Globally, 10 million people are living with Parkinson’s disease, and\u00a0L<\/span>-dopa has been the primary treatment for over 50 years (4<\/em><\/a>). Dopamine becomes progressively depleted in the brains of Parkinson’s disease patients, causing motor impairment, including tremor, rigidity, and slowness of movement.\u00a0L<\/span>-dopa, the precursor of dopamine, is generally taken orally. The drug is absorbed in the small intestine, and unlike dopamine, crosses the blood-brain barrier into the brain, where it is converted to dopamine by decarboxylation. Dopamine replacement alleviates the motor symptoms of Parkinson’s disease, but does not prevent Parkinson’s disease progression.\u00a0L<\/span>-dopa is prematurely decarboxylated to dopamine before it gets to the brain (particularly in the gut), and this limits drug bioavailability and causes gastrointestinal problems (4<\/em><\/a>). Counteracting this effect is achieved by coadministration of peripheral human decarboxylase inhibitors (4<\/em><\/a>). However,\u00a0L<\/span>-dopa bioavailability still varies considerably between patients, and efficacy wanes over time, necessitating increased doses with unpredictable fluctuating motor responses and adverse side effects (4<\/em><\/a>,\u00a05<\/em><\/a>).<\/p>\n Gastrointestinal dysfunction, including constipation, delayed gastric emptying, and small intestine bacterial overgrowth, are key components of Parkinson’s disease, and these impair\u00a0L<\/span>-dopa intestinal absorption and drug responses (5<\/em><\/a>). Gut dysfunction occurs before motor symptoms and worsens as Parkinson’s disease advances. Indeed, an origin of Parkinson’s disease in the gut has been proposed (5<\/em><\/a>,\u00a06<\/em><\/a>). The gut microbiome is altered in patients with Parkinson’s disease (5<\/em><\/a>,\u00a06<\/em><\/a>), and this might underlie gut-brain axis pathophysiology (5<\/em><\/a>\u20137<\/em><\/a>) as well as limit\u00a0L<\/span>-dopa therapies (5<\/em><\/a>). Remarkably, it has been known since 1971 that gut microbes metabolize\u00a0L<\/span>-dopa to dopamine and\u00a0m<\/em>-tyramine in Parkinson’s disease (8<\/em><\/a>), but identifying which microbes and enzymes are responsible for this two-step pathway remained to be discovered.<\/p>\n Maini Rekdal\u00a0et al.<\/em>\u00a0used integrated interdisciplinary approaches to identify the\u00a0L<\/span>-dopa metabolic pathway. For the first step,\u00a0L<\/span>-dopa conversion to dopamine, there were some clues. Tyrosine decarboxylase, present predominantly within the gut bacteria of the\u00a0Enterococcus<\/em>\u00a0and\u00a0Lactobacillus<\/em>\u00a0genera (9<\/em><\/a>\u201311<\/em><\/a>), was reported to also decarboxylate dopamine (9<\/em><\/a>,\u00a011<\/em><\/a>). By screening established human microbiome datasets, Maini Rekdal\u00a0et al.<\/em>\u00a0showed that most tyrosine decarboxylase (tdc<\/em>) genes were present within these genera, particularly in\u00a0Enterococcus<\/em>, consistent with other recent findings (12<\/em><\/a>). Moreover,\u00a0E. faecalis<\/em>\u00a0species were found to be the most efficient strains at decarboxylating\u00a0L<\/span>-dopa. These strains were shown to prefer tyrosine, but decarboxylate\u00a0L<\/span>-dopa and tyrosine simultaneously and with maximal activity at low pH, similar to the acid environment in the small intestine where\u00a0L<\/span>-dopa is absorbed (3<\/em><\/a>,\u00a012<\/em><\/a>). Both studies also showed that\u00a0E. faecalis tdc<\/em>\u00a0gene inactivation obliterates\u00a0L<\/span>-dopa decarboxylation (3<\/em><\/a>,\u00a012<\/em><\/a>).<\/p>\n Finding the gut microbial species and enzymes that dehydroxylate dopamine to\u00a0m<\/em>-tyramine (the second step) was more challenging because no bacterial species was known to have this capability. Maini Rekdal\u00a0et al.<\/em>\u00a0used elegant multidisciplinary approaches and identified this activity to be specific to\u00a0Eggerthella lenta<\/em>\u00a0species and close relatives in\u00a0Actinobacterial<\/em>\u00a0genera. The authors characterized a distinct dopamine-inducible dehydroxylation enzyme that removes the para hydroxyl group of dopamine to produce\u00a0m<\/em>-tyramine. Although all\u00a0Eg. lenta<\/em>\u00a0strains examined were dopamine-inducible, less than 50% dehydroxylated dopamine. Intriguingly, this was due to the presence of a single-nucleotide polymorphism (SNP) that resulted in an Arg506<\/sup>\u00a0to Ser substitution that inactivated the enzyme. This highlights an underappreciated role for SNPs in gut microbial function, and the importance of probing metabolic function, rather than assigning similar functions to gut bacterial strains.