Discovery and Inhibition of an Interspecies Gut Bacterial Pathway for Levodopa Metabolism
By Katie E. Golden
One of the promising areas of emerging microbiome research is the impact of our intestinal flora on drug pharmacokinetics. We know that our resident gut bacteria play a critical role in the metabolism and efficacy of many of the medicines patients take every day, but we are still at the beginning of understanding how microbiological mechanisms inform a specific individual’s response to therapy. In a newly published study, researchers sought to characterize how the microbiome impacts metabolism of Levodopa, the most common drug prescribed to treat Parkinson’s disease.1
Parkinson’s Disease (PD) is a neurodegenerative disorder that results from a loss of dopaminergic neurons in the brain. The main treatment for disease, Levodopa, is converted to dopamine after it crosses the blood-brain barrier, thus mitigating the characteristic motor symptoms of the disease. One of the main challenges in achieving this therapeutic effect, however, is ensuring the drug gets into the brain before it is prematurely converted to dopamine in the body, which not only renders it ineffective for PD symptoms, but can also lead to significant and unwanted side effects. It is thus often co-administered with the drug Carvidopa, which blocks enzymatic transformation of Levodopa in the periphery; even then, however, only about half of the ingested drug reaches the brain.
Prior research suggests that gut microbiota decreases bioavailability of Levodopa, and so Rekdal and his team of researchers wanted to identify the specific species and pathways that metabolize the drug, possibly accounting for the decreased efficacy and variable patient response to the drug. The investigators discovered several important bacterial molecular mechanisms implicated in Levodopa metabolism. Frist, they identified a conserved tyrosine decarboxylase (TyrDC) produced by Enterococcus faecelis (a common gut commensal) that decarboxylates Levodopa, thus converting it to dopamine in the intestine. Second, they identified a single-nucleotide polymorphism (SNP) in a gene from Eggerthella lenta (another gut commensal) that correlates to production of an enzyme with a dopamine dehydroxylase, which further metabolizes the dopamine to m-tyramine, which may be responsible for many of the deleterious side effects of the drug. They then tested bacterial metabolic activity in the presence of the aforementioned Carvidopa, designed to block this harmful metabolism. The researchers found that the drug does not fully inhibit the bacteria’s enzymatic activity, and in fact displayed only ~50% inhibition of the discovered metabolic pathways.
The investigators’ findings map out important therapeutic targets for enhancing drug efficacy for PD treatment. They even identified a pathway by which an amino acid substrate of TyrDC can block their discovered microbial decarboxylation of Levodopa, and found that administration of the amino acid analog significantly increased peak serum concentration of the drug. Their paper displays the exciting potential of microbiome and metabolomic research to improve our treatment of common and prevalent human diseases.
1. Rekdal VM, Bess EN, Bisanz JE, Turnbaugh PJ, Balskus EP. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science, 2019; 364 (6445): eaau6323 DOI: 10.1126/science.aau6323