The Gut Microbiome: A Therapeutically Targetable Site of Peripheral Levodopa Metabolism.

Abstract

Rekdal, VM, Bess, EN, Bisanz, JE, Turnbaugh, PJ, Balskus, EP. Discovery and inhibition of an interspecies gut bacterial pathway for levodopa metabolism. Science 2019; 364( 6445):eaau6323. https://doi.org/10.1126/science.aau6323 Much research has recently focused on the gut–brain axis and its influences on neurodegenerative processes.1 Less studied is the impact of the microbiome on treatment of Parkinson's disease (PD) and other neurodegenerative disorders.2 Levodopa (l-dopa) remains the primary symptomatic treatment for PD. Therapeutic efficacy depends on achieving sufficient central nervous system concentrations, a factor largely influenced by first-pass metabolism outside the brain.2, 3 The major extracerebral site of l-dopa metabolism is the gut. Here, l-dopa undergoes decarboxylation either via human aromatic amino acid decarboxylase (AADC) or by gut organisms.2 Peripheral metabolism to dopamine not only reduces l-dopa availability for central nervous system penetration but also produces unwanted side effects.2 Clinicians therefore coadminister peripheral AADC inhibitors, for example, carbidopa. Despite this blockade, up to 56% of administered l-dopa fails to reach the brain.4 There is significant interindividual variability in serum l-dopa levels following standard oral administration, producing variable therapeutic responses.2, 3 Gut microbiota metabolize l-dopa through a 2-step pathway (initial decarboxylation to dopamine followed by dehydroxylation to m-tyramine).2 Variations in gut microbiota therefore contribute to such therapeutic variations. In this study, Rekdal and colleagues2 characterized the organisms, genes, and enzymes responsible for microbiome-related l-dopa metabolism and explored therapeutic manipulation of this pathway. First, using genome-mining approaches, they identified enterococcus species, particularly Enterococcus faecalis as the major l-dopa decarboxylator (via the enzyme tyrosine decarboxylase [TyrDC]).2 Next, they identified Eggerthella lenta as the strain responsible for dehydroxylating dopamine to m-tyramine.2 Although this step does not influence l-dopa therapeutic efficacy, through regulating peripheral dopamine clearance, it is an important determinant of l-dopa side effects. These findings, alongside demonstrations of l-dopa metabolism in previously nonmetabolizing samples on the addition of E. faecalis, confirmed it as the dominant l-dopa decarboxylator in human microbiota.2 The authors proceeded to determine that host AADC inhibitors, for example, carbidopa, were ineffective against microbiome-related decarboxylation; activity against TyrDC was about 200 times less than toward host AADC.2 Interestingly, another compound, α-fluoromethyltyrosine, a nontoxic selective inhibitor of TyrDC but not AADC, completely inhibited l-dopa decarboxylation in gut microbiota samples.2 In a mouse model colonized with TyrDC-producing E. faecalis, α-fluoromethyltyrosine significantly increased peak l-dopa serum concentrations when compared with a vehicle control.2 This study highlights the role of the microbiome in explaining some of the variability in l-dopa responsiveness in PD. The identification of TyrDC as the predominant mediator of microbiome-associated l-dopa decarboxylation offers a potential biomarker for reduced l-dopa efficacy in certain populations. This also raises the future possibility of personalized, biomarker-driven specific TyrDC inhibition as a therapeutic addition to classic AADC inhibitors. Such therapies, through reducing peripheral l-dopa metabolism, would likely increase peak central nervous system l-dopa levels, thereby improving clinical outcomes. Potential complications of increasing synaptic dopaminergic pulsatility (motor fluctuations, increased risk of dyskinesia), however, will also need to be borne in mind during future studies of any such compounds.5 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. E.M.: 1A, 1B, 1C, 3A K.P.B.: 1A, 1B, 3B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed patient consent and institutional review board approval was not necessary for this work. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. EM reports no financial disclosures.KPB holds research grants from EU Horizon 2020 and has received honoraria to speak at meetings or to attend advisory boards from Ipsen, Cavion, Allergan, Teva Lundbeck and Bial pharmaceutical companies. He also receives royalties from Oxford University Press and a stipend for MDCP editorship.