Gut-Dwelling Bacterium Consumes Parkinson’s Drug

Gut-Dwelling Bacterium Consumes Parkinson’s Drug
Posted on June 25th, 2019 by Dr. Francis Collins

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)

Gut microbes eat our medication for Parkinson

Pills illustration (stock image).
Credit: © georgejmclittle / Adobe Stock
Researchers have discovered one of the first concrete examples of how the microbiome can interfere with a drug’s intended path through the body. Focusing on levodopa (L-dopa), the primary treatment for Parkinson’s disease, they identified which bacteria out of the trillions of species is responsible for degrading the drug and how to stop this microbial interference.

The first time Vayu Maini Rekdal manipulated microbes, he made a decent sourdough bread. At the time, young Maini Rekdal, and most people who head to the kitchen to whip up a salad dressing, pop popcorn, ferment vegetables, or caramelize onions, did not consider the crucial chemical reactions behind these concoctions.

Even more crucial are the reactions that happen after the plates are clean. When a slice of sourdough travels through the digestive system, the trillions of microbes that live in our gut help the body break down that bread to absorb the nutrients. Since the human body cannot digest certain substances — all-important fiber, for example — microbes step up to perform chemistry no human can.

“But this kind of microbial metabolism can also be detrimental,” said Maini Rekdal, a graduate student in the lab of Professor Emily Balskus and first-author on their new study published in Science. According to Maini Rekdal, gut microbes can chew up medications, too, often with hazardous side effects. “Maybe the drug is not going to reach its target in the body, maybe it’s going to be toxic all of a sudden, maybe it’s going to be less helpful,” Maini Rekdal said.

In their study, Balskus, Maini Rekdal, and their collaborators at the University of California San Francisco, describe one of the first concrete examples of how the microbiome can interfere with a drug’s intended path through the body. Focusing on levodopa (L-dopa), the primary treatment for Parkinson’s disease, they identified which bacteria are responsible for degrading the drug and how to stop this microbial interference.

Parkinson’s disease attacks nerve cells in the brain that produce dopamine, without which the body can suffer tremors, muscle rigidity, and problems with balance and coordination. L-dopa delivers dopamine to the brain to relieve symptoms. But only about 1 to 5% of the drug actually reaches the brain.

This number — and the drug’s efficacy — varies widely from patient to patient. Since the introduction of L-dopa in the late 1960s, researchers have known that the body’s enzymes (tools that perform necessary chemistry) can break down L-dopa in the gut, preventing the drug from reaching the brain. So, the pharmaceutical industry introduced a new drug, carbidopa, to block unwanted L-dopa metabolism. Taken together, the treatment seemed to work.

“Even so,” Maini Rekdal said, “there’s a lot of metabolism that’s unexplained, and it’s very variable between people.” That variance is a problem: Not only is the drug less effective for some patients, but when L-dopa is transformed into dopamine outside the brain, the compound can cause side effects, including severe gastrointestinal distress and cardiac arrhythmias. If less of the drug reaches the brain, patients are often given more to manage their symptoms, potentially exacerbating these side effects.

Maini Rekdal suspected microbes might be behind the L-dopa disappearance. Since previous research showed that antibiotics improve a patient’s response to L-dopa, scientists speculated that bacteria might be to blame. Still, no one identified which bacterial species might be culpable or how and why they eat the drug.

So, the Balskus team launched an investigation. The unusual chemistry — L-dopa to dopamine — was their first clue.

Few bacterial enzymes can perform this conversion. But, a good number bind to tyrosine — an amino acid similar to L-dopa. And one, from a food microbe often found in milk and pickles (Lactobacillus brevis), can accept both tyrosine and L-dopa.

Using the Human Microbiome Project as a reference, Maini Rekdal and his team hunted through bacterial DNA to identify which gut microbes had genes to encode a similar enzyme. Several fit their criteria; but only one strain, Enterococcus faecalis (E. faecalis), ate all the L-dopa, every time.

With this discovery, the team provided the first strong evidence connecting E. faecalis and the bacteria’s enzyme (PLP-dependent tyrosine decarboxylase or TyrDC) to L-dopa metabolism.

