A growing body of research suggests that the gut microbiome could play a major role in a debilitating chronic disease that has been on the rise. The illness, known as myalgic encephalomyelitis and commonly called chronic fatigue syndrome, is characterized by intense fatigue, gastrointestinal issues, muscle pain, and cognitive challenges such as headaches and difficulty concentrating, among other symptoms. It often follows a viral infection, but scientists don’t have a clear understanding of how the disease works, and there are no known treatments.
Before the pandemic, researchers estimated that up to 2.5 million Americans suffered from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This number has dramatically increased in recent years because long-term symptoms following COVID-19 infections often meet the criteria for ME/CFS. Between eight million and 23 million Americans are now estimated to be suffering from long COVID, according to the U.S. Government Accountability Office.
Two recent studies funded by the National Institutes of Health point to changes in the microbiome as a possible cause of ME/CFS, and they provide new avenues toward diagnosing and caring for people with the ailment. Certain bacteria in the gut that produce substances involved in metabolism and the immune system were found to be less abundant in patients with ME/CFS than in control groups.
Human digestive systems are home to trillions of microorganisms that help digest food and send signals to other parts of the body. The gut “should be a very rich, diverse, tropical rainforest,” says Suzanne Vernon, research director of the Bateman-Horne Center, a leading center of ME/CFS research. Vernon hypothesizes that viral infections such as COVID-19 can lead to a “disruption” in this gut ecosystem, often felt in the form of nausea, diarrhea, and other gastrointestinal symptoms.
In most people, the microbiome quickly returns to normal. But for some, “the gut disruption stays,” Vernon says, leading to long-term problems in regulating many body functions.
As scientists learn more about microbiome changes associated with these conditions, they could find ways to better diagnose patients and even develop treatments. ME/CFS symptoms are similar to “an accumulating snowball,” says Lawrence Purpura, an infectious disease specialist at Columbia University Medical Center who cares for long COVID patients and studies their microbiomes. “If we intervene earlier on, we could potentially prevent that snowball from enlarging to begin with,” he says.
Disruption in the gut
In the two recent studies published in Cell Host & Microbe, research groups at Columbia University and the Jackson Laboratory, a nonprofit institute headquartered in Maine, performed detailed analyses of the microbes in stool samples from patients with ME/CFS and compared them to healthy controls.
The two groups found similar bacteria species were less present in ME/CFS patients compared to control patients. They homed in on bacteria that produce butyrate, a fatty acid involved in regulating metabolism and the immune system. Butyrate plays several roles in directing the body’s response to infections, while also protecting the barrier between the intestine and the circulatory system, regulating genetic changes in cells, and more, says Brent Williams, lead author on the Columbia study. Williams and his colleagues extensively analyzed the role of butyrate in ME/CFS patients’ guts, even identifying a correlation between low levels of bacteria that produce this acid and more severe symptoms.
Parallel findings from the Jackson Laboratory team suggest the bacteria that produce butyrate could be used to diagnose ME/CFS. Previous research has identified microbiome issues in ME/CFS patients, but the new findings help clarify which microbes could be related to the illness. “What the new studies did was to take it a step further, and to really identify the different bacterial species,” says Vicky Whittemore, program director at NIH’s National Institute of Neurological Disorders and Stroke, who was not involved in the new research.
The new studies also involved larger patient cohorts than past research, with about 100 patients in the Columbia study and 150 in the Jackson Laboratory study. The Columbia study recruited patients from five ME/CFS centers across the country—an important step because microbiomes change due to location, Williams says. Vernon, who assisted with patient recruitment and sample collection for the Jackson Laboratory study, says obtaining similar findings from “that large and that diverse of a sample” was notable.
The Jackson Laboratory paper additionally compared two groups of ME/CFS patients, one diagnosed in the last four years and one that had been living with the condition for more than 10 years. The recently diagnosed group had more damaged microbiomes and lower species diversity, says lead researcher Julia Oh, suggesting the gut ecosystem recovers over time.
However, the longer-term patients showed more signs of severe metabolic issues and reported worse symptoms, even though their microbiomes were more similar to those in the control group. This could suggest that short-term changes to the microbiome contribute to long-term dysfunction in the immune system, Oh says, even as the gut itself recovers.
Fostering a healthy microbiome
More research on butyrate-producing bacteria and other species identified in the studies is necessary to investigate these potential biomarkers of ME/CFS, the authors say. If the findings are replicated, specific gut bacteria could be used to diagnose the illness, which is currently identified based on symptoms alone.
The findings additionally point toward possible treatments, such as probiotics or microbiome-focused diet adjustments—though patients who have been sick for long periods may require drugs that alleviate the damage done to their metabolism or immune system.
At Columbia, Williams plans to implant microbiome samples from ME/CFS patients into mice as the next phase of his research. He aims to find out “whether symptoms develop as a result of the microbiome” and whether microbiome-focused treatments could help alleviate those symptoms.
“We may be able to modify the microbiome in early disease to mitigate or slow disease progression,” Oh says. Future clinical trials could test the impacts of specific bacterial supplements on microbiome health.
But some patients aren’t waiting for clinical trials, opting to experiment with the supplements and diet options that are already available. Whittemore has had patients reach out to her personally asking for diet and probiotic advice, which can include limiting foods that are associated with immune system inflammation such as red meat while adding fermented foods like yogurt or sauerkraut.
“It would be really good to run a study in individuals earlier in disease to see if, in fact, those kinds of simple treatments would bring their guts back into a more normal state,” Whittemore says. Self-experiments among patients could provide leads for such studies. In one such project, known as Remission Biome, two ME/CFS patients who were working scientists before they became sick are testing different bacterial supplements that may help alleviate their symptoms.
Whittemore adds that people with long COVID tend to be diagnosed more quickly than those with ME/CFS, so the condition offers a new opportunity to study how a viral infection may affect the microbiome and trigger long-term symptoms.
Along with research, improved medical education about both ME/CFS and long COVID may help identify and treat patients. “There are hundreds of thousands of people out there who are undiagnosed and are untreated and are trying to biohack their way out of serious post-viral illness,” says Tamara Romanuk, one of the Remission Biome patient-researchers. “Clinicians who know what they’re doing” could better diagnose these people and help manage their symptoms, she says, even as formal treatments may be years off.