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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


Fundamental Knowledge of Microbes Shedding New Light on Human Health

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A laboratory researching the human microbiome
Caption: Human microbiome research requires teamwork. Kimberly Jefferson (second from left), a leader of the Multi-Omic Microbiome Study—Pregnancy Initiative, joins some of the team at Virginia Commonwealth University, Richmond. Credit: Courtesy of Kimberly Jefferson

Basic research in biology generates fundamental knowledge about the nature and behavior of living systems. It is generally impossible to predict exactly where this line of scientific inquiry might lead, but history shows that basic science almost always serves as the foundation for dramatic breakthroughs that advance human health. Indeed, many important medical advances can be traced back to basic research that, at least at the outset, had no clear link at all to human health.

One exciting example of NIH-supported basic research is the Human Microbiome Project (HMP), which began 12 years ago as a quest to use DNA sequencing to identify and characterize the diverse collection of microbes—including trillions of bacteria, fungi, and viruses—that live on and in the healthy human body.

The HMP researchers have subsequently been using those vast troves of fundamental data as a tool to explore how microbial communities interact with human cells to influence health and disease. Today, these explorers are reporting their latest findings in a landmark set of papers in the Nature family of journals. Among other things, these findings shed new light on the microbiome’s role in prediabetes, inflammatory bowel disease, and preterm birth. The studies are part of the Integrative Human Microbiome Project.

If you’d like to keep up on the microbiome and other basic research journeys, here’s a good way to do so. Consider signing up for basic research updates from the NIH Director’s Blog and NIH Research Matters. Here’s how to do it: Go to Email Updates, type in your email address, and enter. That’s it. If you’d like to see other update possibilities, including clinical and translational research, hit the “Finish” button to access Subscriber Preferences.

As for the recent microbiome findings, let’s start with the prediabetes study [1]. An estimated 1 in 3 American adults has prediabetes, detected by the presence of higher than normal fasting blood glucose levels. If uncontrolled and untreated, prediabetes can lead to the more-severe type 2 diabetes (T2D) and its many potentially serious side effects [2].

George Weinstock, The Jackson Laboratory for Genomic Medicine, Farmington, CT, Michael Snyder, Stanford University, Palo Alto, CA, and colleagues report that they have assembled a rich new data set covering the complex biology of prediabetes. That includes a comprehensive analysis of the human microbiome in prediabetes.

The data come from monitoring the health of 106 people with and without prediabetes for nearly four years. The researchers met with participants every three months, drawing blood, assessing the gut microbiome, and performing 51 laboratory tests. All this work generated millions of molecular and microbial measurements that provided a unique biological picture of prediabetes.

The picture showed specific interactions between cells and microbes that were different for people who are sensitive to insulin and those whose cells are resistant to it (as is true of many of those with prediabetes). The data also pointed to extensive changes in the microbiome during respiratory viral infections. Those changes showed clear differences in people with and without prediabetes. Some aspects of the immune response also appeared abnormal in people who were prediabetic.

As demonstrated in a landmark NIH study several years ago [2], people with prediabetes can do a lot to reduce their chances of developing T2D, such as exercising, eating healthy, and losing a modest amount of body weight. But this study offers some new leads to define the biological underpinnings of T2D in its earliest stages. These insights potentially point to high value targets for slowing or perhaps stopping the systemic changes that drive the transition from prediabetes to T2D.

The second study features the work of the Inflammatory Bowel Disease Multi’omics Data team. It’s led by Ramnik Xavier and Curtis Huttenhower, Broad Institute of MIT and Harvard, Cambridge, MA. [4]

Inflammatory bowel disease (IBD) is an umbrella term for chronic inflammations of the body’s digestive tract, such as Crohn’s disease and ulcerative colitis. These disorders are characterized by remissions and relapses, and the most severe flares can be life-threatening. Xavier, Huttenhower, and team followed 132 people with and without IBD for a year, collecting samples of their gut microbiomes every other week along with biopsies and blood samples for a total of nearly 3,000 samples.

