The microorganisms inhabiting the human gut can alter the chemical structures of drugs, leading to changes in their bioavailability, toxicity and efficacy. Although the gut microbial enzymes responsible for these chemical modifications are poorly understood, microbial mediation of therapeutic effects has been reported for metformin, chemotherapeutic drugs and antidepressants.
A gut microbial enzymatic pathway is involved in metabolizing the drug levodopa and might affect drug availability, according to new research led by Dr. Emily P. Balskus from Harvard University.
Previous research in 1971 showed for the first time the contribution of human gut microbiota in metabolizing levodopa to dopamine and then to m-tyramine. Maini Rekdal and colleagues have gone a step further by identifying which gut microbes, genes and enzymes are involved.
By screening the Human Microbiome Project dataset, it was found that the enzyme tyrosine decarboxylase, which is involved in converting levodopa to dopamine, was more abundant in the Enterococcus and Lactobacillus genera. Within them, E. faecalis was the most efficient strain at decarboxylating levodopa.
Consistent with these findings, a recent study has shown that higher amounts of gut bacterial tyrosine decarboxylases from patients with Parkinson’s disease are associated with increasing levodopa dosage and disease duration.
The second step comprising the transformation of dopamine into m-tyramine was found to be specific to Eggerthella lenta and its close relatives within the Actinobacteria genera, such as E. lenta. Although a molybdenum cofactor-dependent dopamine dehydroxylase (Dadh) enzyme was involved in dopamine metabolism, the fact that this ability was present in less than 50% of bacterial species led the authors to explore other sources.
A single-nucleotide polymorphism in the Dadh gene—involving a substitution of a single aminoacid—predicted better dopamine dihydroxylation in complex human gut microbiotas. These findings highlight the importance of even a single nucleotide polymorphism in predicting the functional diversity of gut microbiota, instead of assigning similar functions to gut bacterial strains.
The decarboxylation of levodopa in the gut limits drug bioavailability and causes gastrointestinal symptoms. In stool samples from patients with Parkinson’s disease, the authors showed that the human decarboxylase inhibitor carbidopa was not able to block the microbial enzymes that degrade levodopa.
However, researchers identified a small-molecule inhibitor, alfa-fluoromethyltyrosine, in Parkinson’s disease patient microbiotas, which specifically inhibited microbial levodopa decarboxylase activity in vitro. This molecule also inhibited microbial levodopa decarboxylase activity in gnotobiotic mice colonized with E. faecalis.
Altogether, these results show how gut microbial levodopa decarboxylation might be targeted in order to improve levodopa availability in Parkinson’s disease. Similar to carbodopa, this molecule could help increase levodopa availability in patients with Parkinson’s disease.
To sum up, this study has shown the involvement of gut bacterial tyrosine decarboxylases and specific single-nucleotide polymorphisms in predicting levodopa degradation. Researchers should now explore the extent to which inhibiting the gut microbial enzymatic activity responsible for levodopa metabolism will help improve treatment outcomes for patients with Parkinson’s disease.
Maini Rekdal V, Bess EN, Bisanz JE, et al. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science. 2019; 364(6445). doi: 10.1126/science.aau6323.