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.

[1]  D. Drossman,et al.  The Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology, and Treatment : A Multinational Consensus , 1994 .

[2]  J. Phair,et al.  Serum neopterin and interleukin-6 levels in chronic fatigue syndrome. , 1990, The Journal of infectious diseases.

[3]  M. Maes,et al.  Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. , 2012, Journal of affective disorders.

[4]  M. Maes Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms , 2009, Current opinion in psychiatry.

[5]  P. Sullivan,et al.  Feeling Bad in More Ways than One: Comorbidity Patterns of Medically Unexplained and Psychiatric Conditions , 2007, Journal of General Internal Medicine.

[6]  A. Keshavarzian,et al.  Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative stress, gut leakiness, and liver injury in a rat model of alcoholic steatohepatitis. , 2009, Alcohol.

[7]  T. Bucciarelli,et al.  Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome , 2003, Neuroscience Letters.

[8]  L. Kirmayer,et al.  Latent variable models of functional somatic distress. , 1997, The Journal of nervous and mental disease.

[9]  Gwen Kennedy,et al.  Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. , 2005, Free radical biology & medicine.

[10]  M. P. Derde,et al.  Extraction of information from large data sets by pattern recognition , 1982 .

[11]  K. Ahmadi,et al.  Antibodies to Klebsiella pneumoniae lipopolysaccharide in patients with ankylosing spondylitis. , 1998, British journal of rheumatology.

[12]  N. Klimas,et al.  Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis , 2011, Journal of Translational Medicine.

[13]  G. Kennedy,et al.  Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. , 2008, Clinical science.

[14]  M. Maes,et al.  In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. , 2013, Journal of affective disorders.

[15]  D. Fuchs,et al.  IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein Barr virus-infection. , 2008, Journal of affective disorders.

[16]  M. Maes,et al.  CorrespondenceChronic fatigue syndrome : Harvey and Wessely ' s ( bio ) psychosocial model versus a bio ( psychosocial ) model based on inflammatory and oxidative and nitrosative stress pathways , 2010 .

[17]  Mary Ann Fletcher,et al.  Plasma cytokines in women with chronic fatigue syndrome , 2009, Journal of Translational Medicine.

[18]  M. Maes,et al.  Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. , 2007, Neuro endocrinology letters.

[19]  遠藤 昌夫 Bacterial Translocation (BT) , 2000 .

[20]  P. Rousseeuw,et al.  Epidemiologic and phenomenological aspects of post-traumatic stress disorder: DSM-III-R diagnosis and diagnostic criteria not validated , 1998, Psychiatry Research.

[21]  A. Puri,et al.  Small intestinal bacterial overgrowth (SIBO) in irritable bowel syndrome: Frequency and predictors , 2011, Journal of gastroenterology and hepatology.

[22]  C. Gottfries,et al.  A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). , 2002, Journal of psychosomatic research.

[23]  P. Sullivan,et al.  Irritable Bowel Syndrome: A Co-Twin Control Analysis , 2007, The American Journal of Gastroenterology.

[24]  D. Coomans,et al.  High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. , 2013, Anaerobe.

[25]  P. Blockx,et al.  Clinical subtypes of unipolar depression: Part III. Quantitative differences in various biological markers between the cluster-analytically generated nonvital and vital depression classes , 1990, Psychiatry Research.

[26]  R. Berg,et al.  Translocation of Certain Indigenous Bacteria from the Gastrointestinal Tract to the Mesenteric Lymph Nodes and Other Organs in a Gnotobiotic Mouse Model , 1979, Infection and immunity.

[27]  Ning Li,et al.  Effect of glutamine on change in early postoperative intestinal permeability and its relation to systemic inflammatory response. , 2004, World journal of gastroenterology.

[28]  The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs) , 2014, Molecular Neurobiology.

[29]  M. Maes,et al.  Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. , 2006, Neuro endocrinology letters.

[30]  A. Sperber,et al.  Irritable Bowel Syndrome and Co-morbid Gastrointestinal and Extra-gastrointestinal Functional Syndromes , 2010, Journal of neurogastroenterology and motility.

[31]  R. Wiest,et al.  Bacterial translocation (BT) in cirrhosis , 2005, Hepatology.

[32]  M. Maes,et al.  Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics , 2013, BMC Medicine.