By integrating DNA, RNA, protein, and metabolic analyses, they followed precisely which microbial species were present. They could also track which biochemical functions those microbes were capable of performing, and which functions they actually were performing over the course of the study.

These data now offer the most comprehensive view yet of functional imbalances associated with changes in the microbiome during IBD flares. These data also show how those imbalances may be altered when a person with IBD goes into remission. It’s also noteworthy that participants completed questionnaires on their diet. This dataset is the first to capture associations between diet and the gut microbiome in a relatively large group of people over time.

The evidence showed that the gut microbiomes of people with IBD were significantly less stable than the microbiomes of those without IBD. During IBD activity, the researchers observed increases in certain groups of microbes at the expense of others. Those changes in the microbiome also came with other telltale metabolic and biochemical disruptions along with shifts in the functioning of an individual’s immune system. The shifts, however, were not significantly associated with people taking medications or their social status.

By presenting this comprehensive, “multi-omic” view on the microbiome in IBD, the researchers were able to single out a variety of new host and microbial features that now warrant further study. For example, people with IBD had dramatically lower levels of an unclassified Subdoligranulum species of bacteria compared to people without the condition.

The third study features the work of The Vaginal Microbiome Consortium (VMC). The study represents a collaboration between Virginia Commonwealth University, Richmond, and Global Alliance to Prevent Prematurity and Stillbirth (GAPPS). The VMC study is led by Gregory Buck, Jennifer Fettweis, Jerome Strauss,and Kimberly Jefferson of Virginia Commonwealth and colleagues.

In this study, part of the Multi-Omic Microbiome Study: Pregnancy Initiative, the team followed up on previous research that suggested a potential link between the composition of the vaginal microbiome and the risk of preterm birth [5]. The team collected various samples from more than 1,500 pregnant women at multiple time points in their pregnancies. The researchers sequenced the complete microbiomes from the vaginal samples of 45 study participants, who gave birth prematurely and 90 case-matched controls who gave birth to full-term babies. Both cases and controls were primarily of African ancestry.

Those data reveal unique microbial signatures early in pregnancy in women who went on to experience a preterm birth. Specifically, women who delivered their babies earlier showed lower levels of Lactobacillus crispatus, a bacterium long associated with health in the female reproductive tract. Those women also had higher levels of several other microbes. The preterm birth-associated signatures also were associated with other inflammatory molecules.

The findings suggest a link between the vaginal microbiome and preterm birth, and raise the possibility that a microbiome test, conducted early in pregnancy, might help to predict a woman’s risk for preterm birth. Even more exciting, this might suggest a possible way to modify the vaginal microbiome to reduce the risk of prematurity in susceptible individuals.

Overall, these landmark HMP studies add to evidence that our microbial inhabitants have important implications for many aspects of our health. We are truly a “superorganism.” In terms of the implications for biomedicine, this is still just the beginning of what is sure to be a very exciting journey.

References:

[1] Longitudinal multi-omics of host-microbe dynamics in prediabetes. Zhou W, Sailani MR, Contrepois K, Sodergren E, Weinstock GM, Snyder M, et. al. Nature. 2019 May 29.

[2] National Diabetes Statistics Report, 2017, Center for Disease Control and Prevention (Atlanta, GA)

[3] Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Diabetes Prevention Program Research Group.Lancet Diabetes Endocrinol.2015 Nov;3(11):866-875.

[4] Multi-omics of the gut microbial ecosystem in inflammatory bowel disease. Lloyd-Price J, Arze C. Ananthakrishnan AN, Vlamakis H, Xavier RJ, Huttenhower C, et. al. Nature. 2019 May 29.

[5] The vaginal microbiome and preterm birth. Fettweis JM, Serrano MG, Brooks, JP, Jefferson KK, Strauss JF, Buck GA, et al. Nature Med. 2019 May 29.

