Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease

Abstract

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients.

Metabolic cross-feeding allows a gut microbial community to overcome detrimental diets and alter host behaviour

“…Lactobacilli lack many key genes required for the synthesis of different essential nutrients such as AAs and vitamins Wu et al, 2017). Conversely their genome encodes an unusually large repertoire of transporters highlighting their ability if not requirement to take up nutrients from their environment (Kim et al, 2013;Martino et al, 2016). Using a chemically defined diet , we show that Lp, a bacteria auxotrophic for Ile, is able to proliferate in vitro via the uptake of Ile produced by Ap.…”

“…We also show that this mutualistic relationship buffers the effect of dietary restrictions in both, the microbiome and the host. Diet is an essential, dynamic, and highly diverse environmental variable deeply affecting several aspects of behaviour, including food choice (Leitão-Gonçalves et al, 2017;Simpson et al, 2015;Solon-Biet et al, 2019;Tarlungeanu et al, 2016), as well as the microbiome, which has been shown to play a critical role in human behaviour, including through the metabolism of nutrients and drugs (Dodd et al, 2017;Kessel et al, 2019;Rekdal et al, 2019;Sharon et al, 2019;Smith et al, 2013). Our study highlights the importance of metabolic interactions among different species of gut bacteria in shaping the outcome of diet on the microbiome and its impact on host physiology and behaviour.…”

Parkinson disease, levodopa and the gut microbiota—when microbiology meets pharmacology

“…Plasma levels of levodopa in rats were inversely correlated with bacterial tdc gene levels, suggesting gut transformation of levodopa by bacteria. One might wonder whether the observations reported in this Nature Communications paper (van Kessel et al 2019) are linked to the clinical observation that PD patients need increasing levodopa doses over the course of their disease. El Aidy and colleagues asked whether the treatment of PD patients with proton pump inhibitors to decrease gastric acidity for the management of gastrointestinal problems in these patients leads to bacterial overgrowth in the small intestine where the concomitant increase of bacterial tdc genes decreases the levodopa concentrations reaching the blood.…”

You shall not pass! Gut bacteria can convert levodopa to dopamine

“…It has previously been shown that Lactobacillus and Enterococcus (the most abundant bacteria in the small intestine) harbor tyrosine decarboxylase (TDC), an enzyme that decarboxylates l ‐tyrosine to form tyramine, but can also convert l ‐dopa to dopamine. Van Kessel and colleagues explored whether bacterial TDC might play a role in l ‐dopa/carbidopa metabolism. First, after incubating luminal samples of the rat jejunum with l ‐dopa and analyzing the samples with high‐performance liquid chromatography, the investigators showed that tyrosine and l ‐dopa were effectively decarboxylated, respectively, to tyramine and dopamine.…”

“…Recently, Van Kessel and colleagues demonstrated that small intestine gut bacteria can metabolize levodopa. 1 It has previously been shown that Lactobacillus and Enterococcus (the most abundant bacteria in the small intestine) harbor tyrosine decarboxylase (TDC), an enzyme that decarboxylates L-tyrosine to form tyramine, but can also convert L-dopa to dopamine. Van Kessel and colleagues 1 explored whether bacterial TDC might play a role in L-dopa/carbidopa metabolism.…”