Dr. Ian Lipkin is a renowned professor of epidemiology, neurology, and pathology and director of the Center for Infection and Immunity at Columbia University. He has long been a leader in understanding how microbes cause diseases and in how to treat people with these diseases. Dr. Lipkin was a key scientific and public health adviser during the SARS-CoV-2 pandemic; and, amazingly, he has discovered and described over 2,000 viruses over the course of his career. A key focus of Dr. Lipkin’s lab is understanding how microbes cause chronic diseases like ME/CFS.
Many people with ME/CFS develop the disease after microbial infections. But these infections can involve a wide range of viruses and bacteria (e.g., Borrelia burgdorferi, enteroviruses, Influenza, Mycobacterium tuberculosis). Thus, Dr. Lipkin’s team hypothesized that the innate immune response—the general immune defense against microbes—is key for developing ME/CFS. (In contrast, the adaptive immune response is tailored to specific infectious agents, like specific types of viruses or bacteria.)
To test this hypothesis, the research team compared innate immune responses, metabolite levels, and protein levels in blood samples from people with ME/CFS (n = 56) and healthy people (n = 52). And to relate these comparisons with the quintessential ME/CFS symptoms of fatigue and post-exertional malaise, the researchers also compared samples collected before participants exercised with those collected after they exercised.
First, the team induced the innate immune response in blood samples by using additives that mimic microbial infections (e.g., dead yeast cells; bacterial toxins; or a chemical that resembles some viral genomes). The additives induced a more vigorous innate immune response in samples from people with ME/CFS than in samples from healthy people. The samples from people with ME/CFS produced more inflammatory cytokines. And levels of complement proteins (a key part of the innate immune response that attacks diverse microbes and upregulates inflammation) were higher in samples collected from people with ME/CFS after exercise.
The researchers also found that people with ME/CFS and healthy people had different levels of many metabolites and proteins related to inflammation (the body’s response to infection or injury). The differing metabolites and proteins showed these problems in ME/CFS:
- Problems with connections among cells (e.g., among cells forming the gut wall) and between cells and the extracellular matrix. These problems could cause the gut to release inflammatory contents or cells to release proinflammatory signals.
- Skewed levels of important gut microbe metabolites, including higher levels of short-chain fatty acids, which promote inflammation and dysregulate mitochondria (also critical for regulating inflammation).
- Problems removing harmful, proinflammatory metabolites (e.g., ammonia toxins, microbial toxins, and reactive oxygen species).
- Higher levels of di- and triglycerides (which promote inflammation).
- Problems processing tryptophan into either serotonin (related to cognitive fatigue and mood) or kynurenine (related to brain inflammation).
For the people with ME/CFS, many of these changes got worse after exercise. And those people with the most skewed metabolite and protein levels also had the most severe fatigue and post-exertional malaise. Some ME/CFS-related changes were more pronounced in women (especially older women); in men; or in certain subgroups of people with the disease. But in general, ME/CFS-related fatigue most correlated with hyperactive complement, dysregulated cellular calcium signaling, and compromised extracellular matrix.
Overall, these results support the idea that for many people with ME/CFS, the innate immune system becomes predisposed to overzealously respond to microbial infections. In this model, an initial infection (by any of a wide range of microbes) sensitizes the innate immune system too much and increases chronic inflammation. Thus, later microbial infections can hyperactivate the innate immune response, worsening metabolic problems that cause fatigue and post-exertional malaise.
These results suggest possible treatments for people with ME/CFS. Drugs that dampening the innate immune response (e.g., interleukin-37, metformin, rapamycin) may reduce fatigue and post-exertional malaise. Dietary supplements that strengthen gut lining or that normalize gut flora may reduce intestinal problems. Selective serotonin reuptake inhibitors or 5-hydroxytryptophan may address tryptophan dysregulation. And targeted supplements may reduce inflammation for specific subgroups of patients, like estrogen for older women with ME/CFS.
This study appears in the journal npj Metabolic Health and Disease.
Why This Study Matters to the Patient Community:
- Lays the Groundwork for Preventive Treatments: Suggests strategies to lower ME/CFS-related fatigue and post-exertional malaise, including drugs that regulate the innate immune response; drugs that normalize calcium signaling; and supplements that strengthen the extracellular matrix or gut wall.
- Advances Diagnostic Tools: Describes metabolic and proteomic biomarkers that correlate with fatigue and post-exertional malaise in all people with ME/CFS, as well as in subgroups of people with ME/CFS.
- Validates key symptoms of ME/CFS: Supports a model that explains two cardinal ME/CFS symptoms—fatigue and post-exertional malaise.
- Centers Patient Experience: Explains why infections by any of a wide range of microbes can trigger ME/CFS.