[33]  M. Maes,et al.  Clinical subtypes of unipolar depression: Part I. A validation of the vital and nonvital clusters , 1990, Psychiatry Research.

[34]  P. White,et al.  Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study in primary care , 2009, Psychological Medicine.

[35]  A. Ford,et al.  Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review , 2011, Journal of Gastroenterology.

[36]  H. Tsukamoto,et al.  Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 dimerization enables rapid signal transduction against lipopolysaccharide stimulation on membrane-associated CD14-expressing cells. , 2010, International immunology.

[37]  A. Logan,et al.  A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome , 2009, Gut pathogens.

[38]  M. Maes,et al.  Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression. , 2007, Neuro endocrinology letters.

[39]  G. Ricevuti,et al.  Immunological aspects of chronic fatigue syndrome. , 2009, Autoimmunity reviews.

[40]  Michael R. Anderberg,et al.  NONHIERARCHICAL CLUSTERING METHODS , 1973 .

[41]  K. Chopra,et al.  Role of Lactobacillus acidophilus loaded floating beads in chronic fatigue syndrome: behavioral and biochemical evidences , 2012, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[42]  W. Whitehead,et al.  Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? , 2002, Gastroenterology.

[43]  Desire L. Massart,et al.  The Interpretation of Analytical Chemical Data by the Use of Cluster Analysis , 1983 .

[44]  I. Hickie,et al.  The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. , 1994, Annals of internal medicine.

[45]  D. Buchwald,et al.  A Review of the Evidence for Overlap among Unexplained Clinical Conditions , 2001, Annals of Internal Medicine.

[46]  M. Maes,et al.  Decreased dehydroepiandrosterone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS. , 2005, Neuro endocrinology letters.

[47]  R. Moss‐Morris,et al.  To “Lump” or to “Split” the Functional Somatic Syndromes: Can Infectious and Emotional Risk Factors Differentiate Between the Onset of Chronic Fatigue Syndrome and Irritable Bowel Syndrome? , 2006, Psychosomatic medicine.

[48]  M. Schietroma,et al.  Intestinal Permeability and Systemic Endotoxemia After Laparotomic or Laparoscopic Cholecystectomy , 2006, Annals of surgery.

[49]  M. Maes,et al.  Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. , 2007, Journal of affective disorders.

[50]  M. Maes,et al.  Clinical subtypes of unipolar depression: Part II. Quantitative and qualitative clinical differences between the vital and nonvital depression groups , 1990, Psychiatry Research.

[51]  M. Maes,et al.  Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. , 2007, Neuro endocrinology letters.

[52]  Jin-Mann S. Lin,et al.  Association of peripheral inflammatory markers with chronic fatigue in a population-based sample , 2009, Brain, Behavior, and Immunity.

[53]  M. Maes,et al.  Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. , 2012, Journal of affective disorders.

[54]  M. Maes,et al.  Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) , 2014, Current neuropharmacology.

[55]  Suivi immunobiologique de malades atteints de sclérose en plaques , 2003 .

[56]  P. Scully,et al.  Plasma Cytokine Profiles in Females With Irritable Bowel Syndrome and Extra-Intestinal Co-Morbidity , 2010, The American Journal of Gastroenterology.

[57]  M. Maes,et al.  Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. , 2007, Neuro endocrinology letters.

[58]  D. Nutt,et al.  Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis , 2009, Journal of Clinical Pathology.

[59]  Functional Bowel Disorders , 2006 .

[60]  S. Lakhan,et al.  Gut inflammation in chronic fatigue syndrome , 2010, Nutrition & metabolism.

[61]  H. Waitzkin,et al.  A hierarchical classes analysis (HICLAS) of primary care patients with medically unexplained somatic symptoms , 1998, Psychiatry Research.

[62]  D. P. Lewis,et al.  Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. , 2009, In vivo.

[63]  D. Wilmore,et al.  The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe burns: a randomized, double-blind, controlled clinical trial. , 2003, JPEN. Journal of parenteral and enteral nutrition.

[64]  I. Şimşek Irritable bowel syndrome and other functional gastrointestinal disorders. , 2011, Journal of clinical gastroenterology.

[65]  Ian Hickie,et al.  The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study , 1994, Annals of Internal Medicine.

[66]  B. Klapp,et al.  Somatic comorbidities of irritable bowel syndrome: a systematic analysis. , 2008, Journal of psychosomatic research.