enterocytes, various factors‐induced drd2 loss dampened its expression at both sites. DRD2 deficiencies are characterized by chronic hyperprolactinemia, pituitary lactotroph hyperplasia, and prolactinomas in mice, but the role of intratumoral microbiome in prolactinomas is not known. We employed specific pathogen‐free (SPF) and germ‐free (GF) mice models and patient samples of pituitary adenoma. In the mice pituitary tumor model, we used mice that developed prolactinomas following estradiol treatment or DRD2 deficiencies. Pituitary tumor samples from patients with nonfunctional pituitary adenoma or prolactinomas were obtained after surgical excision. Various molecular, cellular, and sequencing techniques were used to determine the role of intratumoral microbiome in pituitary adenoma. We demonstrate that human patients or murine bearing estradiol‐induction or DRD2 loss are all characterized by the presence of live intratumor bacteria in the pituitary adenoma. Using metagenomic next‐generation sequencing and mass spectrometry techniques, we confirm that the bacterial species of pituitary tumor tissues is Escherichia coli . In vitro tracing and immunofluorescence assay results showed that the pathobiont Escherichia coli translocates from the gut into the pituitary gland along with DRD2 loss while the blood pituitary barrier were both destroyed in mice. The Escherichia coli are phagocytosed by the microglial cells in the pituitary gland, then activate GSDMD protein releasing HMGB1, and promote the tumorigenesis of pituitary adenoma by activating the MAPK pathway. The depletion of bacteria systemically, microglial depletion or HMGB1 inhibitor ethyl pyruvate rescued prolactinomas. Our findings suggest that DRD2 deficiency underlies pituitary adenoma dependent on Escherichia coli translocation from the gut and activating microglia GSDMD/ HMGB1/MAPK pathway, and provide a novel preclinical rationale for antimicrobial agents, microglial depletion, or HMGB1 inhibitor ethyl pyruvate for the treatment of pituitary adenoma.