Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained debilitating fatigue, cognitive dysfunction, gastrointestinal disturbances, and orthostatic intolerance. Here, we report a multi-omic analysis of a geographically diverse cohort of 106 cases and 91 healthy controls that revealed differences in gut microbiome diversity, abundances, functional pathways, and interactions. Faecalibacterium prausnitzii and Eubacterium rectale, which are both recognized as abundant, health-promoting butyrate producers in the human gut, were reduced in ME/CFS. Functional metagenomics, qPCR, and metabolomics of fecal short-chain fatty acids confirmed a deficient microbial capacity for butyrate synthesis. Microbiome-based machine learning classifier models were robust to geographic variation and generalizable in a validation cohort. The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity. These findings demonstrate the functional nature of gut dysbiosis and the underlying microbial network disturbance in ME/CFS, providing possible targets for disease classification and therapeutic trials.

Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelits (CFS/ME).

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidences suggest strong correlations between dysbiosis and pathological condition. The present research explored the composition of the intestinal and oral microbiota in CFS/ME patients as compared to healthy controls. The fecal metabolomic profile of a subgroup of CFS/ME patients was also compared with the one of healthy controls. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons. The metabolomic analysis was performed by an UHPLC-MS. The fecal microbiota of CFS/ME patients showed a reduction of Lachnospiraceae, particularly Anaerostipes, and an increased abundance of genera Bacteroides and Phascolarctobacterium compared to the non-CFS/ME groups. The oral microbiota of CFS/ME patients showed an increase of Rothia dentocariosa. The fecal metabolomic profile of CFS/ME patients revealed high levels of glutamic acid and argininosuccinic acid, together with a decrease of alpha-tocopherol. Our results reveal microbial signatures of dysbiosis in the intestinal microbiota of CFS/ME patients. Further studies are needed to better understand if the microbial composition changes are cause or consequence of the onset of CFS/ME and if they are related to any of the several secondary symptoms.

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

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.

Environmental, Neuro-immune, and Neuro-oxidative Stress Interactions in Chronic Fatigue Syndrome.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS) is a complex, multisystem disease that is characterized by long-term fatigue, exhaustion, disabilities, pain, neurocognitive impairments, gastrointestinal symptoms, and post-exertional malaise, as well as lowered occupational, educational, and social functions. The clinical and biomarker diagnosis of this disorder is hampered by the lack of validated diagnostic criteria and laboratory tests with adequate figures of merit, although there are now many disease biomarkers indicating the pathophysiology of CFS. Here, we review multiple factors, such as immunological and environmental factors, which are associated with CFS and evaluate current concepts on the involvement of immune and environmental factors in the pathophysiology of CFS. The most frequently reported immune dysregulations in CFS are modifications in immunoglobulin contents, changes in B and T cell phenotypes and cytokine profiles, and decreased cytotoxicity of natural killer cells. Some of these immune aberrations display a moderate diagnostic performance to externally validate the clinical diagnosis of CFS, including the expression of activation markers and protein kinase R (PKR) activity. Associated with the immune aberrations are activated nitro-oxidative pathways, which may explain the key symptoms of CFS. This review shows that viral and bacterial infections, as well as nutritional deficiencies, may further aggravate the immune-oxidative pathophysiology of CFS. Targeted treatments with antioxidants and lipid replacement treatments may have some clinical efficacy in CFS. We conclude that complex interactions between immune and nitro-oxidative pathways, infectious agents, environmental factors, and nutritional deficiencies play a role in the pathophysiology of CFS.

Post-bacterial infection chronic fatigue syndrome is not a latent infection.

Post-infectious chronic fatigue syndrome is a public health problem. Etiologies and physiopathological mechanisms are unknown. Some viruses are known to be involved in post-infectious chronic fatigue syndrome, but the role of bacterial infection is still questioned, especially in cases of post-treatment Lyme disease syndrome where subjective symptoms are regularly attributed to the presence of the dormant bacterium without scientific evidence. However, the medical experience of recalcitrant infections, relapses, and reactivations questions the role of "dormant bacteria" in asymptomatic latent infections as well as in subjective symptoms. We summarized scientific literature data on post-bacterial infection chronic fatigue syndrome, the role of dormant bacteria in latent infections, and bacterial asymptomatic carriage. Subjective symptoms described in post-infectious chronic fatigue syndromes are still misunderstood and there is no evidence suggesting that such symptoms could be related to dormant bacterial infection or carriage of viable bacteria. Psychological trauma may be part of these subjective symptoms. Post-infectious chronic fatigue syndrome could nonetheless be due to unknown microorganisms. Antibiotic treatment is not required for latent infections, except for latent syphilis and latent tuberculosis infections to prevent, after the primary infection, progression to the secondary or tertiary stage of the disease.

