Abstract
The gut microbiota is important in the pathogenesis of energy-metabolism related diseases. We focused on the interaction between intestinal bacteria and orally administered chemical drugs. Oral administration of berberine (BBR) effectively treats patients with metabolic disorders. However, because BBR exhibits poor solubility, its absorption mechanism remains unknown. Here, we show that the gut microbiota converts BBR into its absorbable form of dihydroberberine (dhBBR), which has an intestinal absorption rate 5-fold that of BBR in animals. The reduction of BBR to dhBBR was performed by nitroreductases of the gut microbiota. DhBBR was unstable in solution and reverted to BBR in intestine tissues via oxidization. Heat inactivation of intestinal homogenate did not inhibit dhBBR oxidization, suggesting the process a non-enzymatic reaction. The diminution of intestinal bacteria via orally treating KK-Ay mice with antibiotics decreased the BBR-to-dhBBR conversion and blood BBR; accordingly, the lipid- and glucose-lowering efficacy of BBR was reduced. Conclusively, the gut microbiota reduces BBR into its absorbable form of dhBBR, which then oxidizes back to BBR after absorption in intestine tissues and enters the blood. Thus, interaction(s) between the gut microbiota and orally administrated drugs may modify the structure and function of chemicals and be important in drug investigation.
Highlights
BBR (Fig. 1a) is a medicinal alkaloid isolated from Coptis chinensis and has been used orally for decades in China as an over-the-counter (OTC) drug to treat diarrhea with good safety[7]
The compound detection was performed using both liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and gas chromatography coupled with mass spectrometry (GC-MS)
DhBBR was detectable in feces but not in the bile and urine samples. Among these metabolites, dhBBR was the only one that exhibited a change in the backbone structure (Fig. 1a). We assumed that it might be a metabolite generated by the gut microbiota of rats
Summary
BBR (Fig. 1a) is a medicinal alkaloid isolated from Coptis chinensis and has been used orally for decades in China as an over-the-counter (OTC) drug to treat diarrhea with good safety[7]. The therapeutic effect of BBR on lipid- and glucose-related metabolic disorders was recently confirmed in a large number of patients by independent clinical groups both in and outside China[12], demonstrating the botanic compound to be a promising drug. After its oral administration, BBR was detected in most major organs as well as in urine, with the liver exhibiting the highest concentration[15], and these findings raise the question of how BBR is absorbed in the intestine. Our recent study on the metabolism of BBR in the intestine has identified the gut microbiota as the most likely answer, at least in part, to this question, and we consider the finding of general interest in drug discovery and investigation
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