And yet, a human enzyme can and does convert L-dopa to dopamine in the gut, the same reaction carbidopa is designed to stop. Then why, the team wondered, does the E. faecalis enzyme escape carbidopa’s reach?

Even though the human and bacterial enzymes perform the exact same chemical reaction, the bacterial one looks just a little different. Maini Rekdal speculated that carbidopa may not be able to penetrate the microbial cells or the slight structural variance could prevent the drug from interacting with the bacterial enzyme. If true, other host-targeted treatments may be just as ineffective as carbidopa against similar microbial machinations.

But the cause may not matter. Balskus and her team already discovered a molecule capable of inhibiting the bacterial enzyme.

“The molecule turns off this unwanted bacterial metabolism without killing the bacteria; it’s just targeting a non-essential enzyme,” Maini Rekdal said. This and similar compounds could provide a starting place for the development of new drugs to improve L-dopa therapy for Parkinson’s patients.

The team might have stopped there. But instead, they pushed further to unravel a second step in the microbial metabolism of L-dopa. After E. faecalis converts the drug into dopamine, a second organism converts dopamine into another compound, meta-tyramine.

To find this second organism, Maini Rekdal left behind his mother dough’s microbial masses to experiment with a fecal sample. He subjected its diverse microbial community to a Darwinian game, feeding dopamine to hordes of microbes to see which prospered.

Eggerthella lenta won. These bacteria consume dopamine, producing meta-tyramine as a by-product. This kind of reaction is challenging, even for chemists. “There’s no way to do it on the bench top,” Maini Rekdal said, “and previously no enzymes were known that did this exact reaction.”

The meta-tyramine by-product may contribute to some of the noxious L-dopa side effects; more research needs to be done. But, apart from the implications for Parkinson’s patients, E. lenta’s novel chemistry raises more questions: Why would bacteria adapt to use dopamine, which is typically associated with the brain? What else can gut microbes do? And does this chemistry impact our health?

“All of this suggests that gut microbes may contribute to the dramatic variability that is observed in side effects and efficacy between different patients taking L-dopa,” Balskus said.

But this microbial interference may not be limited to L-dopa and Parkinson’s disease. Their study could shepherd additional work to discover exactly who is in our gut, what they can do, and how they can impact our health, for better or worse.

Story Source:

Materials provided by Harvard University. Original written by Caitlin McDermott-Murphy. Note: Content may be edited for style and length.

Cancer Hijacks the Microbiome to Glut Itself on Sugar

Cancer Hijacks the Microbiome to Glut Itself on Glucose

Source: University of Colorado Anschutz Medical Campus.

Cancer needs energy to drive its out-of-control growth. It gets energy in the form of glucose, in fact consuming so much glucose that one method for imaging cancer simply looks for areas of extreme glucose consumption — where there is consumption, there is cancer. But how does cancer get this glucose? A University of Colorado Cancer Center study published today in the journal Cancer Cell shows that leukemia undercuts the ability of normal cells to consume glucose, thus leaving more glucose available to feed its own growth.

“Leukemia cells create a diabetic-like condition that reduces glucose going to normal cells, and as a consequence, there is more glucose available for the leukemia cells. Literally, they are stealing glucose from normal cells to drive growth of the tumor,” says Craig Jordan, PhD, investigator at University of Colorado Cancer Center, division chief of the Division of Hematology and the Nancy Carroll Allen Professor of Hematology at the University of Colorado School of Medicine.

Like diabetes, cancer’s strategies depend on insulin. Healthy cells need insulin to use glucose. In diabetes, either the pancreas under-produces insulin or tissues cannot not respond to insulin and so cells are left starved for energy while glucose builds up in the blood. The current study shows that leukemia goes about creating similar conditions of glucose buildup in two ways.

First, tumor cells trick fat cells into over-producing a protein called IGFBP1. This protein makes healthy cells less sensitive to insulin, meaning that when IGFBP1 is high, it takes more insulin to use glucose than it does when IGFBP1 is low. Unless the supply of insulin goes up, high IGFBP1 means that the glucose consumption of healthy cells goes down. (This protein may also be a link in the chain connecting cancer and obesity: The more fat cells, the more IGFBP1, and the more glucose is available to the cancer.)

Of course, cancer has a second strategy that ensures insulin production does not go up to meet the need created by increased IGFBP1. In fact, cancers turn insulin production down. In large part, they do this in the gut.

