On June 26, the molecular mechanism of the gut microbiota-mediated treatment of hyperlipidemia using berberine was published in Theranostics by the laboratory of Professors Jian-Dong Jiang and Yan Wang from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines in the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College. This work made important progress in elucidating the mechanistic details of the treatment of hyperlipidemia with berberine for gut microbiota regulation, following the publication by their team of the gut microbiota-mediated absorption mechanism of berberine in vivo (Sci Rep , 2015), as well as the use of berberine-induced bioactive metabolites (e.g., butyrate) by the gut microbiota to improve energy metabolism (Metabolism , 2017).
Natural medicines generally have good curative effects but low oral bioavailability; hence, it has been a key scientific difficulty to reveal the therapeutic substances in natural medicines in vivo . Berberine (BBR) is an important example of such a natural drug, and Professor Jian-Dong Jiang’s group first discovered that BBR was a novel antihyperlipidemic drug with a different mechanism from that of statins in 2004. Subsequently, more than ten years of clinical practice has further proven that BBR is effective and safe, and it has been approved by the State Administration of Food and Drug Administration as a new drug for reducing blood lipids, as in the clinical trials. However, BBR is difficult to absorb in the intestine, and its oral bioavailability is less than 5%, which makes it difficult to explain the significant therapeutic effect in vivo . The vast majority of BBR is distributed in the intestine after oral administration, unavoidably resulting in interaction with the gut microbiota. Based on the characteristics of berberine in vivo , with BBR as the probe drug, the laboratory of Professors Jiang and Wang has investigated and established a technological platform for evaluating the interaction between natural drugs and the gut microbiota since 2012. High-resolution and high-sensitivity mass spectrometry (such as LC-MS/MS, LC-MSn-IT-TOF, GC/MS) was applied to carry out the qualitative and quantitative analysis of the complex metabolites generated by the intestinal bacteria. By the combination of these results with 16S rRNA gene analysis and enzymatic identification, a convincing profile of the interaction between natural medicines and gut microbiota has been elucidated. It is revealed that intestinal bacteria can regulate the absorption of BBR in vivo and, furthermore, influence the mechanism by which BBR decreases blood lipids.
The publication reported that their group first found that nitroreductases (NRs) of the gut microbiota could be the key factor in promoting the absorption of BBR in the intestine. NRs are a class of biochemical enzymes in bacteria that catalyze the reductive reactions of nitrogen-containing compounds. In other words, it was NR that transformed BBR into the intestine-absorbable dhBBR. When dhBBR passed through the small intestine wall, it was rapidly oxidized back into the BBR structure and entered into the bloodstream. They showed that feeding hamsters a high-fat diet (HFD) caused an increase in blood lipids and NR activity in the intestine. The elevation of fecal NR by HFD was due to the increase either in the fraction of NR-producing bacteria or in their activity in the intestine. When given orally, BBR bioavailability in the HFD-fed hamsters was higher than that in hamsters fed with normal chow; BBR decreased blood lipids in the HFD-fed hamsters but not in those fed with a normal diet. Clinical studies indicated that patients with hyperlipidemia had higher fecal NR activity than that in healthy individuals. Similarly, after oral administration, the blood level of BBR in hyperlipidemic patients was higher than that in healthy individuals. Correlation analysis revealed a positive relationship between blood BBR and fecal NR activity. Thus, fecal NR activity might serve as a biomarker in the personalized treatment of hyperlipidemia using BBR.
At present, the study of the interaction between oral drugs and intestinal bacteria has just started; therefore, the current work is an important milestone in identifying the molecular mechanism of the therapeutic effects of the natural medicinesin vivo and will open a new field of pharmacy and pharmacology based on the gut microbiota in the future.
Reference： http://www.thno.org/v07p2443.pdf
