Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital Central South University, Changsha 410008, China; International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standards, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital Central South University, Changsha 410008, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Jun;1870(5):167152. doi: 10.1016/j.bbadis.2024.167152. Epub 2024 Apr 5.
Intrahepatic cholangiocarcinoma (ICC) is a kind of hepatobiliary tumor that is increasing in incidence and mortality. The gut microbiota plays a role in the onset and progression of cancer, however, the specific mechanism by which the gut microbiota acts on ICC remains unclear. In this study, feces and plasma from healthy controls and ICC patients were collected for 16S rRNA sequencing or metabolomics analysis. Gut microbiota analysis showed that gut microbiota abundance and biodiversity were altered in ICC patients compared with controls. Plasma metabolism analysis showed that the metabolite glutamine content of the ICC patient was significantly higher than that of the controls. KEGG pathway analysis showed that glutamine plays a vital role in ICC. In addition, the use of antibiotics in ICC animals further confirmed that changes in gut microbiota affect changes in glutamine. Further experiments showed that supplementation with glutamine inhibited ferroptosis and downregulated ALK5 and NOX1 expression in HuCCT1 cells. ALK5 overexpression or NOX1 overexpression increased NOX1, p53, PTGS2, ACSL4, LPCAT3, ROS, MDA and Fe and decreased FTH1, SLC7A11 and GSH. Knockdown of NOX1 suppressed FIN56-induced ferroptosis. In vivo, supplementation with glutamine promoted tumor growth. Overexpression of ALK5 repressed tumor growth and induced ferroptosis in nude mice, which could be reversed by the addition of glutamine. Our results suggested that the gut microbiota altered glutamine metabolism to inhibit ferroptosis in ICC by regulating the ALK5/NOX1 axis.
肝内胆管癌（ICC）是一种发病率和死亡率不断上升的肝胆肿瘤。肠道微生物群在癌症的发生和发展中起作用，然而，肠道微生物群作用于 ICC 的具体机制尚不清楚。在这项研究中，收集了健康对照者和 ICC 患者的粪便和血浆进行 16S rRNA 测序或代谢组学分析。肠道微生物群分析显示，与对照组相比，ICC 患者的肠道微生物群丰度和生物多样性发生了改变。血浆代谢分析显示，ICC 患者的谷氨酰胺代谢物含量明显高于对照组。KEGG 通路分析表明，谷氨酰胺在 ICC 中发挥着重要作用。此外，在 ICC 动物中使用抗生素进一步证实，肠道微生物群的变化会影响谷氨酰胺的变化。进一步的实验表明，补充谷氨酰胺可抑制 HuCCT1 细胞中的铁死亡，并下调 ALK5 和 NOX1 的表达。ALK5 过表达或 NOX1 过表达增加了 NOX1、p53、PTGS2、ACSL4、LPCAT3、ROS、MDA 和 Fe，降低了 FTH1、SLC7A11 和 GSH。NOX1 的敲低抑制了 FIN56 诱导的铁死亡。在体内，补充谷氨酰胺促进肿瘤生长。ALK5 的过表达抑制裸鼠肿瘤生长并诱导铁死亡，而添加谷氨酰胺可逆转这一作用。我们的研究结果表明，肠道微生物群通过调节 ALK5/NOX1 轴改变谷氨酰胺代谢，从而抑制 ICC 中的铁死亡。
