Cluster of interconnected symptoms

ME affects many body systems and produces a wide range of symptoms, including muscle pain and weakness, cognitive difficulties (often described as “brain fog”), autonomic disorders such as digestive problems, postural hypotension and sleep disturbances.

But the defining symptom of ME is post-exertional malaise, a state in which minor exertion—physical, mental or emotional—precipitates a significant worsening of symptoms that can last for hours, days or even weeks.

One of the greatest challenges in studying ME is the heterogeneity of triggers, symptom clusters and disease progression. 

“ME is not a single disease but rather a spectrum comprising several subgroups,” said Moreau.

“Accurate diagnosis is difficult because ME and fibromyalgia present with very similar symptoms that can fluctuate over time. Our molecular analyses have shown that up to 40 per cent of individuals diagnosed with ME are in fact suffering from fibromyalgia—and it’s possible to have both conditions at the same time.”

Long COVID and epigenetics

In about 75 per cent of cases, ME develops after a viral infection. Common triggers include the Epstein-Barr virus (mononucleosis), the influenza virus (the flu), West Nile virus, chikungunya, Zika and, more recently, SARS-CoV-2 (COVID-19).

“Long COVID is a good example,” said Moreau. “It isn’t an entirely new disease but more an intersection of various post-infectious pathways. Among those with the most persistent and severe symptoms, a significant proportion eventually meet the criteria for ME.

“In other words, with COVID-19, medicine is rediscovering a condition already known to follow other infections, such as mononucleosis or the flu. It’s surprising that so many people think long Covid is a new disease. Actually, it’s just another post-infectious syndrome similar to conditions such as Lyme disease.”

Despite considerable effort, genetic research has yet to identify a clear cause of ME. Genetic variations explain only a small fraction of “sporadic” cases, although some families are clearly more genetically predisposed than others. 

In a recent study, Moreau and his team demonstrated that epigenetics, which examines how environmental factors change gene expression without altering the DNA sequence itself, is a more promising avenue for understanding the cause of ME. Factors such as infections and toxins including heavy metals and moulds can effectively “reprogram” specific biological mechanisms.

Promising new biomarkers

Moreau and his team have also identified several markers of ME that could potentially be used to improve diagnosis and serve as therapeutic targets.

These include specific patterns (or “molecular signatures”) of circulating microRNAs that can accurately distinguish ME from similar diseases such as fibromyalgia.

Another biomarker is the protein SMPDL3B. “The concentration of circulating SMPDL3B is directly linked to disease severity, with higher levels of the protein correlating to more intense symptoms,” explained Moreau.

After identifying, in another recent study, the enzyme responsible for these elevated SMPDL3B concentrations, Moreau and his team are now exploring ways to inhibit it. Some diabetes medications could be repurposed for the task, combined with supplements such as myo-inositol.

Clinical trials are now being planned to test this approach, with the hope of developing targeted treatments.

Now a priority

In Moreau’s view, calling the disease chronic fatigue syndrome has contributed to trivializing the condition and undermining its legitimacy as a serious illness. Research now clearly shows that ME is associated with measurable biological abnormalities, in particular neuroinflammation in many patients.

“This validation is crucial because patients have long struggled with a lack of understanding, even within the medical community,” Moreau said.

While the stigma associated with ME is diminishing, the next challenge is conducting targeted studies that combine advanced biological analyses with dynamic tests capable of replicating symptoms, particularly post-exertional malaise.

This approach could reveal the mechanisms underlying ME, especially in the most severely affected patients, who are often excluded from standard research protocols.

“ME remains difficult to define, but recent advances are gradually changing the landscape,” Moreau said. “With the rise of long COVID, this long-marginalized condition is now a scientific priority—a shift that could finally transform patient care.”