Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome | Microbiome

 "Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.

Results
Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.

Conclusions
Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups."



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Associations between Unconventional Natural Gas Development and Nasal and Sinus, Migraine Headache, and Fatigue Symptoms in Pennsylvania

Background: Unconventional natural gas development (UNGD) (fracking) produces environmental contaminants and psychosocial stressors. Despite these concerns, few studies have evaluated the health effects of UNGD.

Objectives: We investigated associations between UNGD activity and symptoms in a cross-sectional study in Pennsylvania.

Methods: We mailed a self-administered questionnaire to 23,700 adult patients of the Geisinger Clinic. Using standardized and validated questionnaire items, we identified respondents with chronic rhinosinusitis (CRS), migraine headache, and fatigue symptoms. We created a summary UNGD activity metric that incorporated well phase, location, total depth, daily gas production and inverse distance-squared to patient residences. We used logistic regression, weighted for sampling and response rates, to assess associations between quartiles of UNGD activity and outcomes, both alone and in combination.



Results: The response rate was 33%. Of 7,785 study participants, 1,850 (24%) had current CRS symptoms, 1,765 (23%) had migraine headache, and 1,930 (25%) had higher levels of fatigue. Among individuals who met criteria for two or more outcomes, adjusted odds ratios for the highest quartile of UNGD activity compared to the lowest were [OR (95% CI)] 1.49 (0.78, 2.85) for CRS plus migraine, 1.88 (1.08, 3.25) for CRS plus fatigue, 1.95 (1.18, 3.21) for migraine plus fatigue, and 1.84 (1.08, 3.14) for all three outcomes together. Significant associations were also present in some models of single outcomes.

Conclusions: This study provides evidence that UNGD is associated with nasal and sinus, migraine headache, and fatigue symptoms in a general population representative sample."



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Indicator of chronic fatigue syndrome found in gut bacteria

Physicians have been mystified by chronic fatigue syndrome, a condition where normal exertion leads to debilitating fatigue that isn't alleviated by rest. There are no known triggers, and diagnosis requires lengthy tests administered by an expert.
Due to this lack of information, some people have even suggested the disease may be psychosomatic.
Now, for the first time, Cornell researchers report they have identified biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.
In a study published June 23 in the journal Microbiome, the team describes how they correctly diagnosed myalgic encephalomyeletis/chronic fatigue syndrome (ME/CFS) in 83 percent of patients through stool samples and blood work, offering a noninvasive diagnosis and a step toward understanding the cause of the disease.
"Our work demonstrates that the gut bacterial microbiome in ME/CFS patients isn't normal, perhaps leading to gastrointestinal and inflammatory symptoms in victims of the disease," said Maureen Hanson, the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics and the paper's senior author. "Furthermore, our detection of a biological abnormality provides further evidence against the ridiculous concept that the disease is psychological in origin.



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Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). - PubMed - NCBI

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain. In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance. Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation. To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined. Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls. These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.

Study shows chronic fatigue associated with abnormal brain connectivity at rest

Full paper at Brain Connectivity 

Scientists discover robust evidence that chronic fatigue syndrome is a biological illness

"Researchers at the Center for Infection and Immunity at Columbia University's Mailman School of Public Health identified distinct immune changes in patients diagnosed with chronic fatigue syndrome, known medically as myalgic encephalomyelitis (ME/CFS) or systemic exertion intolerance disease. The findings could help improve diagnosis and identify treatment options for the disabling disorder, in which symptoms range from extreme fatigue and difficulty concentrating to headaches and muscle pain."



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JAMA Network | Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An IOM Report on Redefining an Illness

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem and often long-lasting disorder, with manifestations that can cause substantial morbidity and can severely impair patients’ health and well-being. It is estimated that between 836 000 and 2.5 million individuals are affected in the United States.1,2 Patients with ME/CFS are typically unable to perform their normal activities, and as many as one-fourth are homebound or bedridden, sometimes for extended periods.3 As a result, the personal and social effects and ramifications of this disease are enormous.