“In the course of doing this systemic analysis, we realized that some of the factors that help regulate glucose are made by the gut or bacteria in the gut. We looked there and found that the composition of the microbiome in leukemic animals was different than in control mice,” Jordan says.

One major difference in the guts of leukemic mice was the lack of a specific kind of bacteria known as bacteroids. These bacteroids produce short-chain fatty acids that in turn feed the health of cells lining your gut. Without bacteroids, gut health suffers. And the current study shows that without bacteroids, gut health suffers in ways that specifically aid cancer.

One way is the loss of hormones called incretins. When blood glucose gets high, for example after you eat, your gut releases incretins, which tamp down blood glucose, reducing it back into the normal range. Working through the gut, leukemia inactivates these incretins, allowing blood glucose to remain higher than it should. Leukemia also nixes the activity of serotonin. Serotonin is well-known as a “feel good” chemical that helps to regulate mood and is found in many antidepressants. But serotonin is also essential for the manufacture of insulin in the pancreas, and by attacking serotonin, leukemia reduces insulin production (and thus, down the line, glucose use).

The result of less insulin secretion and less insulin sensitivity is that cancer undercuts healthy cells’ use of insulin from both sides: Healthy cells need more insulin, just as there is less insulin available. Less insulin use by healthy cells leaves more glucose for the cancer.

“It’s a classic parasite trick: Take advantage of something the host does and subvert it for your own purposes,” Jordan says.

Interestingly, just as a parasite might eat a host’s food leading to malnourishment, cancer’s energy theft may play a role in the fatigue and weight loss common in cancer patients.

“The fairly prevalent observation is that cancer patients have a condition called cachexia, basically wasting away — you lose weight. If cancers are inducing systemic changes that result in depletion of normal energy stores, this could be part of that story,” Jordan says.

However, Jordan and colleagues including first author Haobin Ye, PhD, not only showed how leukemia dysregulates healthy cells’ glucose consumption, but also showed how to “re-regulate” this consumption.

“When we administered agents to recalibrate the glucose system, we found that we could restore glucose regulation and slow the growth of leukemia cells,” Ye says.

These “agents” were surprisingly low-tech. One was serotonin. Another was tributyrin, a fatty acid found in butter and other foods. Serotonin supplementation replaced the serotonin nixed by leukemia and tributyrin helped to replace the short-chain fatty acids that were absent due to loss of bacteroids.

gut

The group calls the combination Ser-Tri therapy. And they show that it is more than a theory. Ser-Tri therapy led to the recovery of insulin levels and reduction of IGFPB1. And leukemic mice treated with Ser-Tri therapy lived longer than those without. Twenty-two days after leukemia was introduced in mice, all of the untreated mice had died, while more than half of the mice treated with Ser-Tri were still alive.

The continuing line of work shows that cancer may depend on the ability to out-compete healthy cells for limited energy. Healthy tissues have strategies to regulate insulin, glucose and other factors controlling energy consumption; cancer cells have strategies to subvert this regulation with the goal of making more energy available for their own use.

“We now have evidence that what we observed in our mouse models is also true for leukemia patients.” Ye says.

Understanding these mechanisms that cancer uses to unbalance the body’s system of energy in their favor is helping doctors and researchers learn to thumb the scale in favor of healthy cells.

“This furthers the notion that you can do things systemically to disfavor leukemia cells and favor normal tissue,” Jordan says. “This could be part of limiting growth of tumors.”

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source: Garth Sundem – University of Colorado Anschutz Medical Campus
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells” by Haobin Ye, Biniam Adane, Nabilah Khan, Erica Alexeev, Nichole Nusbacher, Mohammad Minhajuddin, Brett M. Stevens, Amanda C. Winters, Xi Lin, John M. Ashton, Enkhtsetseg Purev, Lianping Xing, Daniel A. Pollyea, Catherine A. Lozupone, Natalie J. Serkova, Sean P. Colgan, and Craig T. Jordan in Cancer Cell. Published September 27 2018.
doi:10.1016/j.ccell.2018.08.016

How the digestive tract communicates with the brain

Gut Microbiome May Make Chemo Drug Toxic to Patients

Albert Einstein College of Medicineresearchers report that the composition of people’s gut bacteria may explain why some of them suffer life-threatening reactions after taking a key drug for treating metastatic colorectal cancer. The findings, described online today in npj Biofilms and Microbiomes, a Nature research journal, could help predict which patients will suffer side effects and prevent complications in susceptible patients.

