As these GEITP pages have often discussed, the gut microbiome has been underappreciated for many decades, but now we are realizing how important and relevant the flora of our intestine is, with regard to numerous human disorders and drug regimens, as well as our well-being. This topic is front-and-center within our “gene-environment interactions” theme. If all DNA of a human body is isolated, more than 90% of the DNA is derived from bacteria-fungi-viruses that populate our gut. These microbes are capable of modifying and metabolizing dietary components, drugs, and other environmental toxicants that we ingest. Levo-DOPA [L-dopa; 3-hydroxy-L-tyrosine, the precursor to dopamine — commonly used as dopamine replacement agent for treating Parkinson disease (PD); it is most effectively used to control slow/jerky tremors (bradykinetic symptoms) usually seen in PD] exhibits highly variable/interindividual responses — which unfortunately has decreased efficacy over time.
Authors [see attached article & editorial] have identified a 2-step gut microbial enzymatic pathway that degrades L-dopa to dopamine and then
to m-tyramine — thereby potentially limiting drug availability to the patient. Authors also discovered a small molecule that blocks this L-dopa-metabolizing bacterial pathway (which should increase L-dopa availability in PD patients); that small molelcule is AFMT [(S)-α-Fluoro-methyl-tyrosine].
For treatment to be effective, intact L-dopa must enter the brain and be converted to the neurotransmitter dopamine by the human enzyme aromatic amino acid decarboxylase (AADC). However, the intestine is a major site for L-dopa decarboxylation, which is problematic because dopamine generated outside the brain cannot cross the blood-brain barrier and therefore causes unwanted side effects. Thus, L-dopa is co-administered with drugs that block peripheral metabolism — including the AADC inhibitor carbidopa. Even with these two drugs, as much as 56% of L-dopa fails to reach the brain. The efficacy and side effects of L-dopa treatment are therefore extremely heterogeneous, across all PD patients, and this variability cannot be completely explained simply by “differences in host metabolism.”
Authors have therefore characterized an interspecies pathway for gut bacterial L-dopa metabolism and demonstrated its relevance in human gut microbiotas. Variations in these microbial activities could possibly contribute to the heterogeneous responses to L-dopa observed among patients — including decreased efficacy and undesirable side effects. These data should enable efforts to elucidate the gut microbiota’s contribution to treatment outcomes. This study highlights the promise of developing new therapies that target both host and gut microbial drug metabolism. 😊
Science 14 June 2o19; 364: 1055-???? & editorial pp 1030-1031.