Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – NIH Director's Blog (original) (raw)
More Clues into ME/CFS Discovered in Gut Microbiome
Posted on February 14th, 2023 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
Posted In: News
Tags: bacteria, butyrate, chronic fatigue synderome, endocrinology, F. prausnitzii, gut microbiome, immunity, inflammatory bowel disease, ME/CFS, metabolism, microbes, microbiome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Understanding Long-Term COVID-19 Symptoms and Enhancing Recovery
Posted on October 4th, 2022 by Walter J. Koroshetz, M.D., National Institute of Neurological Disorders and Stroke
We are in the third year of the COVID-19 pandemic, and across the world, most restrictions have lifted, and society is trying to get back to “normal.” But for many people—potentially millions globally—there is no getting back to normal just yet.
They are still living with the long-term effects of a COVID-19 infection, known as the post-acute sequelae of SARS-CoV-2 infection (PASC), including Long COVID. These people continue to experience debilitating fatigue, shortness of breath, pain, difficulty sleeping, racing heart rate, exercise intolerance, gastrointestinal and other symptoms, as well as cognitive problems that make it difficult to perform at work or school.
This is a public health issue that is in desperate need of answers. Research is essential to address the many puzzling aspects of Long COVID and guide us to effective responses that protect the nation’s long-term health.
For the past two years, NIH’s National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Allergy and Infectious Diseases (NIAID), and my National Institute of Neurological Disorders and Stroke (NINDS) along with several other NIH institutes and the office of the NIH Director, have been leading NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative, a national research program to understand PASC.
The initiative studies core questions such as why COVID-19 infections can have lingering effects, why new symptoms may develop, and what is the impact of SARS-CoV-2, the virus that causes COVID-19, on other diseases and conditions? Answering these fundamental questions will help to determine the underlying biologic basis of Long COVID. The answers will also help to tell us who is at risk for Long COVID and identify therapies to prevent or treat the condition.
The RECOVER initiative’s wide scope of research is also unprecedented. It is needed because Long COVID is so complex, and history indicates that similar post infectious conditions have defied definitive explanation or effective treatment. Indeed, those experiencing Long COVID report varying symptoms, making it highly unlikely that a single therapy will work for everyone, underscoring the need to pursue multiple therapeutic strategies.
To understand Long COVID fully, hundreds of RECOVER investigators are recruiting more than 17,000 adults (including pregnant people) and more than 18,000 children to take part in cohort studies. Hundreds of enrolling sites have been set up across the country. An autopsy research cohort will also provide further insight into how COVID-19 affects the body’s organs and tissues.
In addition, researchers will analyze electronic health records from millions of people to understand how Long COVID and its symptoms change over time. The RECOVER initiative is also utilizing consistent research protocols across all the study sites. The protocols have been carefully developed with input from patients and advocates, and they are designed to allow for consistent data collection, improve data sharing, and help to accelerate the pace of research.
From the very beginning, people suffering from Long COVID have been our partners in RECOVER. Patients and advocates have contributed important perspectives and provided valuable input into the master protocols and research plans.
Now, with RECOVER underway, individuals with Long COVID, their caregivers, and community members continue to serve a critical role in the Initiative. The National Community Engagement Group (NCEG) has been established to make certain that RECOVER meets the needs of all people affected by Long COVID. The RECOVER Patient and Community Engagement Strategy outlines all the approaches that RECOVER is using to engage with and gather input from individuals impacted by Long COVID.
The NIH recently made more than 40 awards to improve understanding of the underlying biology and pathology of Long COVID. There have already been several important findings published by RECOVER scientists.
For example, in a recent study published in the journal Lancet Digital Health, RECOVER investigators used machine learning to comb through electronic health records to look for signals that may predict whether someone has Long COVID [1]. As new findings, tools, and technologies continue to emerge that help advance our knowledge of the condition, the RECOVER Research Review (R3) Seminar Series will provide a forum for researchers and our partners with up-to-date information about Long COVID research.
It is important to note that post-viral conditions are not a new concept. Many, but not all, of the symptoms reported in Long COVID, including fatigue, post-exertional malaise, chronic musculoskeletal pain, sleep disorders, postural orthostatic tachycardia (POTS), and cognitive issues, overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
ME/CFS is a serious disease that can occur following infection and make people profoundly sick for decades. Like Long COVID, ME/CFS is a heterogenous condition that does not affect everybody in the same way, and the knowledge gained through research on Long COVID may also positively impact the understanding, treatment, and prevention of POTS, ME/CFS, and other chronic diseases.
Unlike other post-viral conditions, people who experience Long COVID were all infected by the same virus—albeit different variants—at a similar point in time. This creates a unique opportunity for RECOVER researchers to study post-viral conditions in real-time.
