Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson's disease by regulating gut microbiota.
Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson's disease by regulating gut microbiota.
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DOI：
10.1038/s41392-020-00456-5
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发表时间：
2021-02-24
影响因子：
39.3
通讯作者：
Jiang JD
中科院分区：
文献类型：
--
作者：
Wang Y;Tong Q;Ma SR;Zhao ZX;Pan LB;Cong L;Han P;Peng R;Yu H;Lin Y;Gao TL;Shou JW;Li XY;Zhang XF;Zhang ZW;Fu J;Wen BY;Yu JB;Cao X;Jiang JD
苯丙氨酸-酪氨酸-多巴胺-多巴胺途径向大脑提供多巴胺。在这个过程中，酪氨酸羟化酶（TH）是酪氨酸羟化并以四氢生物蝶呤（BH4）为辅酶生成左旋多巴（l-dopa）的限速酶。在这里，我们发现口服小檗碱（BBR）可能通过二氢小檗碱（细菌硝基还原酶产生的还原BBR）提供H•，并促进二氢生物蝶呤产生BH4；增加的BH4增强TH活性，从而加速肠道细菌产生左旋多巴。口服BBR的作用方式类似于维生素。肠道细菌产生的左旋多巴通过循环进入大脑，转化为多巴胺。为了验证BBR作用激活的肠脑对话，将粪肠球菌或粪肠球菌移植到帕金森病（PD）小鼠体内。细菌显著增加小鼠脑多巴胺，改善PD表现；此外，BBR与细菌联合治疗效果优于单独使用细菌。此外，2,4,6-三甲基吡喃四氟硼酸盐（TMP-TFB）衍生基质辅助激光解吸质谱（MALDI-MS）多巴胺成像发现，口服肠球菌小鼠大脑纹状体多巴胺水平升高，BBR增强了脑多巴胺的成像强度。这些结果表明，BBR是肠球菌中TH的激动剂，并可能导致肠道内左旋多巴的产生。此外，一项对28例高脂血症患者的研究证实，口服BBR可通过肠道细菌增加血液/粪便中的左旋多巴。因此，BBR可能通过类似维生素的作用，通过上调肠道微生物群中左旋多巴的生物合成来改善大脑功能。
The phenylalanine–tyrosine–dopa–dopamine pathway provides dopamine to the brain. In this process, tyrosine hydroxylase (TH) is the rate-limiting enzyme that hydroxylates tyrosine and generates levodopa (l-dopa) with tetrahydrobiopterin (BH4) as a coenzyme. Here, we show that oral berberine (BBR) might supply H• through dihydroberberine (reduced BBR produced by bacterial nitroreductase) and promote the production of BH4 from dihydrobiopterin; the increased BH4 enhances TH activity, which accelerates the production of l-dopa by the gut bacteria. Oral BBR acts in a way similar to vitamins. The l-dopa produced by the intestinal bacteria enters the brain through the circulation and is transformed to dopamine. To verify the gut–brain dialog activated by BBR’s effect, Enterococcus faecalis or Enterococcus faecium was transplanted into Parkinson’s disease (PD) mice. The bacteria significantly increased brain dopamine and ameliorated PD manifestation in mice; additionally, combination of BBR with bacteria showed better therapeutic effect than that with bacteria alone. Moreover, 2,4,6-trimethyl-pyranylium tetrafluoroborate (TMP-TFB)-derivatized matrix-assisted laser desorption mass spectrometry (MALDI-MS) imaging of dopamine identified elevated striatal dopamine levels in mouse brains with oral Enterococcus, and BBR strengthened the imaging intensity of brain dopamine. These results demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of l-dopa in the gut. Furthermore, a study of 28 patients with hyperlipidemia confirmed that oral BBR increased blood/fecal l-dopa by the intestinal bacteria. Hence, BBR might improve the brain function by upregulating the biosynthesis of l-dopa in the gut microbiota through a vitamin-like effect.
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