Effects of gut bacteria on L-Dopa: revealing the inner pharmacist
Original article: Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science: June 14, 2019.
A new study has discovered both specific gut bacteria and the particular chemical pathway, by which oral L-Dopa is processed in the human gut, affecting how much of it is absorbed into the blood.
Why is it important?
This work sheds light onto the important question of individual differences in response to L-Dopa in people with Parkinson’s, and opens up new possibilities for developing more effective treatments by focusing on the crucial role of gut bacteria.
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“There is a great deal of gut-related research currently being published, but this new research is particularly interesting for three reasons:
1. It validates and expands on results that were published by an independent research group earlier this year.
2. It may partly explain why we see such variability between individuals (and within individuals over time) in response to Levodopa treatment.
And, 3. it points towards how manipulation of the gut could be used to better manage Parkinson’s medication.
It will be very interesting to see where this research heads next.”
L-Dopa is a precursor to dopamine, the chemical that is necessary for normal movement, which is reduced in Parkinson’s due to the loss of the neurons that make it. Although taking appropriate doses of L-Dopa should in theory help, how much of the ingested dose actually gets converted to dopamine varies dramatically from one person to another, or even at different times in the same person.
Digestive difficulties are one reason for this, but in the last few years researchers have been trying to understand the specific chemical pathways that are involved. In this process, attention has focused on gut bacteria, normally found in vast numbers in the human gut. These bacteria are constantly active, and essential for health and wellbeing in ways we are only now beginning to really understand. They live symbiotically, that is, along with their host (the human), sustained by some of the nutrients we ingest through our diet, and in return, process substances thereby sustaining us in return. Their diverse activity also impacts on drugs that we take, often converting them into forms that interfere with their therapeutic effect.
Could certain bacteria be responsible for processing L-Dopa in a way that affects how much of it eventually enters the brain? Given that our gut microbiomes vary, could this explain the differences in response to L-Dopa seen in people with Parkinson’s?
These researchers ran a series of experiments, which included searching through the Human Microbiome Project (HMP), a catalogue of genes of all the different kinds of bacteria found in the human gut. They looked for genes coding for specific enzymes that are necessary for important processing steps affecting L-Dopa in the gut. They found two such bacteria, E. faecalis and E. lenta carrying different enzymes, and discovered these pathways after culturing these bacteria along with L-Dopa added to it, and also culturing them together in a fecal mixture along with L-Dopa. Interestingly, they also found that not all strains of these bacteria were as potent at processing L-Dopa, possibly explaining why there is such wide variation in how different people respond to it.
With knowledge of the specific chemical pathways involved in the action of these bacteria, the team concentrated on trying to alter their activity with a substance called AFMT, which should interfere or stop the microbes’ effect on L-Dopa.
Carbidopa is a drug often given with L-Dopa which also aims to stop its inactivation in the gut. They found that by selectively targeting this microbial pathway, they were able to mimic and even outperform the effects of carbidopa in gut microbiota samples from people with Parkinson’s and a control group.
Finally, they treated mice whose gut was colonized by E faecalis with either AFMT, or carbidopa. They found that after giving both groups L-Dopa, the AFMT group had a significantly greater amount of L-Dopa in their blood.
These findings will require extension and replication, but represent an important step forward in understanding how the gut microbiome affects Parkinson’s and how we can manipulate it to therapeutic effect.
There are still many open questions such as whether gut bacteria also play a role in unpredictable ON-OFFs or wearing off, or indeed whether they are involved at the earliest stages of Parkinson’s. Watch this space!
Original article: Rekdal VM, Bess EN, Bisanz JE, Turnbaugh PJ, Balskus EP. June 14, 2019. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism.