State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, China.
Neuroscience center, Chinese Academy of Medical Sciences, Beijing, China.
Microbiologyopen. 2019 Oct;8(10):e873. doi: 10.1002/mbo3.873. Epub 2019 May 16.
The homeostasis of the gut microbiome is crucial for human health and for liver function. However, it has not been established whether the gut microbiome influence hepatic progenitor cells (HPCs). HPCs are capable of self-renewal and differentiate into hepatocytes and cholangiocytes; however, HPCs are normally quiescent and are rare in adults. After sustained liver damage, a ductular reaction occurs, and the number of HPCs is substantially increased. Here, we administered five broad-spectrum antibiotics for 14 days to deplete the gut microbiomes of male C57BL/6 mice, and we measured the plasma aminotransferases and other biochemical indices. The expression levels of two HPC markers, SRY-related high mobility group-box gene 9 (Sox9) and cytokeratin (CK), were also measured. The plasma aminotransferase activities were not affected, but the triglyceride, lactate dehydrogenase, low-density lipoprotein, and high-density lipoprotein concentrations were significantly altered; this suggests that liver function is affected by the composition of the gut microbiome. The mRNA expression of Sox9 was significantly higher in the treated mice than it was in the control mice (p < 0.0001), and a substantial expression of Sox9 and CK was observed around the bile ducts. The mRNA expression levels of proinflammatory factors (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]-α, and TNF-like weak inducer of apoptosis [Tweak]) were also significantly higher in the antibiotic-treated mice than the levels in the control mice. These data imply that the depletion of the gut microbiome leads to liver damage, negatively impacts the hepatic metabolism and function, and activates HPCs. However, the underlying mechanisms remain to be determined.
肠道微生物组的内稳态对人类健康和肝功能至关重要。然而，肠道微生物组是否影响肝祖细胞（HPCs）尚未确定。HPCs 能够自我更新并分化为肝细胞和胆管细胞；然而，HPCs 在成人中通常处于静止状态，且数量稀少。在持续的肝损伤后，会发生胆管反应，HPCs 的数量会显著增加。在这里，我们用五种广谱抗生素处理雄性 C57BL/6 小鼠 14 天，以耗尽其肠道微生物组，并测量了血浆氨基转移酶和其他生化指标。还测量了两种 HPC 标志物，性别决定区 Y 框基因 9（Sox9）和细胞角蛋白（CK）的表达水平。血浆氨基转移酶活性没有受到影响，但甘油三酯、乳酸脱氢酶、低密度脂蛋白和高密度脂蛋白浓度显著改变；这表明肝功能受到肠道微生物组组成的影响。与对照组相比，处理组小鼠 Sox9 的 mRNA 表达显著升高（p < 0.0001），并且在胆管周围观察到 Sox9 和 CK 的大量表达。促炎因子（白细胞介素 [IL]-1β、IL-6、肿瘤坏死因子 [TNF]-α 和 TNF 样凋亡弱诱导物 [Tweak]）的 mRNA 表达水平在抗生素处理组小鼠中也显著高于对照组。这些数据表明，肠道微生物组的耗竭会导致肝损伤，对肝脏代谢和功能产生负面影响，并激活 HPCs。然而，其潜在机制仍有待确定。
