“Symbiosis is a much higher reflection of intelligent life.” Frederick Lenz
“Why do we do basic research? To learn about ourselves.” Walter Gilbert
Overview: Reading the article entitled “Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism” from V. Maini Rekdal et al., Science 364, eaau6323 (2019) (DOI: 10.1126/science.aau6323- open access) made me realize why I became a scientist and did the whole graduate school (M.S. and Ph.D.) and postdoctoral fellowship routine; and why I have spent the past 37 years career-wise in biomedical research and education at a medical school.
This is tour de force science and a most impressive research investigation regarding Parkinson’s. This work comes from the Emily Balskus laboratory at Harvard University, Cambridge, MA. These results will allow us to compare/contrast gut microbiota to metabolize levodopa during treatment for Parkinson’s. They have also provided the first step in drug discovery to inhibit this bacterial decarboxylase that could, one-day in the future, allow for increased levodopa availability.
“You are not an encapsulated bag of skin dragging around a dreary little ego. You are an evolutionary wonder, a trillion cells singing together in a vast chorale, an organism – environment, a symbiosis of cell and soul.” Jean Houston
Microbiota: We have literally trillions of microorganisms living on us and in us. As detailed in Wikipedia, “A microbiota is an ecological community of commensal, symbiotic and pathogenic microorganisms found in and on all multicellular organisms studied to date from plants to animals. A microbiota includes bacteria, archaea, protists, fungi and viruses.” Microbiome and microbiota are synonymous for one another. Mostly, this is a symbiotic and beneficial relationship/process with the human host; however, sometimes the gut microbiota can alter, modify or degrade some drugs during their absorption and processing getting through the gastrointestinal tract (gut). Although it has been known for a while that the gut microbiota could modify levodopa, neither the organism(s) nor the mechanism had been determined. Why is this important? Levodopa is the immediate precursor to dopamine, the all-essential missing neurotransmitter due to the loss of the substantia nigra in the midbrain, which causes Parkinson’s. And treatment with levodopa is a crucial component in managing many of the symptoms of Parkinson’s.
The usual route is to take levodopa by oral ingestion. Levodopa is converted to dopamine by an enzyme that removes a carboxyl group, and it called a decarboxylase. Importantly, levodopa, not dopamine, crosses the blood-brain barrier (BBB) to enter the brain. We keep spurious modification of levodopa from happening in the gut because we add an excess of a decarboxylase inhibitor named carbidopa. Availability of Sinemet (trademark name for combined levodopa and carbidopa) can vary each time we take it; and sadly, a small percentage of people-with-Parkinson’s (PwP) are just poor in their response to levodopa treatment. The thinking has been this variable availability of levodopa may be due to something beyond just host differences. Many have begun studying the role of microbiota in our gut to not only explain this variable levodopa response curve but even to implicate the gut as a significant player in the genesis of Parkinson’s.
“Over the long term, symbiosis is more useful than parasitism. More fun, too. Ask any mitochondria.” Larry Wall
Description of the paper and what they reported: To summarize this research, I have (i) prepared a schematic “big picture” overview and (ii) a brief synopsis of their key findings.
• They began by studying the Human Microbiome Project that contained millions of DNA sequences. They were targeting bacterial DNA for sequences of enzyme (decarboxylase) that would be able to convert levodopa to dopamine.
• The bacteria group known as Enterococcus had decarboxylase DNA sequences. Further refinement of this bacterial group showed that Enterococcus faecalis, which is a common component of healthy gut, had the ability to metabolize levodopa to dopamine.
• They then turned to culturing studies and identified a bacterial strain named Eggerthella lenta that had the ability to dehydroxylate dopamine to m-tyramine. To further enrich their story, this dehyroxylate activity was only present in samples of single-nucleotide polymorphisms, or SNPs (a variant of Arg-506)
• These enzymatic processes are summarized below:
• They tested carbidopa, which is a known inhibitor of human-derived decarboxylase on the bacterial decarboxylase. Their results suggest that carbidopa had reduced action to inhibit the bacterial enzyme.
• Turning to a translational medicine approach, they studied stool samples from various PwP for their endogenous activity to metabolize levodopa. Interestingly, some sample showed no hydrolysis of levodopa; by contrast, other PwP-stool samples showed substantial modification of levodopa.
• Finally, they took a medicinal chemistry approach to identify a compound named (S)-α-fluoromethyltyrosine (AFMT) that blocked levodopa conversion to dopamine by the bacterial decarboxylase. Using mice colonized with E. faecalis, they added AFMT with carbidopa and levodopa and measured increaed serum levodopa levels compared to the control animals. Although preliminary, these results show that inhibition of microbial gut levodopa-metabolizing activity could increase bioavailability of levodopa.
“I support basic research, which can lead to discoveries that change our world, expand our horizons and save lives.” Lamar S. Smith
Conclusions: The results of this study are both interesting and with much potential. This work implies a role for the human gut microbiota to metabolize levodopa. Will a large scale clinical study allow one to know how effective ‘your gut’ responds to levodopa? Developing novel compounds that specifically inhibit human gut microbes to process levodopa could possibly alter the treatment outcome of Parkinson’s.
Please remember the material provided here is for educational and scientific purposes only. Please, under no circumstance, should you consider this blog post as medical advice. The paper described has much ‘future potential’ in several new aspects regarding Parkinson’s; however, this is the beginning, not the end of their story. There is much to look forward to regarding the role of the human gut microbiota in Parkinson’s. Much like we can only see the ‘tip of the iceberg,’ time will tell regarding the usefulness of this exciting science for the future of treating Parkinson’s.
“Imagine something a million times more powerful than your smartphone that is the size of a brain cell interfacing with your biological neurons. That will be the complete symbiosis. That will be when we augment our brains at the level of the neuron.” Jason Silva