PT  - JOURNAL ARTICLE
AU  - Sebastiaan P. van Kessel
AU  - Alexandra K. Frye
AU  - Ahmed O. El-Gendy
AU  - Maria Castejon
AU  - Ali Keshavarzian
AU  - Gertjan van Dijk
AU  - Sahar El Aidy
TI  - Gut bacterial tyrosine decarboxylases restrict the bioavailability of levodopa, the primary treatment in Parkinson’s disease
AID  - 10.1101/356246
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 356246
4099  - http://biorxiv.org/content/early/2018/06/27/356246.short
4100  - http://biorxiv.org/content/early/2018/06/27/356246.full
AB  - 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-3,4- dihydroxyphenylalanine (L-DOPA) 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 convert L-DOPA to dopamine, 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 gene abundance in Parkinson’s patients. Finally, we show that the tyrosine decarboxylase gene abundance in the microbiota of 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 that specifically, small intestinal abundance of bacterial tyrosine decarboxylase can explain the highly variable L-DOPA dosage regimens required in the treatment of individual Parkinson’s patients.One Sentence Summary L-DOPA conversion by bacterial tyrosine decarboxylase in the small intestine is a significant explanatory factor for the highly variable L-DOPA dosage regimens required in the treatment of individual Parkinson’s patients.