The opportunity enables scientists to study many people simultaneously while they are still infected to monitor their progress and recovery, and to try to understand why some individuals develop ongoing symptoms. A better understanding of the transition from acute to chronic disease may offer an opportunity to intervene, identify who is at risk of the transition, and develop therapies for people who experience symptoms long after the acute infection has resolved.
The RECOVER initiative will soon announce clinical trials, leveraging data from clinicians and patients in which symptom clusters were identified and can be targeted by various interventions. These trials will investigate therapies that are indicated for other non-COVID conditions and novel treatments for Long COVID.
Through extensive collaboration across the multiple NIH institutes and offices that contribute to the RECOVER effort, our hope is critical answers will emerge soon. These answers will help us to recognize the full range of outcomes and needs resulting from PASC and, most important, enable many people to make a full recovery from COVID-19. We are indebted to the over 10,000 subjects who have already enrolled in RECOVER. Their contributions and the hard work of the RECOVER investigators offer hope for the future to the millions still suffering from the pandemic.
Reference:
[1] Identifying who has long COVID in the USA: a machine learning approach using N3C data. Pfaff ER, Girvin AT, Bennett TD, Bhatia A, Brooks IM, Deer RR, Dekermanjian JP, Jolley SE, Kahn MG, Kostka K, McMurry JA, Moffitt R, Walden A, Chute CG, Haendel MA; N3C Consortium. Lancet Digit Health. 2022 Jul;4(7):e532-e541.
Links:
COVID-19 Research (NIH)
Long COVID (NIH)
RECOVER: Researching COVID to Enhance Recovery (NIH)
“NIH builds large nationwide study population of tens of thousands to support research on long-term effects of COVID-19,” NIH News Release, September 15, 2021.
Director’s Messages (National Institute of Neurological Disorders and Stroke/NIH)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 18th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Posted In: Generic
Tags: AI, basic research, chronic disease, clinical research, clinical trials, coronavirus, COVID-19, COVID-19 recovery, COVID-19 treatment, data science, EHR, electronic health records, fatigue, long COVID, Long COVID syndrome, machine learning, ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, National Community Engagement Group, NCEG, novel coronavirus, pain, PASC, post-acute sequelae of COVID-19, post-viral conditions, postural orthostatic tachycardia, POTS, public health, RECOVER Initiative, RECOVER Patient and Community Engagement Strategy, Researching COVID to Enhance Recovery, SARS-CoV-2, sleep disorders
Moving Toward Answers in ME/CFS
Posted on March 21st, 2017 by Dr. Walter Koroshetz and Dr. Francis Collins
Thinkstock/Katarzyna Bialasiewicz
Updated September 27, 2017: The National Institutes of Health (NIH) will award four grants to establish a coordinated scientific research effort on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The total cost of the projects for fiscal year 2017 will be over $7 million, with support from multiple NIH Institutes and Centers that are part of the Trans-NIH ME/CFS Working Group.
The grants will support the creation of a consortium made up of three Collaborative Research Centers (CRC) and a Data Management Coordinating Center (DMCC). The CRCs will each conduct independent research but will also collaborate on several projects, forming a network to help advance knowledge on ME/CFS. The data will be managed by the DMCC and will be shared among researchers within the CRCs and more broadly with the research community.
Imagine going to work or school every day, working out at the gym, spending time with family and friends—basically, living your life in a full and vigorous way. Then one day, you wake up, feeling sick. A bad cold maybe, or perhaps the flu. A few days pass, and you think it should be over—but it’s not, you still feel achy and exhausted. Now imagine that you never get better— plagued by unrelenting fatigue not relieved by sleep. Any exertion just makes you worse. You are forced to leave your job or school and are unable to participate in any of your favorite activities; some days you can’t even get out of bed. The worst part is that your doctors don’t know what is wrong and nothing seems to help.
Unfortunately, this is not fiction, but reality for at least a million Americans—who suffer from a condition that carries the unwieldy name of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a perplexing disease that biomedical research desperately needs to unravel [1]. Very little is currently known about what causes ME/CFS or its biological basis [2]. Among the many possibilities that need to be explored are problems in cellular metabolism and changes in the immune system.
Posted In: Health, Science, Uncategorized
Tags: autoimmunity, biomarkers, cellular metabolism, CFS, chronic disease, chronic fatigue, chronic fatigue synderome, dauer, fatigue, hypometabolism, immune system, ME/CFS, metabolism, music, Myalgic Encephalomyelitis, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Myalgic Encephalopathy, neurology, neurovirology, NIH Clinical Center, telebriefings