The NIH Director’s Blog this week is featuring two recent studies on the microbiome in ME/CFS, including our study plus a study by W. Ian Lipkin’s group from Columbia University, which were both just published in the latest issue of the journal Cell Host & Microbe on February 8, 2023. The studies were funded in part by NIH’s ME/CFS Collaborative Research Network, a consortium supported by multiple institutes and centers at NIH, consisting of three collaborative research centers and a data management coordinating center.
In the blog post, NIH Director Lawrence A. Tabak, D.D.S., Ph.D. explains the importance of this new research, as well as delving into the findings of the two studies in detail. He explains that it is important to see a more collaborative approach to ME/CFS research, as the hope in supporting the Research Network was to cut through the complexity of this disease and help the millions of people suffering from ME/CFS.
We are very excited to announce that JAX investigators in the labs of Julia Oh, PhD and Derya Unutmaz, MD have a new article that was just published today in Cell Host & Microbe. The study delves into host-microbiome interactions in ME/CFS and the potential metabolic consequences that result from these interactions.
ME/CFS is a complex and heterogeneous chronic condition that is highly debilitating and often characterized by persistent, unexplained fatigue not alleviated by rest, muscle and joint pain, sleep problems, and post-exertional malaise (PEM). There is no clear diagnostic test for the disease, so obtaining a diagnosis and medical support can be extremely difficult for patients to achieve, and patients are often dismissed entirely or told that their condition is caused by mental health issues. The JAX investigators hoped to remove some of these obstacles patients experience by answering the question of what’s different in ME/CFS patients that causes such debilitating disease.
Previous studies have suggested there is an altered gut microbiota in ME/CFS, which could be the cause of gastrointestinal problems often associated with the disease. These studies were small however, so the JAX team extended the interrogation of the gut microbiome by performing extensive high-throughput analyses of the study participants. Participants included ME/CFS patients divided into two groups – those with short-term disease who were diagnosed less than four years ago and those with long-term disease who were diagnosed more than ten years ago, as well as sex- and age-matched healthy controls.
Interestingly, the team found that microbial communities in ME/CFS patients were more uneven but less diverse than in healthy controls, with dysbiosis similar to what is seen with aging and chronic inflammatory disorders. When the ME/CFS group was stratified to compare the gut microbiome between the short-term and long-term groups, the researchers found that the short-term group had a more significant disruption in their gut microbiome, while the long-term group looked more similar to healthy controls.
Mark Wanner has also released a Research Highlight article on the Jackson Laboratory website, where he explains the study in detail and speculates on what the findings could mean for the metabolism and for understanding the mechanisms underlying ME/CFS, as well as potential biomarker discovery for the disease.
Top: Community Advisory Committee (CAC) member Jessie Brown-Clark; JAX PI Derya Unutmaz, PhD; Bottom: JAX Co-PI Julia Oh, PhD; BHC Research Director Suzanne Vernon, PhD
The NIH ME/CFS Research Network has launched a webinar series featuring each of the Collaborative Research Centers (CRCs) at Cornell University, Columbia University, and The Jackson Laboratory (JAX), plus the Data Management Coordinating Center (DMCC) at RTI. In the latest webinar in the series, Derya Unutmaz, PhD, the Principal Investigator and Director for the JAX Center for ME/CFS, and the team at JAX discuss their latest findings.
Ruoyun Xiong (top left), Courtney Gunter (bottom left), Julia Oh Lab (middle), Derya Unutmaz (top right), Lucinda Bateman and Suzanne D Vernon (bottom right).
We are very excited to announce that in collaboration with the lab of Julia Oh at The Jackson Laboratory, which studies the microbiome in ME/CFS for the JAX CRC, we have just posted the full preprint of our new ME/CFS microbiome paper on BioRxiv, which will continue to be updated following reviewer comment and peer-review. In this detailed study led by Ruoyun Xiong, we did deep multi-omics, where we performed shotgun metagenomics of the gut microbiota and plasma metabolomics in 79 healthy controls and two cohorts of ME/CFS patients: 75 with short-term disease (<4 years), and 79 patients with long-term disease (>10 years). We also correlated these data to clinical information collected from subject questionnaires, and built multiple state-of-the-art classifiers that were able to differentiate short or long-term ME/CFS from each other, or ME/CFS from healthy controls.
