Piperine improves levodopa availability in the 6‐OHDA‐lesioned rat model of Parkinson's disease by suppressing gut bacterial tyrosine decarboxylase

Abstract

AimTyrosine 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).MethodsMetagenomics 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.ResultsWe 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.ConclusionOral 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.

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

“…519 The gut microbiome influences multiple aspects of dopaminergic system within PD pathophysiology, as well as the efficacy of dopamine-related drugs. 518,[521][522][523] This influence is exemplified by a study in which FMT from PD mice reduced striatal levels of dopamine and its metabolites in recipient mice, accompanied by impaired motor function. 217 Moreover, metagenomic analysis of the gut microbiome in PD patients has detected a reduced capacity to generate dopamine precursors, particularly tyrosine.…”

Berberine impairs spermatogenesis in mice by modulating ornithine metabolism via gut microbiota regulation

“…Rhein, one of the main components of rhubarb, increased the abundance of Lactobacillus and alleviated uric acid-induced chronic colitis [13]. Piperine improved Parkinson's disease by down-regulating the high abundance of E. faecalis [14]. BBR also has low bioavailability, so the gut microbiota is likely to be an important pathway for BBR's effects.…”