However, ME/CFS is poorly accepted and poorly understood, and the characteristics necessary to make the diagnosis are contested. Patients’ concerns are often met with dismay and skepticism, if not outright dismissal. Clinicians, in turn, are confronted by competing definitions, which were usually developed for research and are quite complex and difficult to implement in a busy clinical practice. Patients who are fortunate enough and persistent enough to receive a correct diagnosis frequently report long delays before their disorder was identified. It is almost certainly the case that the majority of affected patients are never diagnosed. This is unfortunate because effective symptom management is often available, whereas the wrong interventions can make symptoms worse.

Making the diagnosis is essential for providing appropriate care. To that end, the Department of Health and Human Services (HHS), together with the National Institutes of Health, US Social Security Administration, US Food and Drug Administration, Centers for Disease Control and Prevention, and Agency for Healthcare Research and Quality, tasked the Institute of Medicine (IOM) to develop “evidence-based clinical diagnostic criteria for ME/CFS for use by clinicians, using a consensus-building methodology,” with input from patients and clinicians; to “recommend whether new terminology for ME/CFS should be adopted”; and to create plans for disseminating these conclusions to clinicians.

Study finds brain abnormalities in chronic fatigue patients

An imaging study by Stanford University School of Medicine investigators
has found distinct differences between the brains of patients with
chronic fatigue syndrome and those of healthy people.

Brain imaging reveals clues about chronic fatigue syndrome

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.
"We chose the basal ganglia because they are primary targets of inflammation in the brain," says lead author Andrew Miller, MD. "Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients."
In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

Two competing proteins affect the chronic inflammation of the nervous system following viral infection

Fatigue and depression are common during and after viral infection, and
in some cases can become chronic long-term ailments. Fever and
inflammation associated with viral infections are triggered by the
release of proinflammatory proteins called cytokines. These proteins can
also trigger persistent inflammation of the central nervous system, or
neuroinflammation, which is thought to be a key factor in the onset of
viral-related depression and fatigue. The exact molecular mechanisms
involved, however, are not fully understood.

Yosky Kataoka, Masanori Yamato and colleagues from the RIKEN Center for
Life Science Technologies have now uncovered the roles of two cytokines,
interleukin 1 beta (IL-1β) and its receptor antagonist IL-1ra, in
triggering and controlling neuroinflammation in rats.

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there
is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation.
¹¹C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (¹¹C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used ¹¹C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. Methods: Nine CFS/ME patients and 10 healthy controls underwent ¹¹C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression.
To measure the density of translocator protein, nondisplaceable binding potential (BP_ND) values were determined using linear graphical analysis with the cerebellum as a reference region. Results: The BP_ND values of ¹¹C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%–199% higher in CFS/ME patients
than in healthy controls. In CFS/ME patients, the BP_ND values of ¹¹C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP_ND values in the cingulate cortex and thalamus positively correlated with pain score, and the BP_ND value in the hippocampus positively correlated with depression score. Conclusion:
Neuroinflammation is present in widespread brain areas in CFS/ME
patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology
and for developing objective diagnostic criteria and effective medical treatments.

Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome.

Epstein-Barr virus (EBV) has long been discussed as a possible cause or
trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the
disease starts with infectious mononucleosis and both enhanced and
diminished EBV-specific antibody titers have been reported. In this
study, we comprehensively analyzed the EBV-specific memory B- and T-cell
response in patients with CFS. While we observed no difference in viral
capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG
titers were low or absent in 10% of CFS patients. Remarkably, when
analyzing the EBV-specific memory B-cell reservoir in vitro a diminished
or absent number of EBNA-1- and VCA-antibody secreting cells was found
in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of
TNF-α and IFN-γ was significantly lower in patients. Multicolor flow
cytometry revealed that the frequencies of EBNA-1-specific triple
TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were
significantly diminished whereas no difference could be detected for
HCMV-specific T-cell responses. When comparing EBV load in blood immune
cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS
patients compared to healthy controls suggesting more frequent latent
replication. Taken together, our findings give evidence for a deficient
EBV-specific B- and T-cell memory response in CFS patients and suggest
an impaired ability to control early steps of EBV reactivation. In
addition the diminished EBV response might be suitable to develop
diagnostic marker in CFS.

Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis.

Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

Evidence for Borna disease virus infection in neuropsychiatric patients in three western China provinces.

 Borna disease virus (BDV) is a non-cytolytic, neurotropic RNA virus that can infect a wide variety of vertebrate species from birds and primates to humans. Several studies have been carried out to investigate whether BDV is associated with neuropsychiatric diseases. However, this association is still inconclusive. Two panels of subjects consisting of 1,679 various neuropsychiatric patients and healthy people from three western China provinces were enrolled in this study. BDV p24 or p40 RNA in peripheral blood mononuclear cells (PBMCs) were detected in the first panel of 1,481 subjects using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and cerebrospinal fluid (CSF) samples from the BDV RNA-positive individuals were subjected to BDV p24 antibodies testing by enzyme-linked immunosorbent assay (ELISA). BDV p24 or p40 RNA in PBMCs and p24 antibodies in plasma were detected in the second panel of 198 subjects by RT-qPCR and Western blot. A higher prevalence for BDV RNA was demonstrated in patients with viral encephalitis (6.70 %), Guillain-Barré syndrome (6.70 %), schizophrenia (9.90 %) and chronic fatigue syndrome (CFS) (12.70 %) compared to healthy controls in the first panel. CSF p24 antibodies were demonstrated in three viral encephalitis patients, two schizophrenia patients and two major depressive disorder (MDD) patients. The prevalences of p24 antibodies in plasma from patients with viral encephalitis (13.24 %), multiple sclerosis (25.00 %) and Parkinson's disease (22.73 %) were significantly higher than healthy controls. This study demonstrates that BDV infection also exists in humans from three western China provinces, and suggests the involvement of the contribution of BDV in the aetiology of Chinese patients with some neuropsychiatric disorders, including viral encephalitis, schizophrenia, CFS, multiple sclerosis and Parkinson's disease.

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome.

 There is no known treatment for chronic fatigue syndrome (CFS). Little is known about its pathogenesis. Human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been proposed as infectious triggers. Thirty CFS patients with elevated IgG antibody titers against HHV-6 and EBV were randomized 2:1 to receive valganciclovir (VGCV) or placebo for 6 months in a double-blind, placebo-controlled trial. Clinical endpoints aimed at measuring physical and mental fatigue included the Multidimensional Fatigue Inventory (MFI-20) and Fatigue Severity Scale (FSS) scores, self-reported cognitive function, and physician-determined responder status. Biological endpoints included monocyte and neutrophil counts and cytokine levels. VGCV patients experienced a greater improvement by MFI-20 at 9 months from baseline compared to placebo patients but this difference was not statistically significant. However, statistically significant differences in trajectories between groups were observed in MFI-20 mental fatigue subscore (P = 0.039), FSS score (P = 0.006), and cognitive function (P = 0.025). VGCV patients experienced these improvements within the first 3 months and maintained that benefit over the remaining 9 months. Patients in the VGCV arm were 7.4 times more likely to be classified as responders (P = 0.029). In the VGCV arm, monocyte counts decreased (P < 0.001), neutrophil counts increased (P = 0.037) and cytokines were more likely to evolve towards a Th1-profile (P < 0.001). Viral IgG antibody titers did not differ between arms. VGCV may have clinical benefit in a subset of CFS patients independent of placebo effect, possibly mediated by immunomodulation and/or antiviral effect. Further investigation with longer treatment duration and a larger sample size is warranted.

Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins.

