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Gut-Dwelling Bacterium Consumes Parkinson’s Drug

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Gut bacteria eating a pill

Scientists continue to uncover the many fascinating ways in which the trillions of microbes that inhabit the human body influence our health. Now comes yet another surprising discovery: a medicine-eating bacterium residing in the human gut that may affect how well someone responds to the most commonly prescribed drug for Parkinson’s disease.

There have been previous hints that gut microbes might influence the effectiveness of levodopa (L-dopa), which helps to ease the stiffness, rigidity, and slowness of movement associated with Parkinson’s disease. Now, in findings published in Science, an NIH-funded team has identified a specific, gut-dwelling bacterium that consumes L-dopa [1]. The scientists have also identified the bacterial genes and enzymes involved in the process.

Parkinson’s disease is a progressive neurodegenerative condition in which the dopamine-producing cells in a portion of the brain called the substantia nigra begin to sicken and die. Because these cells and their dopamine are critical for controlling movement, their death leads to the familiar tremor, difficulty moving, and the characteristic slow gait. As the disease progresses, cognitive and behavioral problems can take hold, including depression, personality shifts, and sleep disturbances.

For the 10 million people in the world now living with this neurodegenerative disorder, and for those who’ve gone before them, L-dopa has been for the last 50 years the mainstay of treatment to help alleviate those motor symptoms. The drug is a precursor of dopamine, and, unlike dopamine, it has the advantage of crossing the blood-brain barrier. Once inside the brain, an enzyme called DOPA decarboxylase converts L-dopa to dopamine.

Unfortunately, only a small fraction of L-dopa ever reaches the brain, contributing to big differences in the drug’s efficacy from person to person. Since the 1970s, researchers have suspected that these differences could be traced, in part, to microbes in the gut breaking down L-dopa before it gets to the brain.

To take a closer look in the new study, Vayu Maini Rekdal and Emily Balskus, Harvard University, Cambridge, MA, turned to data from the NIH-supported Human Microbiome Project (HMP). The project used DNA sequencing to identify and characterize the diverse collection of microbes that populate the healthy human body.

The researchers sifted through the HMP database for bacterial DNA sequences that appeared to encode an enzyme capable of converting L-dopa to dopamine. They found what they were looking for in a bacterial group known as Enterococcus, which often inhabits the human gastrointestinal tract.

Next, they tested the ability of seven representative Enterococcus strains to transform L-dopa. Only one fit the bill: a bacterium called Enterococcus faecalis, which commonly resides in a healthy gut microbiome. In their tests, this bacterium avidly consumed all the L-dopa, using its own version of a decarboxylase enzyme. When a specific gene in its genome was inactivated, E. faecalis stopped breaking down L-dopa.

These studies also revealed variability among human microbiome samples. In seven stool samples, the microbes tested didn’t consume L-dopa at all. But in 12 other samples, microbes consumed 25 to 98 percent of the L-dopa!

The researchers went on to find a strong association between the degree of L-dopa consumption and the abundance of E. faecalis in a particular microbiome sample. They also showed that adding E. faecalis to a sample that couldn’t consume L-dopa transformed it into one that could.

So how can this information be used to help people with Parkinson’s disease? Answers are already appearing. The researchers have found a small molecule that prevents the E. faecalis decarboxylase from modifying L-dopa—without harming the microbe and possibly destabilizing an otherwise healthy gut microbiome.

The finding suggests that the human gut microbiome might hold a key to predicting how well people with Parkinson’s disease will respond to L-dopa, and ultimately improving treatment outcomes. The finding also serves to remind us just how much the microbiome still has to tell us about human health and well-being.

Reference:

[1] Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Maini Rekdal V, Bess EN, Bisanz JE, Turnbaugh PJ, Balskus EP. Science. 2019 Jun 14;364(6445).

Links:

Parkinson’s Disease Information Page (National Institute of Neurological Disorders and Stroke/NIH)

NIH Human Microbiome Project

Balskus Lab (Harvard University, Cambridge, MA)

NIH Support: National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute


Creative Minds: The Human Gut Microbiome’s Top 100 Hits

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Michael Fishbach

Michael Fishbach

Microbes that live in dirt often engage in their own deadly turf wars, producing a toxic mix of chemical compounds (also called “small molecules”) that can be a source of new antibiotics. When he started out in science more than a decade ago, Michael Fischbach studied these soil-dwelling microbes to look for genes involved in making these compounds.

Eventually, Fischbach, who is now at the University of California, San Francisco, came to a career-altering realization: maybe he didn’t need to dig in dirt! He hypothesized an even better way to improve human health might be found in the genes of the trillions of microorganisms that dwell in and on our bodies, known collectively as the human microbiome.


Snapshots of Life: Portrait of a Bacterial Biofilm

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Colony of Pseudomonas aeruginosa

Credit: Scott Chimileski and Roberto Kolter, Harvard Medical School, Boston

In nature, there is strength in numbers. Sometimes, those numbers also have their own unique beauty. That’s the story behind this image showing an intricate colony of millions of the single-celled bacterium Pseudomonas aeruginosa, a common culprit in the more than 700,000 hospital-acquired infections estimated to occur annually in the United States. [1]. The bacteria have self-organized into a sticky, mat-like colony called a biofilm, which allows them to cooperate with each other, adapt to changes in their environment, and ensure their survival.

In this image, the Pseudomonas biofilm has grown in a laboratory dish to about the size of a dime. Together, the millions of independent bacterial cells have created a tough extracellular matrix of secreted proteins, polysaccharide sugars, and even DNA that holds the biofilm together, stained in red. The darkened areas at the center come from the bacteria’s natural pigments.


Creative Minds: Bacteria, Gene Swaps, and Human Cancer

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Julie Dunning Hotopp

Julie Dunning Hotopp

When Julie Dunning Hotopp was a post-doctoral fellow in the early 2000s, bacteria were known for swapping bits of their DNA with other bacteria, a strategy known as lateral gene transfer. But the offloading of genes from bacteria into multicellular organisms was thought to be rare, with limited evidence that a bacterial genus called Wolbachia, which invades the cells of other organisms and takes up permanent residence, had passed off some of its DNA onto a species of beetle and a parasitic worm. Dunning Hotopp wondered whether lateral gene transfer might be a more common phenomenon than the evidence showed.

She and her colleagues soon discovered that Wolbachia had engaged in widespread lateral gene transfer with eight species of insects and nematode worms, possibly passing on genes and traits to their invertebrate hosts [1]. This important discovery put Dunning Hotopp on a research trail that now has taken a sharp turn toward human cancer and earned her a 2015 NIH Director’s Transformative Research Award. This NIH award supports exceptionally innovative research projects that are inherently risky and untested but have the potential to change fundamental research paradigms in areas such as cancer and throughout the biomedical sciences.


LabTV: Curious About the Microbiome

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Keisha FindleyWhen people think about the human microbiome—the scientific term for all of the microbes that live in and on our bodies—the focus is often on bacteria. But Keisha Findley, the young researcher featured in today’s LabTV video, is fascinated by a different part of the microbiome: fungi.

While earning her Ph.D. at Duke University, Durham, N.C., Findley zeroed in on Cryptococcus neoformans, a common, single-celled fungus that can lead to life-threatening infections, especially in people with weakened immune systems. Now, as a postdoctoral fellow at NIH’s National Human Genome Research Institute, Bethesda, MD, she is part of an effort to survey all of the fungi, as well as bacteria, that live on healthy human skin. The goal is to get a baseline understanding of these microbial communities and then examine how they differ between healthy people and those with skin conditions such as acne, athlete’s foot, skin ulcers, psoriasis, or eczema.


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