Department of Neurosurgery, Huashan Hospital Fudan University, Shanghai, 200040, China.
Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Adv Sci (Weinh). 2024 Oct;11(39):e2400684. doi: 10.1002/advs.202400684. Epub 2024 Sep 3.
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::Braf::Pten 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.
颅咽管瘤（CP）是一种高死亡率和发病率的颅内肿瘤。尽管生物学上是良性的，但 CP 会损害下丘脑，导致肥胖、代谢综合征和认知障碍等合并症。本研究旨在探索肠道微生物组和血清代谢组在 CP 相关下丘脑合并症中的作用。CP 患者的 Shannon 多样性、真杆菌属、梭菌属和罗氏菌属增加，而拟杆菌属和双歧杆菌属减少。CP 富集的分类群与血脂异常和认知能力下降呈正相关，而 CP 耗尽的分类群与脂肪肝呈负相关。随后的血清代谢组学鉴定出嘌呤代谢显著上调，综合分析表明，微生物群的改变与次黄嘌呤的升高有关。Rax-CreER::Braf::Pten 小鼠模型的表型研究和多组学分析验证了增加的梭菌属和嘌呤代谢失调在下丘脑合并症中的潜在作用。为了进一步证实这一点，进行了干预实验，发现次黄嘌呤与下丘脑合并症的严重程度和梭菌属的丰度共变，并在靶器官（肝脏和大脑皮层）中诱导嘌呤代谢失调和氧化还原失衡。总之，该研究表明增加的梭菌属和上调的嘌呤代谢可能作为 CP 相关下丘脑合并症的特征，并揭示了升高的梭菌属、嘌呤代谢失调和氧化还原失衡可能介导 CP 相关下丘脑合并症的发生和发展。
