Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, China.
CNS Neurosci Ther. 2024 Feb;30(2):e14383. doi: 10.1111/cns.14383. Epub 2023 Aug 1.
Tyrosine decarboxylase (TDC) presented in the gut-associated strain Enterococcus faecalis can convert levodopa (L-dopa) into dopamine (DA), and its increased abundance would potentially minimize the availability and efficacy of L-dopa. However, the known human decarboxylase inhibitors are ineffective in this bacteria-mediated conversion. This study aims to investigate the inhibition of piperine (PIP) on L-dopa bacterial metabolism and evaluates the synergistic effect of PIP combined with L-dopa on Parkinson's disease (PD).
Metagenomics sequencing was adopted to determine the regulation of PIP on rat intestinal microbiota structure, especially on the relative abundance of E. faecalis. Then, the inhibitory effects of PIP on L-dopa conversion and TDC expression of E. faecalis were tested in vitro. We examined the synergetic effect of the combination of L-dopa and PIP on 6-hydroxydopamine (6-OHDA)-lesioned rats and tested the regulations of L-dopa bioavailability and brain DA level by pharmacokinetics study and MALDI-MS imaging. Finally, we evaluated the microbiota-dependent improvement effect of PIP on L-dopa availability using pseudo-germ-free and E. faecalis-transplanted rats.
We found that PIP combined with L-dopa could better ameliorate the move disorders of 6-OHDA-lesioned rats by remarkably improving L-dopa availability and brain DA level than L-dopa alone, which was associated with the effect of PIP on suppressing the bacterial decarboxylation of L-dopa via effectively downregulating the abnormal high abundances of E. faecalis and TDC in 6-OHDA-lesioned rats.
Oral administration of L-dopa combined with PIP can improve L-dopa availability and brain DA level in 6-OHDA-lesioned rats by suppressing intestinal bacterial TDC.
肠道相关菌株粪肠球菌中存在的酪氨酸脱羧酶（TDC）可将左旋多巴（L-dopa）转化为多巴胺（DA），其丰度的增加可能会降低 L-dopa 的有效性。然而，已知的人类脱羧酶抑制剂对这种细菌介导的转化无效。本研究旨在探讨胡椒碱（PIP）对 L-dopa 细菌代谢的抑制作用，并评估 PIP 与 L-dopa 联合对帕金森病（PD）的协同作用。
采用宏基因组测序确定 PIP 对大鼠肠道微生物群落结构的调控作用，特别是对粪肠球菌相对丰度的调控作用。然后，在体外检测 PIP 对 L-dopa 转化和粪肠球菌 TDC 表达的抑制作用。我们研究了 L-dopa 和 PIP 联合对 6-羟多巴胺（6-OHDA）损伤大鼠的协同作用，并通过药代动力学研究和 MALDI-MS 成像检测 L-dopa 生物利用度和大脑 DA 水平的调节作用。最后，我们使用假无菌和粪肠球菌移植大鼠评估了 PIP 对 L-dopa 可用性的菌群依赖性改善作用。
我们发现，与单独使用 L-dopa 相比，L-dopa 联合 PIP 可通过显著提高 L-dopa 的生物利用度和大脑 DA 水平更好地改善 6-OHDA 损伤大鼠的运动障碍，这与 PIP 通过有效下调 6-OHDA 损伤大鼠中异常高丰度的粪肠球菌和 TDC 来抑制细菌脱羧 L-dopa 的作用有关。
口服 L-dopa 联合 PIP 可通过抑制肠道细菌 TDC 来提高 6-OHDA 损伤大鼠的 L-dopa 生物利用度和大脑 DA 水平。
