Transcriptome and Gut Microbiota Profiling Analysis of ANIT-Induced Cholestasis and the Effects of Da-Huang-Xiao-Shi Decoction Intervention.
Transcriptome and Gut Microbiota Profiling Analysis of ANIT-Induced Cholestasis and the Effects of Da-Huang-Xiao-Shi Decoction Intervention.
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DOI：
10.1128/spectrum.03242-22
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发表时间：
2022-12-21
影响因子：
3.7
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中科院分区：
文献类型：
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胆汁淤积是以胆汁酸循环障碍为特征的疾病，通常与肝细胞屏障功能受损有关。目前，胆汁淤积症患者在寻求诊断和治疗方面面临着一些障碍。大黄消石汤是临床上用于治疗胆汁淤积的古方。然而，潜在的生物活性和治疗机制仍不清楚。本研究通过建立α-异硫氰酸萘酯（ANIT）诱导的胆汁淤积大鼠模型，采用组织病理学和分子生物学方法研究DHXSD的抗胆汁淤积作用。采用转录组学分析结合16 S rRNA基因序列分析的方法，系统研究了DHXSD的作用机制。同时，DHXSD对肠道菌群，短链脂肪酸（SCFAs）和肠道屏障功能的影响进行了评估的基础上ANIT诱导的大鼠胆汁淤积模型。结果表明，DHXSD通过降低肝功能指标有效地减弱ANIT诱导的胆汁淤积（谷丙转氨酶（ALT），碱性磷酸酶（ALP），总胆汁酸（TBA），P <0.01; γ-谷氨酰转肽酶[GGT]，P < 0.001）和肝毒性相关酶水平（P < 0.05），从而促进组织病理学损伤的恢复，调节炎性细胞因子的水平（P < 0.05）。此外，16 S rRNA基因测序分析结合肠道屏障功能分析显示，DHXSD显著改善了ANIT诱导的肠道微生物群失调。使用转录组学分析筛选模型组和治疗组中显著改变的基因。在ANIT和DHXSD处理后，68个基因和4个微生物属同时改变，变化趋势相反。我们建立了一个框架，预测目标和宿主-微生物相互作用机制，以及确定胆汁淤积的替代治疗，这应该进一步验证临床应用。总之，DHXSD似乎是一种有前途的药物，用于保护肝损伤。重要提示胆汁淤积是肝脏疾病的一种严重表现，可导致肝损伤、纤维化和肝功能衰竭，治疗方法有限。迄今为止，只有熊去氧胆酸（UDCA）已被美国食品和药物管理局批准用于治疗胆汁淤积。然而，大约三分之一的胆汁淤积患者对UDCA无反应。因此，迫切需要寻找合适的治疗药物来恢复胆汁成分的停止状态以治疗胆汁淤积。在这项研究中，我们研究了微生物组和转录组数据集如何相互关联，以阐明微生物组改变在宿主代谢中的作用。结合起来，这项研究提供了潜在的分子生物标志物，这些生物标志物应该得到验证，以更准确地诊断胆汁淤积和临床利用肠道微生物群作为治疗目标。
Cholestasis is characterized by bile acid (BA) circulation disorders, which is usually related to damage of hepatocyte barrier function. Currently, patients with cholestasis face several obstacles in seeking diagnosis and therapy. Da-Huang-Xiao-Shi decoction (DHXSD) is an ancient classic formula that has been used clinically for cholestasis treatment. Nevertheless, the underlying biological activities and therapeutic mechanisms remain unclear. In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis rat model was established to examine the anticholestatic effects of DHXSD using histopathological and molecular analyses. Transcriptomic analysis combined with 16S rRNA gene sequencing analysis was systematically applied to study the mechanism of action of DHXSD. Simultaneously, the effect of DHXSD on gut microbiota, short-chain fatty acids (SCFAs), and intestinal barrier function were evaluated based on the ANIT-induced cholestasis model in rats. The results showed that DHXSD effectively attenuated ANIT-induced cholestasis by reducing liver function indicators (alanine transaminase [ALT], P < 0.05; alkaline phosphatase [ALP], P < 0.05; total bile acid [TBA], P < 0.01; γ-glutamyl transpeptidase [GGT], P < 0.001) and levels of hepatotoxicity-related enzymes (P < 0.05), thus improving the recovery of histopathological injuries, and regulating levels of inflammatory cytokines (P < 0.05). In addition, 16S rRNA gene sequencing analysis combined with intestinal barrier function analysis revealed that the DHXSD significantly ameliorated ANIT-induced gut microbiota dysbiosis. Significantly altered genes in the model and treatment groups were screened using transcriptomic analysis. Sixty-eight genes and four microbial genera were simultaneously altered with opposing trends in variation after ANIT and DHXSD treatments. We built a framework for predicting targets and host-microbe interaction mechanisms, as well as identifying alternative treatment for cholestasis, which should be validated further for clinical application. In conclusion, DHXSD appears to be a promising agent for protection against liver injury. IMPORTANCE Cholestasis is a serious manifestation of liver diseases resulting in liver injury, fibrosis, and liver failure with limited therapies. To date, only ursodeoxycholic acid (UDCA) has been approved by the U.S. Food and Drug Administration for the treatment of cholestasis. However, approximately one-third of patients with cholestasis are unresponsive to UDCA. Therefore, it is urgent to search for appropriate therapeutic agents for restoring stoppage status of the bile components to treat cholestasis. In this study, we investigated how the microbiome and transcriptome data sets correlated with each other to clarify the role of microbiome alterations in host metabolism. In combination, this research offers potential molecular biomarkers that should be validated for more accurate diagnosis of cholestasis and the clinical utilisation of gut microbiota as a target for treatment.
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