The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

Abstract

Myalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS) is a neglected, debilitating multi-systemic disease without diagnostic marker or therapy. Despite evidence for neurological, immunological, infectious, muscular and endocrine pathophysiological abnormalities, the etiology and a clear pathophysiology remains unclear. The gut microbiome gained much attention in the last decade with manifold implications in health and disease. Here we review the current state of knowledge on the interplay between ME/CFS and the microbiome, to identify potential diagnostic or interventional approaches, and propose areas where further research is needed. We iteratively selected and elaborated on key theories about a correlation between microbiome state and ME/CFS pathology, developing further hypotheses. Based on the literature we hypothesize that antibiotic use throughout life favours an intestinal microbiota composition which might be a risk factor for ME/CFS. Main proposed pathomechanisms include gut dysbiosis, altered gut-brain axis activity, increased gut permeability with concomitant bacterial translocation and reduced levels of short-chain-fatty acids, D-lactic acidosis, an abnormal tryptophan metabolism and low activity of the kynurenine pathway. We review options for microbiome manipulation in ME/CFS patients including probiotic and dietary interventions as well as fecal microbiota transplantations. Beyond increasing gut permeability and bacterial translocation, specific dysbiosis may modify fermentation products, affecting peripheral mitochondria. Considering the gut-brain axis we strongly suspect that the microbiome may contribute to neurocognitive impairments of ME/CFS patients. Further larger studies are needed, above all to clarify whether D-lactic acidosis and early-life antibiotic use may be part of ME/CFS etiology and what role changes in the tryptophan metabolism might play. An association between the gut microbiome and the disease ME/CFS is plausible. As causality remains unclear, we recommend longitudinal studies. Activity levels, bedridden hours and disease progression should be compared to antibiotic exposure, drug intakes and alterations in the composition of the microbiota. The therapeutic potential of fecal microbiota transfer and of targeted dietary interventions should be systematically evaluated.

Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…We propose that the sequence during critical illness—from splanchnic hypoperfusion to hypoxia, redox imbalance, altered gut microbiome, intestinal injury, gut-related endotoxemia, pro-inflammatory cytokines and systemic inflammatory—may also contribute to explain the emergence of ME/CFS following a physiological insult. Our proposal is in alignment with others' findings that intestinal injury and resulting inflammation are central to ME/CFS ( 73 – 81 ) and consistent with findings linking the gut microbiome to inflammation ( 82 – 85 ) and to fatigue symptoms in ME/CFS ( 86 ). If verified, the existence of a vicious inflammatory cycle centered around intestinal injury could contribute to explain the perpetuation of ME/CFS.…”

Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

“…Lachnospiracea e and other Clostridiales produce short-chain fatty acids that mediate a range of beneficial effects in the gut such as enhancing tolerance and the epithelial barrier function, anti-inflammatory effects, as well as activating regulatory T cells ( 64 , 67 ). Hence, excessive, mistargeted immune reactions against these favorable commensals are conceptually in line with CD and irritable bowel syndrome, a common comorbidity reported by patients with severe ME/CFS ( 10 ). Notably, CD patients (compared to healthy individuals) have an increased risk to also develop ME/CFS ( 68 ).…”

“…Recently, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has also been reported to cause persisting ME/CFS–like symptoms in a subset of recovered patients [termed as long coronavirus disease 2019 (long COVID), post–COVID-19 syndrome, or chronic COVID syndrome] ( 34 – 38 ), with implications for studying “classical” ME/CFS ( 39 ). Increased translocation of intestinal bacterial species into systemic translocation ( 40 ) and elevated systemic antibody responses against bacterial lipopolysaccharide (LPS) in ME/CFS ( 41 ) could also point toward immune responses against gut microbiota as a potential trigger for disease development ( 10 ). Beyond microbes, a potential involvement of autoimmunity has also been discussed, as ME/CFS is associated with hypothyroidism and Sjögren’s syndrome ( 42 , 43 ).…”

When a 17-Year-Old Girl Is Diagnosed with Myalgic Encephalomyelitis: A Case Study from the Swedish Health Care System—A Parent Perspective

“…These theories hypothesize that the mitochondria have entered a form of "protective" mode that prevents them from producing energy, which in turn may suggest an opportunity for treatment in somehow "restarting" the mitochondria. Different studies in England, Switzerland and Germany are focusing on the function of the microbiome [25]. Patients with ME seem to have lowered diversity in their bacterial flora and at the same time elevated levels of bacteriophagic viruses that attack bacteria [25].…”

“…Different studies in England, Switzerland and Germany are focusing on the function of the microbiome [25]. Patients with ME seem to have lowered diversity in their bacterial flora and at the same time elevated levels of bacteriophagic viruses that attack bacteria [25]. This strand of research suggests that if there is a disturbed balance between certain types of micro-organisms, the immune system may start to fight beneficial body bacteria and cells.…”