Chronic fatigue syndrome (CFS): Suggestions for a nutritional treatment in the therapeutic approach.

Chronic fatigue syndrome (CFS) is known as a multi-systemic and complex illness, which induces fatigue and long-term disability in educational, occupational, social, or personal activities. The diagnosis of this disease is difficult, due to lacking a proper and suited diagnostic laboratory test, besides to its multifaceted symptoms. Numerous factors, including environmental and immunological issues, and a large spectrum of CFS symptoms, have recently been reported. In this review, we focus on the nutritional intervention in CFS, discussing the many immunological, environmental, and nutritional aspects currently investigated about this disease. Changes in immunoglobulin levels, cytokine profiles and B- and T- cell phenotype and declined cytotoxicity of natural killer cells, are commonly reported features of immune dysregulation in CFS. Also, some nutrient deficiencies (vitamin C, vitamin B complex, sodium, magnesium, zinc, folic acid, l-carnitine, l-tryptophan, essential fatty acids, and coenzyme Q10) appear to be important in the severity and exacerbation of CFS symptoms. This review highlights a far-driven analysis of mineral and vitamin deficiencies among CFS patients.

Chronic fatigue syndrome patients have alterations in their oral microbiome composition and function.

Host-microbe interactions have been implicated in the pathogenesis of chronic fatigue syndrome (CFS), but whether the oral microbiome is altered in CFS patients is unknown. We explored alterations of the oral microbiome in Chinese Han CFS patients using 16S rRNA gene sequencing and alterations in the functional potential of the oral microbiome using PICRUSt. We found that Shannon and Simpson diversity indices were not different in CFS patients compared to healthy controls, but the overall oral microbiome composition was different (MANOVA, p < 0.01). CFS patients had a higher relative abundance of Fusobacteria compared with healthy controls. Further, the genera Leptotrichia, Prevotella, and Fusobacterium were enriched and Haemophilus, Veillonella, and Porphyromonas were depleted in CFS patients compared to healthy controls. Functional analysis from inferred metagenomes showed that bacterial genera altered in CFS patients were primarily associated with amino acid and energy metabolism. Our findings demonstrate that the oral microbiome in CFS patients is different from healthy controls, and these differences lead to shifts in functional pathways with implications for CFS pathogenesis. These findings increase our understanding of the relationship between the oral microbiota and CFS, which will advance our understanding of CFS pathogenesis and may contribute to future improvements in treatment and diagnosis.

Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review.

Evidence suggests that the gut microbiota might play an important role in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). Our goal is to systematically review the reported effect of probiotic treatments in patients diagnosed with FMS or CFS. A systematic review was carried out using 14 databases (PubMed, Cochrane Library, Scopus, PsycINFO, and others) in February 2016 to search for randomised controlled trials (RCTs) and pilot studies of CFS or FMS patient, published in the last ten years (from 2006 to 2016). The Jadad scale was used to asseverate the quality of the clinical trials considered. Two studies (n=83) met the inclusion criteria, which were performed in CFS patients and both studies were considered as a 'High range of quality score'. The administration of Lactobacillus casei strain Shirota in CFS patients, over the course of 8 weeks, reduced anxiety scores. Likewise, this probiotic changed the faecal composition following 8 weeks of treatment. Additionally, the treatment with Bifidobacterium infantis 35624 in CFS patients, during the same period, reduced inflammatory biomarkers. The evidence about the usefulness of probiotics in CFS and FMS patients remains limited. The studied strains of probiotics have demonstrated a significant effect on modulating the anxiety and inflammatory processes in CFS patients. However, more experimental research, focusing mainly on the symptoms of the pathologies studied, is needed.

Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME.

INTRODUCTION: Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) point to an autoimmune disease directed against neurotransmitter receptors. We had observed elevated autoantibodies against ß2 adrenergic receptors, and muscarinic 3 and 4 acetylcholine receptors in a subset of patients. Immunoadsorption (IA) was shown to be effective in removing autoantibodies and improve outcome in various autoimmune diseases. METHODS: 10 patients with post-infectious CFS/ME and elevated ß2 autoantibodies were treated with IA with an IgG-binding column for 5 days. We assessed severity of symptoms as outcome parameter by disease specific scores. Antibodies were determined by ELISA and B cell phenotype by flow cytometry. RESULTS: IgG levels dropped to median 0.73 g/l (normal 7-16 g/l) after the 4th cycle of IA, while IgA and IgM levels remained unchanged. Similarly, elevated ß2 IgG antibodies rapidly decreased during IA in 9 of 10 patients. Also 6 months later ß2 autoantibodies were significantly lower compared to pretreatment. Frequency of memory B cells significantly decreased and frequency of plasma cells increased after the 4th IA cycle. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting moderate to marked improvement for 6-12+ months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening. CONCLUSIONS: IA can remove autoantibodies against ß2 adrenergic receptor and lead to clinical improvement. B cell phenotyping provides evidence for an effect of IA on memory B cell development. Data from our pilot trial warrants further studies in CFS/ME.

