Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, China.
Eur J Endocrinol. 2024 Oct 29;191(5):509-522. doi: 10.1093/ejendo/lvae139.
The aim of this study was to investigate the gut microbial signatures and related pathophysiological implications in patients with Cushing's disease (CD).
Twenty-seven patients with CD and 45 healthy controls were enrolled. Based on obtained metagenomics data, we performed correlation, network study, and genome interaction group (GIG) analysis. Fecal metabolomics and serum enzyme linked immunosorbent assay (ELISA) analysis were conducted in dichotomized CD patients. Caco-2 cells were incubated with gradient concentrations of cortisol for subsequent transepithelial electrical resistance (TEER) measurement, FITC-dextran transwell permeability assay, qPCR, and western blot analysis.
Gut microbial composition in patients with CD was notably different from that in healthy controls. Network analysis revealed that Eubacterium siraeum might serve as the core specie in the gut microbial system of CD patients. Subsequent GIG analysis identified the positive correlations between GIG9 and UFC. Further serum ELISA and fecal metabolomics uncovered that CD patients with elevated UFC levels were characterized with increased lipopolysaccharide binding protein (LBP). Moreover, remarkable positive association was found between LBP level and relative abundance of E. siraeum. TEER and FITC-dextran transwell assays demonstrated that hypercortisolism induced increased gut permeability. Further qPCR and western blot analysis suggested that dysregulated AhR/Claudin 2 axis might be involved in the development of hypercortisolism-induced defective gut barrier function.
Disease activity associated dysbiosis and defective gut barrier might jointly facilitate the development of systemic inflammation in patients with CD.
本研究旨在探讨库欣病（CD）患者的肠道微生物特征及其相关的病理生理意义。
共纳入 27 例 CD 患者和 45 例健康对照者。基于获得的宏基因组学数据，我们进行了相关性、网络研究和基因组相互作用群（GIG）分析。对二分法 CD 患者进行粪便代谢组学和血清酶联免疫吸附试验（ELISA）分析。将 Caco-2 细胞与梯度浓度的皮质醇孵育，随后进行跨上皮电阻（TEER）测量、FITC-葡聚糖透壁通透性测定、qPCR 和 Western blot 分析。
CD 患者的肠道微生物组成明显不同于健康对照者。网络分析显示，Eubacterium siraeum 可能是 CD 患者肠道微生物系统的核心种。随后的 GIG 分析确定了 GIG9 和 UFC 之间的正相关。进一步的血清 ELISA 和粪便代谢组学揭示，UFC 水平升高的 CD 患者的特征是脂多糖结合蛋白（LBP）增加。此外，LBP 水平与 E. siraeum 的相对丰度之间存在显著的正相关。TEER 和 FITC-葡聚糖透壁试验表明，高皮质醇血症诱导肠道通透性增加。进一步的 qPCR 和 Western blot 分析表明，失调的 AhR/ Claudin 2 轴可能参与了高皮质醇血症诱导的肠道屏障功能缺陷的发生。
与疾病活动相关的失调和肠道屏障功能缺陷可能共同促进 CD 患者的全身炎症发展。
