Gut bacterial tyrosine decarboxylases restrict the bioavailability of levodopa, the primary treatment in Parkinson’s disease

Abstract

Human gut bacteria play a critical role in the regulation of immune and metabolic systems, as well as in the function of the nervous system. The microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we identify and characterize gut-associated bacteria in their ability to decarboxylate L-DOPA (also known as Levodopa or L-3,4-dihydroxyphenylalanine) to dopamine via the tyrosine decarboxylases, which are mainly present in the class Bacilli. Although the bacterial tyrosine decarboxylases have a higher affinity for tyrosine compared to L-DOPA, this does not affect their ability to decarboxylate L-DOPA, nor does any inhibitor of the human decarboxylase. This study indicates that in situ bioavailability of L-DOPA is compromised by the gut bacterial tyrosine decarboxylase abundance in Parkinsons patients. Finally, we show that the tyrosine decarboxylase abundance in the microbiota at the site of L-DOPA absorption, the proximal small intestine, significantly influences L-DOPA bioavailability in the plasma of rats. Our results highlight the role of microbial metabolism in drug bioavailability, and specifically, that small intestinal abundance of bacterial tyrosine decarboxylase can explain the highly variable L-DOPA dosage regimens required in the treatment of individual Parkinsons patients.\n\nHighlightsO_LISmall intestinal bacteria is able to convert L-DOPA to dopamine\nC_LIO_LIL-DOPA metabolism by gut bacteria reduce the bioavailability of L-DOPA in the body, thus is a significant explanatory factor of the highly variable L-DOPA dosage regimens required in the treatment of individual Parkinsons patients.\nC_LIO_LIInhibitors of the human DOPA decarboxylase are not potent inhibitors for bacterial tyrosine decarboxylases\nC_LI