The gut microbiome has been recently studied as a potential contributor to ME/CFS, and previous groups have shown that ME/CFS patients have frequent gastrointestinal (GI) disturbances, and changes in their gut microbiota compared to healthy controls. A few of the major differences that we found are that ME/CFS subjects had reduced gut microbiome diversity (fewer members) and richness. High diversity is associated with ecosystem health, and less diverse ecosystems are associated with decreased resilience and a susceptibility to colonization by pathogenic microbes. We also noticed a change in the ratio of the overall amounts of Firmicutes to Bacteroidetes phyla. Changes in this ratio have previously been noted in some chronic disorders and inflammatory diseases, such as inflammatory bowel disease (IBD). When looking at short-term vs. long-term ME/CFS, we found that subjects with a disease duration of <4 years had more microbial dysbiosis, but ME/CFS subjects with a disease duration of <10 years had more severe phenotypic and metabolic abnormalities.
One of the major problems that ME/CFS patients face is that there is no standard diagnostic test for ME/CFS. Our use of multiple ‘omics data greatly increased classification accuracy between ME/CFS subjects and healthy controls, and identified microbial and metabolic features that could be interesting to investigate further to find therapeutic strategies.
This Saturday, October 23rd, the Massachusetts ME/CFS and FM Association (MassME) will be holding their 2021 annual meeting from 12:30 – 4:00 pm ET. In addition to their annual report on MassME activities, there will be an update from the NIH ME/CFS Collaborative Research Centers (CRCs). Research updates will be given by the study lead of each of the CRCs, including Dr. Derya Unutmaz of JAX, Dr. W. Ian Lipkin of Columbia University, and Dr. Maureen Hanson of Cornell University. There will also be presentations by Dr. Avindra Nath of NIH and Dr. Lucinda Bateman of Bateman Horne Center. Following the updates, there will be a panel discussion where meeting participants can ask questions of the researchers.
Each of the CRC PIs will be discussing the principal goals of their research, what they have learned about ME/CFS that they didn’t know when they started their research, in what ways they are closer to understanding the underlying pathophysiology of ME/CFS and identifying biomarkers, and what remains to be done.
We previously posted that the JAX ME/CFS CRC project was temporarily put on hold during the beginning of 2020 due to COVID. In August of 2020, we started receiving samples again from subjects in our ME/CFS and healthy control cohorts, and our clinical partners at the Bateman Horne Center have now finished collecting samples from time points 1 and 2, and are working on the last set, the time point 3 samples. To date, we have over 450 blood and stool samples that have been collected across the 3 time points, and will likely have close to 500 samples once we’re done collecting time point 3. In early March 2021, we began our flow cytometry experiments on all of the blood samples we have received to look for differences in the immune cells between people with ME/CFS and healthy controls. We run all time points from the same subject in one experiment so that they can be easily compared to each other. We hope to run all the blood samples through flow cytometry in the next year or so, and analyze all of the data so that we can see the functional differences between healthy controls and people with ME/CFS.
Another exciting development at our Center is that we have very recently received NIH and Institutional Review Board (IRB) approval to begin an additional collaboration with the Bateman Horne Center to collect samples from a new cohort of patients who previously had COVID-19, and have since been experiencing ME/CFS-like symptoms, or “long-COVID.” Long-COVID, or post-acute COVID syndrome (PACS), is very similar to ME/CFS, with sufferers experiencing many of the same chronic and debilitating symptoms. The goal of this new collaboration is to recruit about 40 subjects with PACS, and collect blood samples from them every 3 months over the course of the next year. We will then be able to compare the immune profiles of people with PACS to our subjects with ME/CFS to see how similar these two diseases are. BHC has just started recruiting subjects, and last week we received blood samples from our first 2 subjects, and expect to receive a few more this week. For this project, we are also collaborating with the ME/CFS CRC at Columbia University, and W. Ian Lipkin’s group will be probing the metabolome and looking at proteomic and transcriptomic data of these very same subjects. We are very excited about this collaboration, and hope that it can bring us new understanding about PACS and its relationship to ME/CFS.
