Integrated Microbiome and Metabolome Analysis Reveals Hypothalamic‐Comorbidities Related Signatures in Craniopharyngioma

Abstract Craniopharyngioma (CP) is an intracranial tumor with high mortality and morbidity. Though biologically benign, CP will damage the hypothalamus, inducing comorbidities such as obesity, metabolic syndrome, and cognitive impairments. The roles of gut microbiome and serum metabolome in CP‐associated hypothalamic comorbidities are aimed to be explored. Patients with CP are characterized by increased Shannon diversity, Eubacterium, Clostridium, and Roseburia, alongside decreased Alistipes and Bacteroides. CP‐enriched taxa are positively correlated with dyslipidemia and cognitive decline, while CP‐depleted taxa are negatively associated with fatty liver. Subsequent serum metabolomics identified notably up‐regulated purine metabolism, and integrative analysis indicated an association between altered microbiota and elevated hypoxanthine. Phenotypic study and multi‐omics analysis in the Rax‐CreER^T2::Braf^V600E/+::Pten^Flox/+ mouse model validated potential involvement of increased Clostridium and dysregulated purine metabolism in hypothalamic comorbidities. To further consolidate this, intervention experiments are performed and it is found that hypoxanthine co‐variated with the severity of hypothalamic comorbidities and abundance of Clostridium, and induced dysregulated purine metabolism along with redox imbalance in target organs (liver and brain cortex). Overall, the study demonstrated the potential of increased Clostridium and up‐regulated purine metabolism as signatures of CP‐associated hypothalamic‐comorbidities, and unveiled that elevated Clostridium, dysregulated purine metabolism, and redox imbalance may mediate the development and progression of CP‐associated hypothalamic‐comorbidities.