microbes
More Clues into ME/CFS Discovered in Gut Microbiome
Posted on by Lawrence Tabak, D.D.S., Ph.D.
As many as 2.5 million Americans live with myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS for short. It’s a serious disease that can often arise after an infection, leaving people profoundly ill for decades with pain, cognitive difficulties, severe fatigue, and other debilitating symptoms.
Because ME/CFS has many possible causes, it doesn’t affect everybody in the same way. That’s made studying the disease especially challenging. But NIH is now supporting specialized research centers on ME/CFS in the hope that greater collaboration among scientists will cut through the biological complexity and reveal answers for people with ME/CFS and their families.
So, I’m pleased to share some progress on this research front from two NIH-funded ME/CFS Collaborative Research Centers. The findings, published in two papers from the latest issue of the journal Cell Host & Microbe, add further evidence connecting ME/CFS to distinctive disruptions in the trillions of microbes that naturally live in our gastrointestinal tracts, called the gut microbiome [1,2].
Right now, the evidence establishes an association, not direct causation, meaning more work is needed to nail down this lead. But it’s a solid lead, suggesting that imbalances in certain bacterial species inhabiting the gut could be used as measurable biomarkers to aid in the accurate and timely diagnosis of ME/CFS. It also points to a possible therapeutic target to explore.
The first paper comes from Julia Oh and her colleagues at The Jackson Laboratory, Farmington, CT, and the second publication was led by Brent L. Williams and colleagues at Columbia University, New York. While the causes of ME/CFS remain unknown, the teams recognized the disease involves many underlying factors, including changes in metabolism, immunity, and the nervous system.
Earlier studies also had pointed to a role for the gut microbiome in ME/CFS, although those studies were limited in their size and ability to tease out precise microbial differences. Given the intimate connections between the microbiome and immune system, the teams behind these new studies set out to look even deeper into the microbiome in larger numbers of people with and without ME/CFS.
At the Jackson Laboratory, Oh, Derya Unutmaz, and colleagues joined forces with other ME/CFS experts to study microbiome abnormalities in different phases of ME/CFS. They matched clinical data (the medical history) with fecal and blood samples (the biological history) from 149 people with ME/CFS, including 74 who had been diagnosed within the previous four years and another 75 who had been diagnosed more than a decade ago. They also enlisted 79 people to serve as healthy volunteers.
Their in-depth microbial analyses showed that the more short-term ME/CFS group had less microbial diversity in their guts than the other two groups. This suggested a disruption, or imbalance, in a previously stable gut microbiome early in the disease. Interestingly, those who had been diagnosed longer with ME/CFS had apparently re-established a stable gut microbiome that was comparable to the healthy volunteers.
Oh’s team also examined detailed clinical and lifestyle data from the participants. Combining this information with genetic and metabolic data, they found that they could accurately classify and differentiate ME/CFS from healthy controls. Through this classification approach, they discovered that individuals with long-term ME/CFS had a more balanced microbiome but showed more severe clinical symptoms and progressive metabolic irregularities compared to the other two groups.
In the second study, Williams, Columbia’s W. Ian Lipkin, and their collaborators also analyzed the genetic makeup of gut bacteria in fecal samples from a geographically diverse group of 106 people with ME/CFS and another 91 healthy volunteers. Their extensive genomic analyses revealed key differences in microbiome diversity, abundance, metabolism, and the interactions among various dominant species of gut bacteria.
Of particular note, Williams team found that people with ME/CFS had abnormally low levels of several bacterial species, including Faecalibacterium prausnitzii (F. prausnitzii) and Eubacterium rectale. Both bacteria ferment non-digestible dietary fiber in the GI tract to produce a nutrient called butyrate. Intriguingly, Oh’s team also uncovered changes in several butyrate-producing microbial species, including F. prausnitzii.
Further detailed analyses in the Williams lab confirmed that the observed reduction in these bacteria was associated with reduced butyrate production in people with ME/CFS. That’s of special interest because butyrate serves as a primary energy source for cells that line the gut. Butyrate provides those cells with up to 70 percent of the energy they need, while supporting gut immunity.
Butyrate and other metabolites detected in the blood are important for regulating immune, metabolic, and endocrine functions throughout the body. That includes the amino acid tryptophan. The Oh team also found all ME/CFS participants had a reduction in gut microbes associated with breaking down tryptophan.
While butyrate-producing bacteria were found in smaller numbers, other microbes with links to autoimmune and inflammatory bowel diseases were increased. Williams’ group also reported an abundance of F. prausnitzii was inversely associated with fatigue severity in ME/CFS, further suggesting a possible link between changes in these gut bacteria and disease symptoms.
It is exciting to see this more-collaborative approach to ME/CFS research starting to cut through the biological complexity of this disease. More data and fresh leads will be coming in the months and years ahead. It is my sincere hope that they bring us closer to our ultimate goal: to help the millions of people with ME/CFS recover and reclaim their lives from this terrible disease.
I should also mention later this year on December 12-13, NIH will host a research conference on ME/CFS. The conference will be held in-person at NIH, Bethesda, MD, and virtually. It also will highlight recent research advances in the field. The NIH will post information about the conference in the months ahead. Be sure to check back, if you’d like to attend.
References:
[1] Multi-‘omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Xiong, et al. Cell Host Microbe. 2023 Feb 8;31(2):273-287.e5.
[2] Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS. Guo, et al. Cell Host Microbe. 2023 Feb 8;31(2):288-304.e8.
Links:
About ME/CFS (NIH)
ME/CFS Resources (NIH)
Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Working Group (ME/CSFnet.org)
Advancing ME/CFS Research (NIH)
Brent Williams (Columbia University, New York)
Julia Oh (The Jackson Laboratory, Farmington, CT)
Video: Perspectives on ME/CFS featuring Julia Oh (Vimeo)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; National Center for Advancing Translational Sciences; National Institute of Mental Health; National Institute of General Medical Sciences
Gut-Dwelling Bacterium Consumes Parkinson’s Drug
Posted on by Dr. Francis Collins
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)
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
Posted on by Dr. Francis Collins
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
Posted on by Dr. Francis Collins
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
Posted on by Dr. Francis Collins
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.
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