Prokopis Konstanti is a PhD candidate focusing on the molecular analysis of microbial communities, the role of microbes in human physiology and the gut-brain axis in the group of Molecular Ecology at the Laboratory of Microbiology at the Wageningen University (the Netherlands).
Researchers from Groningen University, The Netherlands discovered that bacteria from our gut can metabolize and block the action of the main drug used to treat Parkinson’s disease [1].
Parkinson’s disease is related to low levels of dopamine in the brain and the main treatment for the patients is levodopa (L-dopa), a precursor of dopamine. The drug is absorbed in the small intestine and through the bloodstream is transported to the brain, where it is converted into dopamine.
Prior studies showed that only part of the drug reaches the brain. This is because the human enzyme tyrosine decarboxylase (TDC) converts L-dopa to dopamine before it can get to the brain. Dopamine is too big to cross the strict barrier between the blood and the brain (while L-dopa can cross this barrier), so when this happens the drug can’t reach the brain regions that it needs to reach to treat Parkinson’s disease.
To avoid this early conversion of L-dopa to dopamine, patients receive L-dopa in combination with another drug, Carbidopa, which inhibits the activity of the human TDC enzyme. However, even with the combined treatment, L-dopa efficacy varies greatly between patients, meaning that for some patients the drug works well but for others, it doesn’t.
Since it was known that some bacteria have also TDC enzymes, researchers from Groningen University tried to answer whether these enzymes are present also in the gut bacterial communities and if yes, what is their implication with L-dopa treatment. For the first time, researcher El Aidy and her team discovered that some bacteria from the small intestine of the rats had TDC enzymes and were able to convert L-Dopa into dopamine similarly to the human TDC [1].
Furthermore, rats that had a lot of bacterial TDC in the small intestines also had less L-dopa and more dopamine in the bloodstream. This suggests that bacterial TDC is converting L-dopa to dopamine in the gut before it reaches the brain.
The next step was to test the effect of drugs, known to be effective against human TDC such as Carbidopa, against bacterial TDC. Carbidopa was highly effective in blocking the action of the human TDC (as we already knew), but it had minimal effect on the bacterial enzymes. This can explain why the effect of the drug differs between patients, even when they are given Carbidopa. It all depends on how much bacterial TDC a person has in his or her intestines.
To confirm these findings, researchers used also human fecal samples from patients with Parkinson’s disease. Indeed, results were in accordance with the animal studies: patients with high bacterial TDC in their gut were the ones who required higher dosages of L-dopa.
The human gut is colonized by a wide diversity of micro-organisms, and the more we learn about these bacteria, the more it becomes clear that it is very important to our overall health. However, even though our knowledge the gut bacteria increased rapidly the past decade, little still is known about their effect on drug metabolism. This seminal study, for the first time, describes how gut bacteria affect drug availability in patients with Parkinson’s disease and explains why some people require a higher dosage of L-dopa for the treatment to be effective. The next step is to find a way to also limit the effect of bacterial TDC on L-dopa and allow the drug to work as intended.