Category: Pathophysiology

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.

Source: König RS, Albrich WC, Kahlert CR, Bahr LS, Löber U, Vernazza P, Scheibenbogen C, Forslund SK. The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Front Immunol. 2022 Jan 3;12:628741. doi: 10.3389/fimmu.2021.628741. PMID: 35046929; PMCID: PMC8761622. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761622/ (Full text)

 

Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.

Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).

Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.

One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

Source: Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI. Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. medRxiv [Preprint]. 2022 Jan 11:2021.06.14.21258895. doi: 10.1101/2021.06.14.21258895. PMID: 35043127; PMCID: PMC8764736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764736/ (Full text)

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Introduction:

We here provide an overview of the pathophysiological mechanisms during heat stroke and describe similar mechanisms found in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Both conditions are characterized by disturbed homeostasis in which inflammatory pathways play a central role. Splanchnic vasoconstriction, increased gut permeability, gut-related endotoxemia, systemic inflammatory response, central nervous system dysfunction, blood coagulation disorder, endothelial-cell injury, and mitochondrial dysfunction underlie heat stroke. These mechanisms have also been documented in ME/CFS.

Moreover, initial transcriptomic studies suggest that similar gene expressions are altered in both heat stroke and ME/CFS. Finally, some predisposing factors for heat stroke, such as pre-existing inflammation or infection, overlap with those for ME/CFS. Notwithstanding important differences – and despite heat stroke being an acute condition – the overlaps between heat stroke and ME/CFS suggest common pathways in the physiological responses to very different forms of stressors, which are manifested in different clinical outcomes. The human studies and animal models of heat stroke provide an explanation for the self-perpetuation of homeostatic imbalance centered around intestinal wall injury, which could also inform the understanding of ME/CFS. Moreover, the studies of novel therapeutics for heat stroke might provide new avenues for the treatment of ME/CFS. Future research should be conducted to investigate the similarities between heat stroke and ME/CFS to help identify the potential treatments for ME/CFS.

Source: Dominic Stanculescu, Nuno Sepúlveda, Chin Leong Lim and Jonas Bergquist. Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurol., 13 December 2021 | https://doi.org/10.3389/fneur.2021.789784  https://www.frontiersin.org/articles/10.3389/fneur.2021.789784/full (Full text)

The role of mitochondria in ME/CFS: a perspective

Abstract:

Chronic fatigue syndrome (CFS) also known as Myalgic encephalomyelitis (ME) is a debilitating disease, characterized by the symptom of severe fatigue. ME/CFS is a heterogeneous condition in both clinical presentation and disease duration. A diagnosis of ME/CFS is based on the exclusion of other diseases due to a current lack of known biomarkers for the disease. Patients may be split into categories based on the severity of their illness – mild, moderate and severe. Here we consider some of the recent advances in the understanding of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation that may have relevance to ME/CFS.

Thus far, we have shown that ME/CFS patients do not harbor proven mtDNA mutations, another exclusion, albeit an important one. As such this group of patients do not fall within the category of patients with mitochondrial disorder. If ME/CFS patients have some form of mitochondrial dysfunction, the form and cause of this dysfunction is a matter of debate. The current data underlines the need to move from small studies to larger endeavors applying multiple methods to well-defined cohorts with samples taken longitudinally.

Source: Cara Tomas & Joanna L Elson (2019) The role of mitochondria in ME/CFS: a perspective, Fatigue: Biomedicine, Health & Behavior, 7:1, 52-58, DOI: 10.1080/21641846.2019.1580855 https://www.tandfonline.com/doi/abs/10.1080/21641846.2019.1580855  (Full text)

Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS.

In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor.

In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.

Source: Li X, Julin P, Li TQ. Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Tomography. 2021 Nov 1;7(4):675-687. doi: 10.3390/tomography7040056. PMID: 34842817.  https://www.mdpi.com/2379-139X/7/4/56 (Full text)

No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [ 11 C]-PK11195

Abstract:

Background and objectives: The pathophysiology of chronic fatigue syndrome (CFS) and Q fever fatigue syndrome (QFS) remains elusive. Recent data suggest a role for neuroinflammation as defined by increased expression of translocator protein (TSPO). In the present study, we investigated whether there are signs of neuroinflammation in female patients with CFS and QFS compared with healthy women, using PET with the TSPO ligand 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide ([11C]-PK11195).

