Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, People's Republic of China.
Children's Rehabilitation Center, Jining Maternal and Child Health Family Planning Service Center, Jining, 272000, People's Republic of China.
Drug Des Devel Ther. 2022 Nov 8;16:3877-3891. doi: 10.2147/DDDT.S381667. eCollection 2022.
We designed this study to investigate the potential correlations between gut microbiota compositions and hepatic metabolomic disorders in mice with methotrexate (MTX)-induced hepatoxicity.
We used MTX to induce hepatoxicity in healthy Kunming mice, and we determined plasma ALT and AST levels and assessed the liver tissue histopathology. We applied an integrated gas chromatography-mass spectrometry (GC-MS) and 16S ribosomal RNA (rRNA) gene sequencing approach to evaluate the effects of MTX on the gut microbiota and hepatic metabolic profiles of mice. We uncovered correlations between the gut microbiota and hepatic metabolomic profiles by calculating the Spearman correlation coefficient.
MTX caused ALT and AST level elevations and hepatoxicity in our mouse model. MTX disrupted amino acid metabolic pathways (including biosyntheses of valine, leucine, and isoleucine; and arginine; and, metabolism of alanine, aspartate, and glutamate; histidine; beta-alanine; and glycine, serine, and threonine); biosyntheses of aminoacyl-tRNA; and pantothenate, and CoA; and, metabolic pathways of energy, glutathione, and porphyrin; and chlorophyll. In addition, MTX increased the abundances of , and , but decreased the amounts of , and . Our correlation analyses showed that different flora abundance changes including those of , and were associated with liver injury.
We present evidence supporting the notion that MTX causes hepatoxicity by altering the gut microbiota and hepatic metabolite profiles, our findings provide new venues for the management of MTX-induced hepatoxicity.
本研究旨在探讨甲氨蝶呤（MTX）诱导肝毒性小鼠肠道微生物组成与肝代谢紊乱之间的潜在相关性。
我们使用 MTX 诱导健康昆明小鼠肝毒性，并测定血浆 ALT 和 AST 水平，评估肝组织病理。我们采用气相色谱-质谱联用（GC-MS）和 16S 核糖体 RNA（rRNA）基因测序方法评估 MTX 对小鼠肠道微生物和肝代谢谱的影响。我们通过计算 Spearman 相关系数揭示肠道微生物群和肝代谢组学图谱之间的相关性。
MTX 导致我们的小鼠模型 ALT 和 AST 水平升高和肝毒性。MTX 破坏了氨基酸代谢途径（包括缬氨酸、亮氨酸和异亮氨酸；精氨酸；丙氨酸、天冬氨酸和谷氨酸；组氨酸；β-丙氨酸；甘氨酸、丝氨酸和苏氨酸的生物合成；氨酰-tRNA 的生物合成；泛酸和 CoA；以及能量、谷胱甘肽和卟啉代谢途径；和叶绿素）。此外，MTX 增加了 、 、 的丰度，但降低了 、 、 的含量。我们的相关性分析表明，不同菌群丰度的变化，包括 、 、 的变化与肝损伤有关。
我们提供了证据支持 MTX 通过改变肠道微生物群和肝代谢物谱导致肝毒性的观点，我们的研究结果为 MTX 诱导的肝毒性的治疗提供了新的途径。