Links:

Insulin Resistance & Prediabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Crohn’s Disease (NIDDK/NIH)

Ulcerative colitis (NIDDK/NIH)

Preterm Labor and Birth: Condition Information (Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH)

Global Alliance to Prevent Prematurity and Stillbirth (Seattle, WA)

NIH Integrative Human Microbiome Project

NIH Human Microbiome Project

NIH Support:

Prediabetes Study: Common Fund; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Human Genome Research; National Center for Advancing Translational Sciences

Inflammatory Bowel Disease Study: Common Fund; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences; National Institute of Human Genome Research; National Institute of Dental and Craniofacial Research

Preterm Birth Study: Common Fund; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development


Some ‘Hospital-Acquired’ Infections Traced to Patient’s Own Microbiome

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Bacteria in both blood and gut

Caption: New computational tool determines whether a gut microbe is the source of a hospital-acquired bloodstream infection
Credit: Fiona Tamburini, Stanford University, Palo Alto, CA

While being cared for in the hospital, a disturbingly large number of people develop potentially life-threatening bloodstream infections. It’s been thought that most of the blame lies with microbes lurking on medical equipment, health-care professionals, or other patients and visitors. And certainly that is often true. But now an NIH-funded team has discovered that a significant fraction of these “hospital-acquired” infections may actually stem from a quite different source: the patient’s own body.

In a study of 30 bone-marrow transplant patients suffering from bloodstream infections, researchers used a newly developed computational tool called StrainSifter to match microbial DNA from close to one-third of the infections to bugs already living in the patients’ large intestines [1]. In contrast, the researchers found little DNA evidence to support the notion that such microbes were being passed around among patients.


Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic?

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Ice cream sundae

Thinkstock/piyaphat50

Most of us know how hard it is to resist the creamy sweetness of ice cream. But it might surprise you to learn that, over the past 15 years or so, some makers of ice cream and many other processed foods—from pasta to ground beef products—have changed their recipes to swap out some of the table sugar (sucrose) with a sweetening/texturizing ingredient called trehalose that depresses the freezing point of food. Both sucrose and trehalose are “disaccharides.” Though they have different chemical linkages, both get broken down into glucose in the body. Now, comes word that this switch may be an important piece of a major medical puzzle: why Clostridium difficile (C. diff) has emerged as a leading cause of hospital-acquired infections.

A new study in the journal Nature indicates that trehalose-laden food may have helped fuel the recent epidemic spread of C. diff., which is a microbe that can cause life-threatening gastrointestinal distress, especially in older patients getting antibiotics and antacid medicines [1, 2]. In laboratory experiments, an NIH-funded team found that the two strains of C. diff. most likely to make people sick possess an unusual ability to thrive on trehalose, even at very low levels. And that’s not all: a diet containing trehalose significantly increased the severity of symptoms in a mouse model of C. diff. infection.


Expanding Our View of the Human Microbiome

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Girl and her micrbiomeMany people still regard bacteria and other microbes just as disease-causing germs. But it’s a lot more complicated than that. In fact, it’s become increasingly clear that the healthy human body is teeming with microorganisms, many of which play essential roles in our metabolism, our immune response, and even our mental health. We are not just an organism, we are a “superorganism” made up of human cells and microbial cells—and the microbes outnumber us! Fueling this new understanding is NIH’s Human Microbiome Project (HMP), a quest begun a decade ago to explore the microbial makeup of healthy Americans.

About 5 years ago, HMP researchers released their first round of data that provided a look at the microbes present in the mouth, gut, nose, and several other parts of the body [1]. Now, their second wave of data, just published in the journal Nature, has tripled this treasure trove of information, promising to further expand our understanding of the human microbiome and its role in health and disease [2]. For example, the new DNA data offer clues as to the functional roles those microbes play and how those can vary over time in different parts of the human body and from one person to the next.


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