Each year, there is an ME/CFS Advocacy Week to bring awareness to this devastating disease, and many of the big advocacy groups host events that patients, caregivers, clinicians, and researchers can attend. The Solve Me/CFS Initiative just held their ME/CFS & Long COVID Virtual Advocacy Week 2021 from April 18-24th, where attendees were able to participate virtually from home. In 2021, they expanded their annual advocacy events in order to bring together advocates from many complex chronic illness communities, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID, postural orthostatic tachycardia syndrome (POTS), other forms of dysautonomia, Ehlers-Danlos syndrome (EDS), hypermobility spectrum disorder (HSD) and mast cell activation syndrome (MCAS).
They are also still encouraging people to use their Action Kit, which provides everything needed to post to social media, send customized tweets, and engage with your members of Congress about ME/CFS.
A new article by Alex Putterman about the COVID-19 variants was just released in the Hartford Courant yesterday, February 6, 2021. The variants, which include B117, B1351, and P1, or more commonly known as the UK, South Africa, and Brazil variants, are beginning to circulate in the United States. In the article, experts in the field, which include deputy director Mark Adams and ME/CFS CRC lead Derya Unutmaz, both of The Jackson Laboratory, discuss what we currently know about these variants, and how they could affect the vaccine rollout and reopening in Connecticut.
So far, Connecticut has only seen 17 cases of the UK variant, or less than 1% of total positive tests in the state, and no cases of the South Africa or Brazil variants. However, the UK strain is believed to be at least 50% more transmissible than other variants, which could complicate how quickly herd immunity can be reached. Derya Unutmaz says that, “before, let’s say we just needed to vaccinate 70% of the population and we would have been fine, now I think we need to vaccinate 85-90% of the population.”
Unutmaz also says that, importantly, the vaccines are still very effective against the new variants, and prevent severe disease. For now, it seems the best course forward is to ramp up vaccine distribution while maintaining social distancing to stop the spread of the virus.
A new post on The Schor Line, an NIH National Institute of Neurological Disorders and Stroke (NINDS) blog, was just published about the long-term effects of COVID-19. In the blog post, Nina Schor, M.D., Ph.D. discusses how COVID-19 patients who are critically ill are likely to take months or even years to fully recover, and how even some people who experience milder symptoms are experiencing a longer-term recovery process. Called post-acute COVID syndrome (PACS), she likens the symptoms experienced by people with PACS to those of people with ME/CFS, drawing a parallel between the two. This is very important, as many in the ME/CFS community have been concerned that post-COVID syndrome will overshadow ME/CFS when the overlap between the two is so clear.
NINDS has recently appropriated $1.15 billion in support of understanding the recovery process after COVID-19 and in developing treatments for people with PACS. Schor says that, “through these studies, we hope to identify new targets for therapies and preventive measures and to soon welcome a future in which no one must live with ME/CFS or PACS.”
Happy New Year from everyone here at the JAX ME/CFS CRC! The COVID-19 pandemic has made 2020 a year unlike any other in recent history. This year has tested us all beyond measure, but has also demonstrated the interconnectedness of our world. We look forward to the coming year for generating novel findings about ME/CFS, as well as how COVID-19 is connected to this devastating disease.
In the third year of research at the ME/CFS Center at JAX, our study was halted temporarily due to COVID-19, and we took a several month break from receiving samples from individuals with ME/CFS and healthy controls from our clinical partners at the Bateman Horne Center. We started receiving samples again in July 2020, and to date we have collected both blood and stool samples for all of time point 1, and the majority of time point 2. We have also begun collecting time point 3 samples from subjects recruited early in the study. We have processed all of these biological samples for immune profiling, microbiome, and metabolism data analysis for biomarker discovery in our labs. We have recently made some exciting changes to our immune profiling panels to add additional analyses, and have begun our immune profiling experiments on our samples. Our collaborations with the Cornell and Columbia ME/CFS Centers are also running at full speed, and we are hoping to begin an additional collaboration soon with the Bateman Horne Center to collect samples from patients who previously had COVID-19, and have since been experiencing ME/CFS-like symptoms, or “long-COVID.”
As we ramp our studies back up, we are even more hopeful now that our progress will continue to accelerate into 2021 and bring many new ideas and inspiration. We wish that all of the ME/CFS community and their loved ones be blessed with laughter, peace, and love. May the magic and the wonder of the holiday season stay with you throughout the coming year, and the New Year bring you new achievements, joy, and hope!
Have a wonderful New Year, and see you in 2021! – the JAX ME/CFS team, Derya Unutmaz, and Courtney Gunter
Advances in ME/CFS 