“We’ve known for some time that people’s genetic makeup can affect how they respond to a medication,” says study leader Libusha Kelly, Ph.D., assistant professor of systems & computational biology and of microbiology & immunology at Einstein. “Now, it’s becoming clear that variations in one’s gut microbiome–the population of bacteria and other microbes that live in the digestive tract–can also influence the effects of treatment.”

Irinotecan is one of three first-line chemotherapy drugs used to treat colorectal cancer that has spread, or metastasized, to other parts of the body. However, up to 40 percent of patients who receive irinotecan experience severe diarrhea that requires hospitalization and can lead to death. “As you can imagine, such patients are already quite ill, so giving them a treatment that causes intestinal problems can be very dangerous,” says Dr. Kelly. “At the same time, irinotecan is an important weapon against this type of cancer.”

Irinotecan is administered intravenously in an inactive form. Liver enzymes metabolize the drug into its active, toxic form that kills cancer cells. Later, other liver enzymes convert the drug back into its inactive form, which enters the intestine via bile for elimination. But some people harbor digestive-tract bacteria that use part of inactivated irinotecan as a food source by digesting the drug with enzymes called beta-glucuronidases. Unfortunately, this enzyme action metabolizes and reactivates irinotecan into its toxic form, which causes serious side effects by damaging the intestinal lining.

To minimize irinotecan-related toxicity, doctors have tried using oral antibiotics to kill bacteria that make the enzymes. But antibiotics kill protective gut microbes as well, including those that counteract disease-causing bacteria. A 2010 study in Science involving mice found that drugs that selectively target E. coli beta-glucuronidases can reduce irinotecan’s toxicity.

In the current study, Dr. Kelly and her colleagues investigated whether the composition of a person’s microbiome influenced whether irinotecan would be reactivated or not. The researchers collected fecal samples from 20 healthy individuals and treated the samples with inactivated irinotecan. Then using metabolomics (the study of the unique chemical fingerprints that cellular processes leave behind), the researchers grouped the fecal samples according to whether they could metabolize, or reactivate, the drug. Four of the 20 individuals were found to be “high metabolizers” and the remaining 16 were “low metabolizers.”

Fecal samples in the two groups were then analyzed for differences in the composition of their microbiomes, with a focus on the presence of beta-glucuronidases. The researchers found that the microbiomes of high metabolizers contained significantly higher levels of three previously unreported types of beta-glucuronidases compared to low metabolizers.

“We hypothesize that people who are high metabolizers would be at increased risk for side effects if given irinotecan, but that will require examining the microbiomes of cancer patients–something we are now doing,” says Dr. Kelly.

The findings suggest that analyzing the composition of patients’ microbiomes before giving irinotecan might predict whether patients will suffer side effects from the drug. In addition, as suggested by the 2010 mouse study, it might be possible to prevent adverse reactions by using drugs that inhibit specific beta-glucuronidases.

“Another intriguing idea is to give patients prebiotics,” says Dr. Kelly. “Beta-glucuronidases have an appetite for the carbohydrates found in the inactive form of irinotecan. If we feed patients another source of carbohydrates when we administer irinotecan, perhaps we could prevent those enzymes from metabolizing the drug.”

Beta-glucuronidases in the gut might also interact with commonly used drugs including ibuprofen and other nonsteroidal anti-inflammatory drugs, morphine, and tamoxifen. “In these cases, the issue for patients may not be diarrhea,” says Dr. Kelly. “Instead, if gut bacteria reactivate those drugs, then patients might be exposed to higher-than-intended doses. Our study provides a broad framework for understanding such drug-microbiome interactions.”

Trauma and the Gut, Dr PerlMutter

I’m very excited to bring you this research study from my friend Dr. Emeran Mayer. It’s a very intriguing report that demonstrates not only how changes in the gut bacteria correlate with irritable bowel syndrome, but, in addition, how these changes in the gut bacteria correlate with the size of various brain areas…

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