State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China.
Biomed Pharmacother. 2021 Jul;139:111595. doi: 10.1016/j.biopha.2021.111595. Epub 2021 Apr 14.
Akkermansia spp. plays important roles in maintenance of host health. Increasing evidence reveals that berberine (BBR) may exert its pharmacological effects via, at least partially, promotion of Akkermansia spp. However, how BBR stimulates Akkermansia remains largely unknown.
In this study, we investigated the mechanism underlying the Akkermansia-promoting effect of BBR.
The effect of BBR on Akkermansia was assessed in BBR-gavaged mice and direct incubation. The influence of BBR on intestinal mucin production was determined by alcian-blue staining and real-time PCR. The feces were analysis by gas chromatography-time-of-flight mass spectrometry (GC-TOF/MS) metabolomics. The role of polyamines in BBR-elicited mucin secretion and Akkermansia growth was evaluated by administration of difluoromethylornithine (DFMO) in mice.
Gavage of BBR dose-dependently and time-dependently increased the abundance of Akkermansia in mice. However, it did not stimulate Akkermansia growth in direct incubation, suggesting that BBR may promote Akkermansia in a host-dependent way. Oral administration of BBR significantly increased the transcription of mucin-producing genes and mucin secretion in colon. Untargeted metabolomics analysis showed that BBR increased polyamines production in feces which are known to stimulate goblet cell proliferation and differentiation, but treatment with eukaryotic polyamine synthase inhibitor DFMO did not abolish the stimulating effect of BBR on mucin secretion and Akkermansia growth, indicating that the gut bacteria-derived but not the host-derived polyamines may involve in the BBR-promoted Akkermansia growth.
Our results reveal that BBR is a promising prebiotic for Akkermansia, and it promotes Akkermansia growth via stimulating mucin secretion in colon.
阿克曼氏菌属在宿主健康维持中发挥重要作用。越来越多的证据表明，小檗碱（BBR）可能通过至少部分促进阿克曼氏菌属来发挥其药理作用。然而，BBR 如何刺激阿克曼氏菌属仍知之甚少。
本研究旨在探讨 BBR 促进阿克曼氏菌属生长的作用机制。
通过 BBR 灌胃和直接孵育评估 BBR 对阿克曼氏菌属的作用。通过阿尔辛蓝染色和实时 PCR 测定 BBR 对肠道黏蛋白产生的影响。通过气相色谱-飞行时间质谱（GC-TOF/MS）代谢组学分析粪便。通过在小鼠中给予二氟甲基鸟氨酸（DFMO）评估多胺在 BBR 诱导的黏蛋白分泌和阿克曼氏菌属生长中的作用。
BBR 灌胃剂量依赖性和时间依赖性地增加了小鼠体内阿克曼氏菌属的丰度。然而，它在直接孵育中并没有刺激阿克曼氏菌属的生长，这表明 BBR 可能以宿主依赖的方式促进阿克曼氏菌属的生长。BBR 口服给药显著增加了结肠中黏蛋白生成基因的转录和黏蛋白分泌。非靶向代谢组学分析显示，BBR 增加了粪便中多胺的产生，已知多胺刺激杯状细胞增殖和分化，但用真核多胺合酶抑制剂 DFMO 处理并没有消除 BBR 对黏蛋白分泌和阿克曼氏菌属生长的刺激作用，表明可能涉及肠道细菌衍生而不是宿主衍生的多胺参与 BBR 促进的阿克曼氏菌属生长。
我们的结果表明，BBR 是一种有前途的阿克曼氏菌属的益生元，它通过刺激结肠中的黏蛋白分泌来促进阿克曼氏菌属的生长。
