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.