<\/p>\n <\/p>\n The gut bacterium\u00a0Enterococcus faecalis<\/em>\u00a0(scanning electron micrograph shown) degrades the Parkinson’s disease drug levodopa, perhaps limiting its availability in patients.<\/p>\n <\/p>\n <\/p>\n What do these findings mean for people with Parkinson’s disease? Maini Rekdal\u00a0et al.<\/em>\u00a0show that the enzymes that degrade\u00a0L<\/span>-dopa occur in microbiomes from human stool samples and that\u00a0L<\/span>-dopa degradation occurs with considerable variation in people with and without Parkinson’s disease. They show that\u00a0L<\/span>-dopa degradation can be predicted predominantly by microbial\u00a0tdc<\/em>\u00a0gene expression and\u00a0E. faecalis<\/em>\u00a0abundance in stool samples, and also by the presence of Arg506<\/sup>\u00a0in\u00a0Eg. lenta<\/em>. Furthermore, recent studies show that higher amounts of\u00a0tdc<\/em>\u00a0in stool from Parkinson’s disease patients correlate with increasing\u00a0L<\/span>-dopa dosage and disease duration (12<\/em><\/a>).<\/p>\n Do human decarboxylase inhibitors, such as carbidopa, block the microbial enzymes? It has been shown in culture that this is not the case (12<\/em><\/a>), and Maini Rekdal\u00a0et al.<\/em>\u00a0confirmed this result in Parkinson’s disease patient stool samples. To potentially counteract\u00a0L<\/span>-dopa degradation, Maini Rekdal\u00a0et al.<\/em>\u00a0identified a small-molecule inhibitor, \u03b1-fluoromethyltyrosine (AFMT), that specifically inhibited microbial\u00a0L<\/span>-dopa decarboxylase activity, including in Parkinson’s disease patient microbiotas. AFMT shows potential to block degradation of\u00a0L<\/span>-dopa by\u00a0E. faecalis<\/em>\u00a0in mice. Moreover, blood plasma\u00a0L<\/span>-dopa concentrations were higher in rats when\u00a0L<\/span>-dopa and carbidopa were coadministered with non\u2013L<\/span>-dopa\u2013metabolizing\u00a0E. faecalis<\/em>\u00a0mutants compared with active strains (12<\/em><\/a>). Together, these findings indicate that blocking bacterial\u00a0L<\/span>-dopa decarboxylase activity in patients with Parkinson’s disease, with knowledge of the abundance of this enzyme in an individual, could personalize and potentially improve\u00a0L<\/span>-dopa therapies. Substantial information is available on the regulation of tyrosine decarboxylase and the\u00a0tdc<\/em>\u00a0operon in\u00a0E. faecalis<\/em>\u00a0(10<\/em><\/a>,\u00a013<\/em><\/a>), providing complementary avenues to understanding and modulating this enzyme’s activity in Parkinson’s disease.<\/p>\n The identification of specific gut bacteria and enzymes involved in drug metabolism, such as\u00a0L<\/span>-dopa, is a vital, but underexplored, research area. An increasing number of drugs have been identified to be metabolized by gut microbes, enabling their activation, inactivation, and sometimes toxicity. In turn, drugs can sculpt and regulate gut microbial composition (1<\/em><\/a>,\u00a02<\/em><\/a>). The findings that similar biochemical pathways occur in the human brain and gut microbes, as shown for\u00a0L<\/span>-dopa and dopamine, highlight an intricate metabolic cross-talk between gut microbiome and human brain metabolism. Deciphering the extent to which potential alterations in such gut microbiota\u2013brain metabolism contributes to brain health, the development of Parkinson’s disease, and Parkinson’s disease therapeutics is an important research avenue. It is now crucial to further investigate whether measuring and inhibiting gut microbial tyrosine and\u00a0L<\/span>-dopa decarboxylase activity could predict and potentially improve\u00a0L<\/span>-dopa efficacy and treatment outcomes for people with Parkinson’s disease.<\/p>\n <\/p>\n <\/p>\n <\/p>\n![\"Embedded](\"https:\/\/science.sciencemag.org\/sites\/default\/files\/highwire\/sci\/364\/6445\/1030\/embed\/graphic-1.gif\")
<\/span><\/div>\nPHOTO: NANO CREATIVE\/SCIENCE SOURCE<\/q><\/div>\n<\/div>\n