Chronic fatigue syndrome is a puzzle. Your gut microbiome may hold the key.

A growing body of research suggests that the gut microbiome could play an important role in a debilitating chronic disease on the rise. The disease, known as myalgic encephalomyelitis and commonly referred to as chronic fatigue syndrome, is characterized by intense fatigue, gastrointestinal problems, muscle pain, and cognitive problems 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 estimate that up to 2.5 million Americans suffered from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This number has risen dramatically in recent years as long-lasting symptoms after COVID-19 infections often meet the criteria for ME/CFS. According to the US Government Accountability Office, it is estimated that between eight million and 23 million Americans are now suffering from long-term COVID.

Two recent studies funded by the National Institutes of Health point to changes in the microbiome as a possible cause of ME/CFS, and offer new avenues for diagnosing and caring for people with the condition. Certain gut bacteria that produce substances involved in metabolism and the immune system were found to be less abundant in patients with ME/CFS than in controls.

Human digestive systems contain 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, director of research at the Bateman-Horne Center, a leading center for ME/CFS research. Vernon hypothesizes that viral infections like 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 remains,” says Vernon, leading to long-term problems regulating many bodily functions.

As scientists learn more about microbiome changes associated with these conditions, they may find ways to better diagnose patients and even develop treatments. ME/CFS symptoms are like “an accumulating snowball,” says Lawrence Purpura, an infectious disease specialist at Columbia University Medical Center who cares for lung COVID patients and studies their microbiome. “If we intervene sooner, we may be able to prevent that snowball from getting bigger,” he says.

Disturbance in the gut

In the two recent studies published in Cell Host & MicrobeResearch groups at Columbia University and the Jackson Laboratory, a non-profit institute headquartered in Maine, performed detailed analyzes of the microbes in stool samples from patients with ME/CFS and compared them to healthy controls.

The two groups found that similar bacterial species were less present in ME/CFS patients compared to control patients. They focused 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 gut and the circulatory system, regulating genetic changes in cells, and more, said Brent Williams, lead author of the Columbia study. Williams and colleagues extensively analyzed the role of butyrate in the guts of ME/CFS patients, 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 that butyrate-producing bacteria could be used to diagnose ME/CFS. Previous research has identified microbiome problems in ME/CFS patients, but the new findings help clarify which microbes might be related to the disease. “What the new studies did was take it a step further and really identify the different bacterial species,” said Vicky Whittemore, program director at the 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 previous studies, 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 with location, Williams says. Vernon, who helped recruit patients and collect samples for the Jackson Laboratory study, says it was remarkable to obtain similar findings from “such a large and so diverse sample.”

The Jackson Laboratory paper also compared two groups of ME/CFS patients, one diagnosed in the past four years and one who had lived 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 that the gut ecosystem recovers over time.

However, the longer-term patients showed more signs of severe metabolic problems and reported worse symptoms, even though their microbiomes were more similar to those in the control group. This could suggest that short-term changes in the microbiome contribute to long-term immune system dysfunction, says Oh, even as the gut repairs itself.

Promoting a healthy microbiome

More research on butyrate-producing bacteria and other species identified in the studies is needed to explore these potential biomarkers of ME/CFS, the authors say. If the findings are replicated, specific gut bacteria could be used to diagnose the disease, which is currently identified based on symptoms alone.

The findings also point to possible treatments, such as probiotics or microbiome-targeted dietary modifications, although patients with long-term illness may need medications that alleviate damage 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’s trying to find out “whether symptoms develop as a result of the microbiome” and whether microbiome-targeted treatments can help alleviate those symptoms.

“Maybe we can modify the microbiome early in the disease to reduce or slow disease progression,” says Oh. Future clinical trials could test the effects of specific bacterial supplements on microbiome health.

But some patients don’t wait for clinical trials and choose to experiment with the supplements and diet options already available. Whittemore has had patients contact her personally to seek nutritional and probiotic advice, including limiting foods associated with inflammation of the immune system, such as red meat, while adding fermented foods such as yogurt or sauerkraut.

“It would be really good to do a study on people who were previously sick to see if simple treatments like that would indeed return their guts to a more normal state,” says Whittemore. Self-experiments among patients can provide starting points for such studies. In one such project, known as Remission Biome, two ME/CFS patients who were working scientists before becoming ill are testing various bacterial supplements that may help ease their symptoms.

Whittemore adds that people with long-term COVID are diagnosed more quickly than people with ME/CFS, so the condition presents a new opportunity to study how a viral infection can affect the microbiome and cause long-lasting symptoms.

Together with research, improved medical education about both ME/CFS and lung COVID can help identify and treat patients. “There are hundreds of thousands of people who are undiagnosed and untreated, trying to navigate their way out of serious post-viral illness,” said Tamara Romanuk, one of Remission Biome’s patient investigators. “Clinicians who know what they’re doing” can better diagnose these people and help manage their symptoms, she says, even if formal treatments are years away.

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