Intestinal microbiota has been extensively studied in the context of host health benefit, and it has recently become clear that the gut microbiota influences drug pharmacokinetics and correspondingly efficacy. Intestinal microbiota dysbiosis is closely related with liver cirrhosis, especially the depletion of Lactobacillus. Therefore, the bioavailability of orally administered glycyrrhizic acid (GL) was speculated to be influenced under a pathological state. In the present study, L. murinus was isolated and screened for GL bioconversion capacity in vitro. Compared with Lactobacillus rhamnosus and Lactobacillus acidophilus, L. murinus was chosen for further investigation because it has the highest biotransformation rate. Our results showed that L. murinus could significantly improve the translocation of GL on Caco-2 cell models. Meanwhile, L. murinus was observed to have the ability to bind with the surface of Caco-2 cells and prominently downregulate the transporter gene expression level of multidrug resistance gene 1 (MDR1) and multidrug resistance protein 2 (MRP2), which were involved in the efflux of drugs. Furthermore, L. murinus was selected to be orally administred into rats in healthy and liver cirrhosis groups by a daily gavage protocol. Our data highlighted that supplements of L. murinus significantly improved the bioavailability of orally administered GL in rats, especially under a pathological condition, which may provide a novel strategy for improving the clinical therapeutic effect of liver protective drugs.

Natural flavonoids, formononetin and ononin, possess antioxidant, antibacterial, anti-inflammatory and neuroprotective effects. Many complications caused by SARS-CoV-2 make patients difficult to recover. Flavonoids, especially formononetin and ononin, have the potential to treat SARS-CoV-2 and improve myocardial injury. However, their poor water solubility, poor oral absorption, high toxicity, and high-cost purification limit industrial practical application. Succinylation modification provides a solution for the above problems. Formononetin-7-O-β-(6″-O-succinyl)-D-glucoside (FMP), a new compound, was succinyl glycosylated from formononetin by the organic solvent tolerant bacteria Bacillus amyloliquefaciens FJ18 in a 10.0% DMSO (v/v) system. The water solubility of the new compound was improved by over 106 times compared with formononetin, which perfectly promoted the application of formononetin and ononin. The conversion rate of formononetin (0.5 g/L) was almost 94.2% at 24 h, while the yield of formononetin-7-O-β-(6″-O-succinyl)-D-glucoside could achieve 97.2%. In the isoproterenol (ISO)-induced acute ischemia mice model, the myocardial injury was significantly improved with a high dose (40 mg/kg) of formononetin-7-O-β-(6″-O-succinyl)-D-glucoside. The lactate dehydrogenase level was decreased, and the catalase and superoxide dismutase levels were increased after formononetin-7-O-β-(6″-O-succinyl)-D-glucoside treatment. Thus, formononetin-7-O-β-(6″-O-succinyl)-D-glucoside has high water solubility, low toxicity, and shows significant antimyocardial ischemia effects.

Background: Oral administration remains the most common route for drug absorption. Emerging evidence highlights the important role of gut microbiome in the pharmacokinetics of oral medications. Glycyrrhizic acid (GL), a widely used hepatoprotective drug, is orally administrated and subsequently biotransformed by the gut microbiota into its active metabolite, glycyrrhetinic acid (GA), which exerts a therapeutic effect. However, it remains unclear whether the disturbance of the gut microbiome directly impacts the metabolism of GL. Methods: Antibiotic cocktail and probiotic Lacticaseibacillus rhamnosus R0011 were applied as two interventions targeting the gut microbiome. Pharmacokinetic parameters were evaluated by LC-MS, and 16S rRNA sequencing was applied to analyze the gut microbiome composition. The transcriptome analysis of Caco-2 cells was used to elucidate the regulation mechanism of polar metabolites resulting from gut microbiome perturbation. Results: R0011 supplementation could significantly increase the Area Under Curve (AUC) value of GA, which was positively correlated with the change in gut microbiome composition. In contrast, the plasma levels of GA were nearly undetectable following antibiotic intervention. Furthermore, the relative expressions of transporter multidrug resistance gene 1 (MDR1) in the ileum were site specifically downregulated under the probiotic intervention. The polar gut microbial metabolites may play a crucial role in differentiated regulating MDR1 expression, likely through the modulation of transcription factors FoxO1 and TP53. Conclusions: Our research provides new insights into the regulatory mechanism by which the gut microbiome affects the bioabsorption of orally administrated drugs, potentially offering strategies to optimize drug bioavailability and improve clinical efficacy.

Glycyrrhizinic acid (GL) is clinically applied to treat liver injury, and the bioavailability of orally administered GL is closely related to the gut microbiota. Therefore, the dysbiosis of gut flora in liver injury could significantly influence GL bioavailability. Still, less is known about the impact of probiotic supplementation on the bio-absorption process of oral medication, especially under a pathological state. Herein, probiotic L. rhamnosus R0011 (R0011) with a high viability in the harsh gastrointestinal environment was selected, and the effect of R0011 on the GL bioavailability in rats was investigated. Four groups of rats (n = 6 per group) were included: the normal group (N group), the normal group supplemented with R0011 (NLGG group), CCl4-induced chronic liver injury model (M group), and the model group supplemented with R0011 (MLGG group). Our results showed that liver injury was successfully induced in the M and MLGG groups via an intraperitoneal injection of 50% (v/v) CCl4 solution. Healthy rats supplemented with R0011 could increase the bioavailability of GL by 1.4-fold compared with the normal group by plasma pharmacokinetic analysis. Moreover, the GL bioavailability of MLGG group was significantly increased by 4.5-fold compared with the model group. R0011 directly improved gut microbial glucuronidase and downregulated the host intestinal drug transporter gene expression of multidrug resistance protein 2 (MRP2). More critically, R0011 restored the gut microbiota composition and regulated the metabolic function, significantly enhancing the microbial tryptophan metabolic pathway compared with the pathological state, which may indirectly promote the bioavailability of GL. Overall, these data may provide possible strategies by which to address the low bioavailability of traditional medicine through probiotic intervention.