 Myalgic encephalomyelitis (ME) is a debilitating illness of unknown etiology characterized by neurocognitive dysfunction, inflammation, immune abnormalities and gastrointestinal distress. An increasing body of evidence suggests that disruptions in the gut may contribute to the induction of neuroinflammation. Therefore, reports of human endogenous retroviral (HERV) expression in association with neuroinflammatory diseases prompted us to investigate the gut of individuals with ME for the presence of HERV proteins. In eight out of 12 individuals with ME, immunoreactivity to HERV proteins was observed in duodenal biopsies. In contrast, no immunoreactivity was detected in any of the eight controls. Immunoreactivity to HERV Gag and Env proteins was uniquely co-localized in hematopoietic cells expressing the C-type lectin receptor CLEC4C (CD303/BDCA2), the co-stimulatory marker CD86 and the class II major histocompatibility complex HLA-DR, consistent with plasmacytoid dendritic cells (pDCs). Although the significance of HERVs present in the pDCs of individuals with ME has yet to be determined, these data raise the possibility of an involvment of pDCs and HERVs in ME pathology. To our knowledge, this report describes the first direct association between pDCs and HERVs in human disease.

NLRP3 Inflammasome is activated in Fibromyalgia: the effect of Coenzyme Q10.

 Fibromyalgia (FM) is a prevalent chronic pain syndrome characterized by generalized hyperalgesia associated with a wide spectrum of symptoms such as fatigue and joint stiffness. Diagnosis of FM is difficult due to the lack of reliable diagnostic biomarkers, while treatment is largely inadequate. We have investigated the role of coenzyme Q10 (CoQ10) deficiency and mitochondrial dysfunction in inflammasome activation in blood cells from FM patients, and in vitro and in vivo CoQ10 deficiency models. Results: Mitochondrial dysfunction was accompanied by increased protein expression of IL-1β, NLRP3 and caspase-1 activation, and increase of serum levels of pro-inflammatory cytokines (IL-1β and IL-18). CoQ10 deficiency induced by p-aminobenzoate treatment in BMCs and mice showed NLRP3 inflammasome activation with marked algesia. A placebo-controlled trial of CoQ10 in FM patients has shown a reduced NLRP3 inflammasome activation and IL-1β and IL-18 serum levels. Innovations: These results show an important role for the NLRP3 inflammasome in the pathogenesis of FM, and the capacity of CoQ10 in the control of inflammasome. Conclusions: These findings provide new insights into the pathogenesis of FM and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.

Inherited virus (HHV-6) can cause cognitive dysfunction and fatigue

"Many experts believe that chronic fatigue syndrome (CFS) has several root causes including some viruses. Now, lead scientists Shara Pantry, Maria Medveczky and Peter Medveczky of the University of South Florida's Morsani College of Medicine, along with the help of several collaborating scientists and clinicians, have published an article in the Journal of Medical Virology suggesting that a common virus, Human Herpesvirus 6 (HHV-6), is the possible cause of some CFS cases.

J.Med Virol "Persistent human herpesvirus-6 infection in patients with an inherited form of the virus

CFS in Children and Adolescent: Ten Years of Retrospective Clinical Evaluation.

To estimate number of children being diagnosed with chronic fatigue syndrome (CFS). Methods. For a period of 10 years (2002-2011) data from children being referred for fatigue symptoms were collected retrospectively. Results. Thirty-seven children were referred. Four were excluded due to incorrect coding. Six (18%) patients received other diagnoses at the end of evaluation time. Of the 27 who received the diagnosis G93.3, four had a previous chronic illness, while 23 patients were previously healthy. All patients reported onset of fatigue symptom in relation to an infection, and all tested positive for IgG to either Epstein-Barr virus, cytomegalovirus or borrelia, indicating previous infection. There were 16 (59%) boys among the 27 patients. The mean age at the debut of fatigue symptoms was 141 months (SD 30) for boys and 136 months (SD 31) for girls, respectively. Being underweight, defined as BMI < 17.5, was found in 12 (44%) patients. Conclusion. An increasing number of children and adolescents are evaluated for CFS. The clinical assessment of children and adolescents with possible CFS need systematically evaluation. Nutritional status, possible eating disorder, and psychosocial issues need to be addressed and evaluated carefully. A multidisciplinary approach is essential when assessing CFS in children and adolescents. There is a need for European guidelines.

In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation.

METHODS:

We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale).

RESULTS:

The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.

DISCUSSION:

The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder.