Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

Specnuezhenide(SNZ)is among the main components of Fructus Ligustri Lucidi,which has antiinflammation,anti-oxidation,and anti-tumor effect.The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ.In this study,the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored.SNZ can be rapidly metabolized by the gut microbiome,and two intestinal bacterial metabolites of SNZ,salidroside and tyrosol,were discovered.In addition,carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism.At the same time,no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate,indicating that the gut microbiota is the main part involved in the metabolism of SNZ.In addition,pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota.Interestingly,tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ,which indicated that SNZ exhibited potential to inhibit tumor growth,and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues.At the same time,SNZ modulated the structure of gut microbiota and fungal group,which may be the mechanism governing the antitumoral activity of SNZ.Furthermore,SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo.In the future,targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.

Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota

At present,clinical interventions for chronic kidney disease are very limited,and most patients rely on dialysis to sustain their lives for a long time.However,studies on the gut—kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney disease.This study showed that berberine,a natural drug with low oral availability,significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins,including p-cresol.Furthermore,berberine reduced the content of pcresol sulfate in plasma mainly by lowering the abundance of g_Clostridium_sensu_stricto_1 and inhibiting the tyrosine—p-cresol pathway of the intestinal flora.Meanwhile,berberine increased the butyric acid producing bacteria and the butyric acid content in feces,while decreased the renal toxic trimethylamine N-oxide.These findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut—kidney axis.