Does the microbiome and virome contribute to myalgic encephalomyelitis/chronic fatigue syndrome?

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.

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

BACKGROUND: 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.

Support for the microgenderome invites enquiry into sex differences.

The microgenderome defines the interaction between microbiota, sex hormones and the immune system. Our recent research inferred support for the microgenderome by showing sex differences in microbiota-symptom associations in a clinical sample of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). This addendum expands upon the sex-specific pattern of associations that were observed. Interpretations are hypothesized in relation to genera versus species-level analyses and D-lactate theory. Evidence of sex-differences invites future research to consider sex comparisons in microbial function even when microbial abundance is statistically similar. Pairing assessment of clinical symptoms with microbial culture, DNA sequencing and metabolomics methods will help advance our current understandings of the role of the microbiome in health and disease.

Gut Microbiota, Bacterial Translocation, and Interactions with Diet: Pathophysiological Links between Major Depressive Disorder and Non-Communicable Medical Comorbidities.

BACKGROUND: Persistent low-grade immune-inflammatory processes, oxidative and nitrosative stress (O&NS), and hypothalamic-pituitary-adrenal axis activation are integral to the pathophysiology of major depressive disorder (MDD). The microbiome, intestinal compositional changes, and resultant bacterial translocation add a new element to the bidirectional interactions of the gut-brain axis; new evidence implicates these pathways in the patho-aetiology of MDD. In addition, abnormalities in the gut-brain axis are associated with several chronic non-communicable disorders, which frequently co-occur in individuals with MDD, including but not limited to irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), obesity, and type 2 diabetes mellitus (T2DM). METHODS: We searched the PubMed/MEDLINE database up until May 1, 2016 for studies which investigated intestinal dysbiosis and bacterial translocation (the 'leaky gut') in the pathophysiology of MDD and co-occurring somatic comorbidities with an emphasis on IBS, CFS, obesity, and T2DM. RESULTS: The composition of the gut microbiota is influenced by several genetic and environmental factors (e.g. diet). Several lines of evidence indicate that gut-microbiota-diet interactions play a significant pathophysiological role in MDD and related medical comorbidities. Gut dysbiosis and the leaky gut may influence several pathways implicated in the biology of MDD, including but not limited to immune activation, O&NS, and neuroplasticity cascades. However, methodological inconsistencies and limitations limit comparisons across studies. CONCLUSIONS: Intestinal dysbiosis and the leaky gut may constitute a key pathophysiological link between MDD and its medical comorbidities. This emerging literature opens relevant preventative and therapeutic perspectives.

Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: Gastrointestinal disturbances are among symptoms commonly reported by individuals diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, whether ME/CFS is associated with an altered microbiome has remained uncertain. Here, we profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n = 39). We also examined a set of inflammatory markers in blood: C-reactive protein (CRP), intestinal fatty acid-binding protein (I-FABP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble CD14 (sCD14). RESULTS: We observed elevated levels of some blood markers for microbial translocation in ME/CFS patients; levels of LPS, LBP, and sCD14 were elevated in ME/CFS subjects. Levels of LBP correlated with LPS and sCD14 and LPS levels correlated with sCD14. Through deep sequencing of bacterial rRNA markers, we identified differences between the gut microbiomes of healthy individuals and patients with ME/CFS. We observed that bacterial diversity was decreased in the ME/CFS specimens compared to controls, in particular, a reduction in the relative abundance and diversity of members belonging to the Firmicutes phylum. In the patient cohort, we find less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory. Using a machine learning approach trained on the data obtained from 16S rRNA and inflammatory markers, individuals were classified correctly as ME/CFS with a cross-validation accuracy of 82.93 %. CONCLUSIONS: Our results indicate dysbiosis of the gut microbiota in this disease and further suggest an increased incidence of microbial translocation, which may play a role in inflammatory symptoms in ME/CFS.

Support for the Microgenderome: Associations in a Human Clinical Population.

The 'microgenderome' provides a paradigm shift that highlights the role of sex differences in the host-microbiota interaction relevant for autoimmune and neuro-immune conditions. Analysis of cross-sectional self-report and faecal microbial data from 274 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) suggests that commensal gut microorganisms may play both protective and deleterious roles in symptom expression. Results revealed significant sex-specific interactions between Firmicutes (Clostridium, Streptococcus, Lactobacillus and Enterococcus) and ME/CFS symptoms (including neurological, immune and mood symptoms), regardless of compositional similarity in microbial levels across the sexes. Extending animal studies, we provide support for the microgenderome in a human clinical population. Applied and mechanistic research needs to consider sex-interactions when examining the composition and function of human microbiota.

