Gut microbes metabolize Parkinson’s disease drug

 

 

The trillions of microorganisms that form the gut microbiota contain a treasure trove of enzymes. These directly modify and metabolize dietary components, drugs, and toxins that humans ingest. Although this is often beneficial, the gut microbiota can modify drug bioavailability and efficacy (1, 2). Levodopa (L-dopa), the major drug treatment for Parkinson’s disease, displays highly variable and interindividual responses with reduced efficacy over time. On page 1055 of this issue, Maini Rekdal et al. (3) identify a two-step gut microbial enzymatic pathway that degrades L-dopa to dopamine and then to m-tyramine, thus potentially limiting drug availability in patients. Moreover, they identify a small molecule that blocks this L-dopa–metabolizing bacterial pathway, with the aim of increasing L-dopa availability in Parkinson’s disease patients.

Globally, 10 million people are living with Parkinson’s disease, and L-dopa has been the primary treatment for over 50 years (4). Dopamine becomes progressively depleted in the brains of Parkinson’s disease patients, causing motor impairment, including tremor, rigidity, and slowness of movement. L-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. L-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). Counteracting this effect is achieved by coadministration of peripheral human decarboxylase inhibitors (4). However, L-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, 5).

Gastrointestinal dysfunction, including constipation, delayed gastric emptying, and small intestine bacterial overgrowth, are key components of Parkinson’s disease, and these impair L-dopa intestinal absorption and drug responses (5). 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, 6). The gut microbiome is altered in patients with Parkinson’s disease (5, 6), and this might underlie gut-brain axis pathophysiology (5–7) as well as limit L-dopa therapies (5). Remarkably, it has been known since 1971 that gut microbes metabolize L-dopa to dopamine and m-tyramine in Parkinson’s disease (8), but identifying which microbes and enzymes are responsible for this two-step pathway remained to be discovered.

Maini Rekdal et al. used integrated interdisciplinary approaches to identify the L-dopa metabolic pathway. For the first step, L-dopa conversion to dopamine, there were some clues. Tyrosine decarboxylase, present predominantly within the gut bacteria of the Enterococcus and Lactobacillus genera (9–11), was reported to also decarboxylate dopamine (9, 11). By screening established human microbiome datasets, Maini Rekdal et al. showed that most tyrosine decarboxylase (tdc) genes were present within these genera, particularly in Enterococcus, consistent with other recent findings (12). Moreover, E. faecalis species were found to be the most efficient strains at decarboxylating L-dopa. These strains were shown to prefer tyrosine, but decarboxylate L-dopa and tyrosine simultaneously and with maximal activity at low pH, similar to the acid environment in the small intestine where L-dopa is absorbed (3, 12). Both studies also showed that E. faecalis tdc gene inactivation obliterates L-dopa decarboxylation (3, 12).

Finding the gut microbial species and enzymes that dehydroxylate dopamine to m-tyramine (the second step) was more challenging because no bacterial species was known to have this capability. Maini Rekdal et al. used elegant multidisciplinary approaches and identified this activity to be specific to Eggerthella lenta species and close relatives in Actinobacterial genera. The authors characterized a distinct dopamine-inducible dehydroxylation enzyme that removes the para hydroxyl group of dopamine to produce m-tyramine. Although all Eg. lenta strains 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 to 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.

 

 

 

What do these findings mean for people with Parkinson’s disease? Maini Rekdal et al. show that the enzymes that degrade L-dopa occur in microbiomes from human stool samples and that L-dopa degradation occurs with considerable variation in people with and without Parkinson’s disease. They show that L-dopa degradation can be predicted predominantly by microbial tdc gene expression and E. faecalis abundance in stool samples, and also by the presence of Arg⁵⁰⁶ in Eg. lenta. Furthermore, recent studies show that higher amounts of tdc in stool from Parkinson’s disease patients correlate with increasing L-dopa dosage and disease duration (12).

Do human decarboxylase inhibitors, such as carbidopa, block the microbial enzymes? It has been shown in culture that this is not the case (12), and Maini Rekdal et al. confirmed this result in Parkinson’s disease patient stool samples. To potentially counteract L-dopa degradation, Maini Rekdal et al. identified a small-molecule inhibitor, α-fluoromethyltyrosine (AFMT), that specifically inhibited microbial L-dopa decarboxylase activity, including in Parkinson’s disease patient microbiotas. AFMT shows potential to block degradation of L-dopa by E. faecalis in mice. Moreover, blood plasma L-dopa concentrations were higher in rats when L-dopa and carbidopa were coadministered with non–L-dopa–metabolizing E. faecalis mutants compared with active strains (12). Together, these findings indicate that blocking bacterial L-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 L-dopa therapies. Substantial information is available on the regulation of tyrosine decarboxylase and the tdc operon in E. faecalis (10, 13), providing complementary avenues to understanding and modulating this enzyme’s activity in Parkinson’s disease.

The identification of specific gut bacteria and enzymes involved in drug metabolism, such as L-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, 2). The findings that similar biochemical pathways occur in the human brain and gut microbes, as shown for L-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–brain 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 L-dopa decarboxylase activity could predict and potentially improve L-dopa efficacy and treatment outcomes for people with Parkinson’s disease.

 

 

 

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