Interference of the gut microbiota with the treatment of parkinson’s disease

Parkinson’s disease is a neurodegenerative disease affecting more than 1% of people over 60 worldwide. Its treatment produces very heterogeneous results in terms of efficacy and side-effects, depending on patients. Based on a study published in the journal Science, the gut microbiota could be the cause behind this variability.

Treatment with heterogeneous effects

The current treatment is based on a drug, levodopa (L-dopa), which, when metabolized in the brain, replaces dopamine that neural cells do not produce anymore. Problem: a significant part of L-dopa is transformed into dopamine in the intestines; however dopamine thus produced at the peripheral level cannot cross the blood-brain barrier and cannot reach the brain, which not only reduces the treatment’s efficacy but may also generate severe side-effects (gastrointestinal disorders and cardiac arrhythmias). Therefore, another molecule, carbidopa, is administered concomitantly in order to block this metabolization process: despite that, up to 56% of L-dopa does not reach the brain.

Interference of the gut microbiota

Although the interference of the gut microbiota with treatment’s efficacy was already suspected, its mechanism of action remained unclear until this study. The exploration of the bacterial metagenome first helped identify a species–Enterococcus faecalis–with tyrosine decarboxylase activity that degrades L-dopa into dopamine. The researchers then brought to light the conversion of dopamine into m-tyramine under the action of another enzyme–a molybdenum-dependent dehydroxylase–present in Eggerthella lenta. Differences in these microbial activities could potentially contribute to heterogeneous responses to L-dopa observed in patients, thus explaining its reduced efficacy and its side-effects observed in some of them.

Blocking the gut degradation of L-dopa

The researchers then tried to understand why carbidopa proved hardly effective to prevent the gut metabolization of L-dopa. Their conclusion was that although this molecule is indeed able to inhibit human decarboxylase involved in the metabolization of L-dopa, it turned out to have no effect on the decarboxylase present in E. faecalis in vivo. They then identified an inhibitor (AFMT (sidenote: AFMT (S)-α-fluoromethyltyrosine ) ) able to block the bacterial enzyme. The last phase of their works showed that the administration of standard treatment (L-dopa + carbidopa) combined with AFMT to gnotobiotic mice (sidenote: Gnotobiotic mice refers to laboratory animals in which only certain known strains of microorganisms are present )  colonized by E. faecalis, increases the serum concentration of L-dopa, thus demonstrating in vivo the inhibition of L-dopa degradation by the gut microbiota. This is a promising discovery (sidenote: Professor E. Balskus received the 2019 International Award of the Biocodex Microbiota Foundation for these works and as support for upcoming projects on this subject matter )  that could open the way to new therapies targeting the microbiota.