For some people with Parkinson’s disease, Levodopa is a wonder drug, capable of eliminating almost overnight the tremors and movement difficulties that characterize the neurodegenerative disorder. Other patients are not so lucky – the drug is either much less effective, or its power seems to wane after just a few years.
Recent research has suggested a surprising answer for why the drug, commonly known as L-Dopa, has such variable results. Normally L-Dopa works by being metabolized in the brain into the neurotransmitter dopamine, which is lacking in Parkinson’s patients. But microbes that reside in the gut of some patients may be metabolizing the drug before it ever reaches the brain.
Now a new study by UC San Francisco and Harvard scientists — published in Science — has gone even further: identifying specific enzymes produced by two different bacterial species that work together to digest L-Dopa in the human gut. Blocking one of these bacterial enzymes could significantly boost the drug’s efficacy in these patients.
“While there have been a number of recent studies linking the gut microbiome to Parkinson’s disease, we still know very little about the potential role gut microbes play in the response to common treatments of this or other neurodegenerative diseases,” said Peter Turnbaugh, PhD, an associate professor of microbiology and immunology at UCSF who oversaw the new study in collaboration with Harvard chemist Emily Balskus, PhD.
The two bacterial species — Enterococcus faecalis and Eggerthella lenta — were identified from healthy human stool samples based on their ability to sequentially metabolize L-Dopa and then the dopamine it produces. The identification of the enzymes responsible enabled the researchers to predict whether microbial communities taken from healthy individuals and Parkinson’s patients and grown in laboratory dishes would digest the drug or leave it alone. Unlike related enzymes produced by human cells, the bacterial enzymes were not sensitive to a commonly administered drug meant to prevent L-Dopa from being metabolized by our own tissues prior to reaching its targets in the brain.
These findings suggested that a drug capable of blocking one or both of these bacterial enzymes could potentially be used to improve L-Dopa’s efficacy in Parkinson’s patients. Based on their knowledge of the chemistry of these two enzymatic pathways, the researchers identified a small molecule that could block the enzyme produced by E. faecalis, and showed that it indeed preserved higher levels of L-Dopa in laboratory cultures of gut microbes from Parkinson’s patients and in mice whose guts had been colonized with the L-Dopa-digesting bacteria.
The researchers hope their work will lead to improvements in treatment for Parkinson’s patients and broader efforts to manipulate the metabolic activity of human microbes to promote health.
“This study, together with other recent publications, emphasizes the utility of detailed biological and chemical knowledge about how our associated microbes shape the treatment of disease,” Turnbaugh said. “We hope that this area of research will help us move towards a more comprehensive and data-driven approach to medicine and a renewed effort to understand and manipulate the metabolism of human-associated microbial communities.”