| Glycyrrhizic acid is the main active ingredient in licorice,and it has anti-inflammatory and hepatoprotective effects.Glycyrrhizic acid is a widely used hepatoprotective drug in clinical and is widely used in the treatment of acute and chronic liver diseases.Modern medicine believes that the liver and the intestine are closely related.There is a two-way communication pathway between them,called the"gut-liver" axis.Many studies found that the presence of the "gut-liver" axis between the liver and the intestinal tract makes the development of liver disease closely related to dysbacteriosis.In addition,After oral administration of glycyrrhizic acid,it needs to be hydrolyzed into glycyrrhetinic acid by the intestinal flora,and then glycyrrhetinic acid is absorbed into the blood to exert its efficacy.Studies have shown that dysbacteriosis may affect the metabolism,absorption and efficacy of drugs that are metabolized by the intestinal flora to exert pharmacological activity.At the same time,drugs may also affect the function,composition and structure of the flora,thereby improving the diseases.Therefore,we propose the following hypothesis:Glycyrrhizic acid can improve intestinal flora disorder caused by chronic liver injury Intestinal flora disorder may lead to changes in the metabolism of glycyrrhizic acid in the gastrointestinal tract,leading to changes in its pharmacokinetic behavior in vivo.Improving the composition of the intestinal flora can affect the biotransformation and oral bioavailability of glycyrrhizic acidIn this study,a rat model of chronic liver injury was established by intraperitoneal injection of 50%carbon tetrachloride olive oil solution,and serum ALT and AST levels were tested to evaluate whether the model is successful.After the administration of glycyrrhizic acid,the hepatoprotective effect of glycyrrhizic acid was investigated by measuring serum biochemical indicators and observing the pathological sections of liver tissue.The results showed that glycyrrhizic acid can significantly reduce serum ALT,AST and other liver function indexes in model rats,and reduce hepatic inflammatory infiltration and fibrosis to protect liver.The relative expression of genes related to liver injury was determined by RT-PCR to study the hepatoprotective mechanism of glycyrrhizic acid.The results showed that glycyrrhizic acid could reduce the relative expression of TNF-?,LBP and TLR4 in the liver of model rats,inhibit the inflammatory response and protect the liver.Studies found that bacterial lipopolysaccharide binding protein(LBP)and Toll-like receptor(TLR4)both can be activated by bacterial lipopolysaccharide(LPS),which promotes the progression of liver injury.Therefore,this suggests that glycyrrhizic acid may affect the intestinal flora.Based on the above speculation,this study used 16S rRNA sequencing technology to analyze the diversity and composition of rat intestinal flora,and studied the effect of glycyrrhizic acid on intestinal flora of rats with chronic liver injury.The results showed that the composition of intestinal flora in rats with liver injury changed significantly,and the main manifestations were the decrease of probiotics and the increase of pathogenic bacteria.Glycyrrhizin could improve the dysbacteriosis caused by liver injury and regulate the diversity and composition of the flora.Glycyrrhizin could significantly increase the relative abundance of Lactobacillus.The results of 16S function prediction showed that the content of PTS and 16-?-phosphoglucosidase were decreased in the model group,and glycyrrhizic acid increased the content of PTS and 16-?-phosphoglycosidase.It has been reported that the deglycosylation process of saponin components by Lactobacillus is dependent on the phosphotransferase system(PTS).This result indicated that glycyrrhizic acid could increase the abundance of Lactobacillus once again.In addition,based on this results,we speculated that glycyrrhizic acid could be deglycosylated by Lactobacillus,and increasing the number of Lactobacillus could promote the bioconversion and absorption of glycyrrhizic acid.Based on the above experimental results,this study established a LC-MS method for simultaneous determination of glycyrrhizic acid and glycyrrhetinic acid in biological samples.The method was used to analyze the metabolism of glycyrrhizic acid by Lactobacillus in vitro and the effect of Lactobacillus on the pharmacokinetics of glycyrrhizic acid in vivo.The results showed that Lactobacillus(such as L rhamnosus,L.acidophilus and L.The pharmacokinetic parameters of glycyrrhetinic acid in normal rats and model rats were significantly different,and the absorption and the oral bioavailability of glycyrrhizic acid in rats with liver injury was reduced.After administration of Lactobacillus by intragastric administration,the pharmacokinetic parameters of glycyrrhetinic acid in rats were significantly changed.The results demonstrated that Lactobacillus could metabolize glycyrrhizic acid into glycyrrhetinic acid and increase the bioavailability of glycyrrhizic acidIn order to research the effect and related mechanisms of Lactobacillus on the absorption of glycyrrhizic acid,this study used Caco-2 cell model to investigate the effect of Lactobacillus on transmembrane transport of glycyrrhizic acid and the effect of glycyrrhizic acid and glycyrrhetinic acid on cell adhesion rate of Lactobacillus,The effect of Lactobacillus on the relative expression of Intestinal transporter genes was studied by real-time PCR.The results demonstrated that Lactobacillus could promote the absorption of glycyrrhizic acid and glycyrrhetinic acid,and the results were consistent with the results of pharmacokinetic experiments in vivo.In addition.glycyrrhizic acid and glycyrrhetinic acid could increase the adhesion of Lactobacillus to cells,and Lactobacillus could reduce the relative expression of MDR1,P-gP and MRP-2 genes.The results indicated that the mechanism by which Lactobacillus promotes the absorption of glycyrrhizic acid and glycyrrhetinic acid may be that glycyrrhizin can increase the adhesion of Lactobacillus to Caco-2 cells,and the adhesion of Lactobacillus to cells reduces the expression of the drug efflux transporter gene,thereby promoting absorption of glycyrrhizic acid and glycyrrhetinic acid. |
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