High prevalence of asymptomatic carriers of Tropheryma whipplei in different populations from the North of Spain.

INTRODUCTION: Tropheryma whipplei is the causative agent of Whipple disease. T. whipplei has also been detected in asymptomatic carriers with a very different prevalence. To date, in Spain, there are no data regarding the prevalence of T. whipplei in a healthy population or in HIV-positive patients, or in chronic fatigue syndrome (CFS). Therefore, the aim of this work was to assess the prevalence of T. whipplei in stools in those populations. METHODS: Stools from 21 HIV-negative subjects, 65 HIV-infected, and 12 CFS patients were analysed using real time-PCR. HIV-negative and positive subjects were divided into two groups, depending on the presence/absence of metabolic syndrome (MS). Positive samples were sequenced. RESULTS: The prevalence of T. whipplei was 25.51% in 98 stool samples analysed. Prevalence in HIV-positive patients was significantly higher than in HIV-negative (33.8% vs. 9.09%, p=0.008). Prevalence in the control group with no associated diseases was 20%, whereas no positive samples were observed in HIV-negative patients with MS, or in those diagnosed with CFS. The prevalence observed in HIV-positive patients without MS was 30.35%, and with MS it was 55.5%. The number of positive samples varies depending on the primers used, although no statistically significant differences were observed. CONCLUSIONS: There is a high prevalence of asymptomatic carriers of T. whipplei among healthy and in HIV-infected people from Spain. The role of T. whipplei in HIV patients with MS is unclear, but the prevalence is higher than in other populations.

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

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.

Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI). Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI. METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA. RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance. Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI. CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.

Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome.

BACKGROUND: There is evidence that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by gastro-intestinal symptoms; and IgA and IgM responses directed against lipopolysaccharides (LPS) of commensal bacteria, indicating bacterial translocation. METHODS: This study was carried out to examine gastro-intestinal symptoms in subjects with ME/CFS versus those with chronic fatigue (CF). The two groups were dissected by dichotomizing those fulfilling and not fulfilling Fukuda's critera. In these groups, we examined the association between gastro-intestinal symptoms and the IgA and IgM responses directed against commensal bacteria. RESULTS: Using cluster analysis performed on gastro-intestinal symptoms we delineated that the cluster analysis-generated diagnosis of abdominal discomfort syndrome (ADS) was significantly higher in subjects with ME/CFS (59.6%) than in those with CF (17.7%). The diagnosis of ADS was strongly associated with the diagnosis of irritable bowel syndrome (IBS). There is evidence that ME/CFS consists of two subgroups, i.e. ME/CFS with and without ADS. Factor analysis showed four factors, i.e. 1) inflammation-hyperalgesia; 2) fatigue-malaise; 3) gastro-intestinal symptoms/ADS; and 4) neurocognitive symptoms. The IgA and IgM responses to LPS of commensal bacteria were significantly higher in ME/CFS patients with ADS than in those without ADS. CONCLUSIONS: The findings show that ADS is a characteristic of a subset of patients with ME/CFS and that increased bacterial translocation (leaky gut) is associated with ADS symptoms. This study has defined a pathway phenotype, i.e bacterial translocation, that is related to ME/CFS and ADS/IBS and that may drive systemic inflammatory processes.

Therapeutic modulation of gut microbiota: current clinical applications and future perspectives.

Human beings and gut microbiota are in a symbiotic relationship, and the hypothesis of a "super organism" composed of the human organism and microbes has been recently proposed. The gut microbiota fulfills important metabolic and immunological tasks, and the impairment of its composition might alter homeostasis and lead to the development of microbiota-related diseases. The most common illnesses associated with alterations of the gut microbiota include inflammatory bowel disease, gastroenteric infections, irritable bowel syndrome and other gastrointestinal functional diseases, colorectal cancer, metabolic syndrome and obesity, liver diseases, allergic diseases, and neurological diseases such as autism. In theory, every disease associated with the impairment of intestinal microflora might benefit from the therapeutic modulation of the gut microbiota. A number of attempts to manipulate the microbiota have not produced identical results for every disease. Although antibiotics and probiotics have been available for a long time, the so-called fecal microbiota transplantation, which is a very old remedy, was only recently re-evaluated as a promising therapeutic approach for microbiota impairment. A comprehensive understanding of the gut microbiota composition, in states of both health and various diseases, is needed for the development of future approaches for microbiota modulation and for developing targeted therapies. In this review, we describe the role of the microbiota in several diseases and the related treatment options that are currently available.