The effects of rhein on D-GalN/LPS-induced acute liver injury in mice: Results from gut microbiome-metabolomics and host transcriptome analysis

Abstract

BackgroundRhubarb is an important traditional Chinese medicine, and rhein is one of its most important active ingredients. Studies have found that rhein can improve ulcerative colitis by regulating gut microbes, but there are few reports on its effects on liver diseases. Therefore, this study aims to investigate these effects and underlying mechanisms.MethodsMice were given rhein (100 mg/kg), with both a normal control group and a model group receiving the same amount of normal saline for one week. Acute liver injury was induced in mice by intraperitoneal injection of D-GalN (800 mg/kg)/LPS (10 ug/kg). Samples (blood, liver, and stool) were then collected and assessed for histological lesions and used for 16S rRNA gene sequencing, high-performance liquid chromatography-mass spectrometry (LC-MS) and RNA-seq analysis.ResultsThe levels of ALT and AST in the Model group were abnormal higher compared to the normal control group, and the levels of ALT and AST were significantly relieved in the rhein group. Hepatic HE staining showed that the degree of liver injury in the rhein group was lighter than that in the model group, and microbiological results showed that norank_o:Clostridia_UCG-014, Lachnoclostridium, and Roseburia were more abundant in the model group compared to the normal control group. Notably, the rhein treatment group showed reshaped disturbance of intestinal microbial community by D-GalN/LPS and these mice also had higher levels of Verrucomicrobia, Akkermansiaceae and Bacteroidetes. Additionally, There were multiple metabolites that were significantly different between the normal control group and the model group, such as L-α-amino acid, ofloxacin-N-oxide, 1-hydroxy-1,3-diphenylpropan-2-one,and L-4-hydroxyglutamate semialdehyde, but that returned to normal levels after rhein treatment. The gene expression level in the model group also changed significantly, various genes such as Cxcl2, S100a9, Tnf, Ereg, and IL-10 were up-regulated, while Mfsd2a and Bhlhe41 were down-regulated, which were recovered after rhein treatment.ConclusionOverall, our results show that rhein alleviated D-GalN/LPS-induced acute liver injury in mice. It may help modulate gut microbiota in mice, thereby changing metabolism in the intestine. Meanwhile, rhein also may help regulate genes expression level to alleviate D-GalN/LPS-induced acute liver injury.

A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure

“…Rhein is isolated from rhubarb, which is one of the most important and ancient herbs in traditional Chinese medicine . In recent years, rhein has been widely used for the treatment of liver-related diseases in animal and clinical experiments. , However, the applications of rhein have been largely limited by its poor solubility, low bioavailability, short half-life, easy degradation, and nonspecific organ toxicity. , Morphological imaging confirmed by transmission electron microscopy (TEM) demonstrated that RBC membranes were coated with RMBN but not RMN, which is a control nanoparticle lacking an erythrocyte membrane coating (Figure A). Furthermore, the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results revealed similar protein compositions for the RMBN and RBC membranes, suggesting that the RMBNs were successfully coated with the RBC membrane (Figure B).…”

“… 34 In recent years, rhein has been widely used for the treatment of liver-related diseases in animal and clinical experiments. 35 , 36 However, the applications of rhein have been largely limited by its poor solubility, low bioavailability, short half-life, easy degradation, and nonspecific organ toxicity. 37 , 38 Morphological imaging confirmed by transmission electron microscopy (TEM) demonstrated that RBC membranes were coated with RMBN but not RMN, which is a control nanoparticle lacking an erythrocyte membrane coating ( Figure 2 A).…”

An UHPLC–QTOF–MS‐based strategy for systematic profiling of chemical constituents and associated in vivo metabolites of a famous traditional Chinese medicine formula, Yinchenhao decoction

“…p ‐Coumaric acid suppresses lipid accumulation via increasing lipolysis and promoting fatty acid β ‐oxidation (Yan et al, 2020). Rhein reshapes the gut microbiome and modulates the host transcriptome against acute liver injury (Liu, Yin, et al, 2022).…”

Anti-Inflammatory Effects of a Novel Nuclear Factor–κ B Inhibitory Derivative Derived from Pyrazolo[3,4-d]Pyrimidine in Three Inflammation Models

“…In the hepatitis model, prophylactic administration of INH #1 suppressed the immediate production of TNF-α and several pro-inflammatory mediators, then prevented the early death of mice caused by LPS/d-GalN, while no paradoxical IL-1β production was observed as reported in NF-kB impaired myeloid cells (Greten FR, et al, 2007). However, liver toxicity and survival rate were not rescued with a single regardless of treatment since LPS/d-GalN caused liver failure and focal hepatocyte necrosis via metabolic dysfunction of carbohydrates and phospholipids (Tanaka N, et al, 2012;Kopec AK, et al, 2016;Liu S, et al, 2022). These findings suggested that in this model the beneficial effects of INH #1 were limited to short-term cytokine inhibition.…”