Methods: The study population consisted of patients with CFS (n = 9), patients with QFS (n = 10), and healthy subjects (HSs) (n = 9). All subjects were women, matched for age (±5 years) and neighborhood, aged between 18 and 59 years, who did not use any medication other than paracetamol or oral contraceptives, and were not vaccinated in the last 6 months. None of the subjects reported substance abuse in the past 3 months or reported signs of underlying psychiatric disease on the Mini-International Neuropsychiatric Interview. All subjects underwent a [11C]-PK11195 PET scan, and the [11C]-PK11195 binding potential (BPND) was calculated.

Results: No statistically significant differences in BPND were found for patients with CFS or patients with QFS compared with HSs. BPND of [11C]-PK11195 correlated with symptom severity scores in patients with QFS, but a negative correlation was found in patients with CFS.

Discussion: In contrast to what was previously reported for CFS, we found no significant difference in BPND of [11C]-PK11195 when comparing patients with CFS or QFS with healthy neighborhood controls. In this small series, we were unable to find signs of neuroinflammation in patients with CFS and QFS.

Source: Raijmakers R, Roerink M, Keijmel S, Joosten L, Netea M, van der Meer J, Knoop H, Klein H, Bleeker-Rovers C, Doorduin J. No Signs of Neuroinflammation in Women With Chronic Fatigue Syndrome or Q Fever Fatigue Syndrome Using the TSPO Ligand [11C]-PK11195. Neurol Neuroimmunol Neuroinflamm. 2021 Nov 23;9(1):e1113. doi: 10.1212/NXI.0000000000001113. PMID: 34815320. https://pubmed.ncbi.nlm.nih.gov/34815320/

The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications

Abstract:

The well-known symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are chronic pain, cognitive dysfunction, post-exertional malaise and severe fatigue. Another class of symptoms commonly reported in the context of ME/CFS are gastrointestinal (GI) problems. These may occur due to comorbidities such as Crohn’s disease or irritable bowel syndrome (IBS), or as a symptom of ME/CFS itself due to an interruption of the complex interplay between the gut microbiota (GM) and the host GI tract. An altered composition and overall decrease in diversity of GM has been observed in ME/CFS cases compared to controls. In this review, we reflect on genetics, infections, and other influences that may factor into the alterations seen in the GM of ME/CFS individuals, we discuss consequences arising from these changes, and we contemplate the therapeutic potential of treating the gut to alleviate ME/CFS symptoms holistically.

Source: Varesi A, Deumer US, Ananth S, Ricevuti G. The Emerging Role of Gut Microbiota in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Current Evidence and Potential Therapeutic Applications. J Clin Med. 2021 Oct 29;10(21):5077. doi: 10.3390/jcm10215077. PMID: 34768601. https://pubmed.ncbi.nlm.nih.gov/34768601/

Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms

Abstract:

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.

Results Using shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.

Conclusions Our findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.

Source: Cheng Guo, Xiaoyu Che, Thomas Briese, Orchid Allicock, Rachel A. Yates, Aaron Cheng, Amit Ranjan, Dana March, Mady Hornig, Anthony L. Komaroff, Susan Levine, Lucinda Bateman, Suzanne D. Vernon, Nancy G. Klimas, Jose G. Montoya, Daniel L. Peterson, W. Ian Lipkin, Brent L. Williams. Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms. medRxiv 2021.10.27.21265575; doi: https://doi.org/10.1101/2021.10.27.21265575 https://www.medrxiv.org/content/10.1101/2021.10.27.21265575v1?fbclid=IwAR16pb6by73xZx5lZM3j-5dOc_YT2JapILaRS-DcUZj5EHZxnoSa2fAAIuE (Full text available to download)

Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review

Abstract:

The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS.

In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review. TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.

Source: Du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S. Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review. Int J Environ Res Public Health. 2021 Oct 12;18(20):10708. doi: 10.3390/ijerph182010708. PMID: 34682454; PMCID: PMC8535478. https://pubmed.ncbi.nlm.nih.gov/34682454/ (Full text)

Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

Objective: Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients.

Methods: 60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed, using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound).

Results: End-tilt cerebral blood flow reduction was -29 (6)%, improving to -16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: -7 (2)%, moderate: -16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients.

Conclusions: During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients.

Significance: The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.

Source: van Campen CLMC, Rowe PC, Visser FC. Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients. Clin Neurophysiol Pract. 2021 Sep 23;6:245-255. doi: 10.1016/j.cnp.2021.09.001. PMID: 34667909; PMCID: PMC8505270. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505270/  (Full text)