From IBS to ME – The dysbiotic march hypothesis

Abstract:

Irritable bowel syndrome (IBS) is often associated with other unexplained complaints like chronic fatigue syndrome (CFS), fibromyalgia and myalgic encephalopathy (ME). The pathogenesis of the relationship is unknown. Intestinal dysbiosis may be a common abnormality, but based on 1100 consecutive IBS patients examined over a nine years period, we hypothesize that the development of the disease, often from IBS to ME, actually manifests a “dysbiotic march”. In analogy with “the atopic march” in allergic diseases, we suggest “a dysbiotic march” in IBS; initiated by extensive use of antibiotics during childhood, often before school age. Various abdominal complaints including IBS may develop soon thereafter, while systemic symptom like CFS, fibromyalgia and ME may appear years later.

Source: Berstad A, Hauso O, Berstad K, Berstad JER. From IBS to ME – The dysbiotic march hypothesis. Med Hypotheses. 2020 Feb 26;140:109648. doi: 10.1016/j.mehy.2020.109648. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32126475

The Effect of Comorbid Medical and Psychiatric Diagnoses on Chronic Fatigue Syndrome

Abstract:

OBJECTIVE: To determine if presence of co-existing medically unexplained syndromes or psychiatric diagnoses affect symptom frequency, severity or activity impairment in Chronic Fatigue Syndrome.

PATIENTS: Sequential Chronic Fatigue Syndrome patients presenting in one clinical practice.

DESIGN: Participants underwent a psychiatric diagnostic interview and were evaluated for fibromyalgia, irritable bowel syndrome and/or multiple chemical sensitivity.

RESULTS: Current and lifetime psychiatric diagnosis was common (68%) increasing mental fatigue/health but not other illness variables and not with diagnosis of other medically unexplained syndromes. 81% of patients had at least one of these conditions with about a third having all three co-existing syndromes. Psychiatric diagnosis was not associated with their diagnosis. Increasing the number of these unexplained conditions was associated with increasing impairment in physical function, pain and rates of being unable to work.

CONCLUSIONS: Patients with Chronic Fatigue Syndrome should be evaluated for current psychiatric conditions because of their impact on patient quality of life, but they do not act as a symptom multiplier for the illness. Other co-existing medically unexplained syndromes are more common than psychiatric co-morbidities in patients presenting for evaluation of medically unexplained fatigue and are also more associated with increased disability and the number and severity of symptoms.

Key Messages: When physicians see patients with medically unexplained fatigue, they often infer that this illness is due to an underlying psychiatric problem. This paper shows that the presence of co-existing psychiatric diagnoses does not impact on any aspect of the phenomenology of medically unexplained fatigue also known as chronic fatigue syndrome. Therefore, psychiatric status is not an important causal contributor to CFS. In contrast, the presence of other medically unexplained syndromes [irritable bowel syndrome; fibromyalgia and/or multiple chemical sensitivity] do impact on the illness such that the more of these that co-exist the more health-related burdens the patient has.

Source: Natelson BH, Lin JS, Lange G, Khan S, Stegner A, Unger ER. The Effect of Comorbid Medical and Psychiatric Diagnoses on Chronic Fatigue Syndrome. Ann Med. 2019 Oct 23:1-18. doi: 10.1080/07853890.2019.1683601. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31642345

Do anorexia, irritable bowel syndrome, chronic fatigues share a common cause?

Irritable bowel syndrome, chronic fatigue syndrome and anorexia nervosa may all have a common origin according to researchers.

They speculate that all three disorders may be caused by antibodies to the body’s own nerve cells because of a mistake by the immune system following infection.

At the moment, the ultimate cause of these illnesses remains a mystery.

Writing in Medical Hypotheses, Dr Jim Morris from the University Hospitals of Morecambe Bay NHS Trust, Dr Sue Broughton and Dr Quenton Wessels from Lancaster University say current explanations are unsatisfactory.

“Psychological factors might be important, but are unconvincing as the primary or major cause.

“There might, for instance, be an increased incidence of physical and sexual abuse in childhood in those who go on to manifest functional disorders. It is easy to see how this could influence symptoms in adults but it stretches credulity to imagine abuse as the sole and sufficient cause of the functional disorder.”

It is already well known that women are more at increased risk of autoimmune disease especially ones in which antibodies to the body’s own cells are thought to play a role, like thyroid disease, pernicious anemia and myasthenia gravis.

The researchers said: “The female to male ratio in these conditions is of the order of 10. The female excess in Irritable Bowel Syndrome, Chronic Fatigue Syndrome and Anorexia Nervosa is equally extreme and therefore this fits with the idea that auto-antibodies to nerve cells could be part of the pathogenesis of these conditions.”

The formation of auto-antibodies is found mostly among women and increases with age, which could be why these disorders are more common in midlife. Even with anorexia, which reaches a peak at the age of 30, auto-antibodies have been found in the bodies of patients.

There are also links with infection in that the onset of IBS commonly follows an episode of infectious diarrhea while chronic fatigue syndrome can be triggered by infectious mononucleosis and viral hepatitis.

Even anorexia could be influenced by secretions from bacteria affecting the brain, triggering the production of antibodies which affect mood and motivation.

“Auto-antibodies acting on the (brain’s) limbic system could induce extremes of emotion including disgust and fear. These then become linked, in the minds of adolescent girls, to culturally determined ideas of what is, and what is not, the ideal body shape and size. It is then a small step for disgust and fear to be directed to food and obesity which the fashion industry currently demonizes.”

If their idea is proven, the researchers suggest that these disorders may be amenable to treatment using pooled immunoglobulin from the blood of healthy people, especially in severe cases of anorexia where life is threatened. It should also be possible to identify and eliminate from the gut the bacteria which are triggering auto-antibodies.

Journal Reference: J.A. Morris, S.J. Broughton, Q. Wessels. Microbes, molecular mimicry and molecules of mood and motivation. Medical Hypotheses, 2016; 87: 40 DOI:10.1016/j.mehy.2015.12.011

 

Source: Lancaster University. “Do anorexia, irritable bowel syndrome, chronic fatigues share a common cause?.” ScienceDaily. ScienceDaily, 25 April 2016. https://www.sciencedaily.com/releases/2016/04/160425100204.htm

 

Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies

Abstract:

BACKGROUND: Fibromyalgia often coexists and overlaps with other syndromes such as chronic fatigue, irritable bowel syndrome, and interstitial cystitis. Chronic stress has been implicated in the pathogenesis of these illnesses. The sympathetic nervous system is a key element of the stress response system. Sympathetic dysfunction has been reported in these syndromes, raising the possibility that such dysautonomia could be their common clustering underlying pathogenesis.

OBJECTIVE: The objective of this study was to carry out a review of all published comparative case-control studies investigating sympathetic nervous system performance in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis.

METHODS: Online databases PubMed and EMBASE were accessed using the following key words: autonomic (OR) sympathetic (AND) fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis. All entries up to December 10th 2012 were reviewed by 2 independent investigators searching for case-control studies in humans. The Method for Evaluating Research and Guidelines Evidence adapted to the Scottish Intercollegiate Guidelines Network was used to rank the level of evidence contained in the selected articles.

RESULTS: A total of 196 articles are included in this review. The most often used methods to assess sympathetic functionality were heart rate variability analysis, sympathetic skin response, tilt table testing, and genetic studies. The majority of studies (65%) described sympathetic nervous system predominance in these overlapping syndromes. In contrast, 7% of the studies found parasympathetic predominance.

CONCLUSIONS: This review demonstrates that sympathetic nervous system predominance is common in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis. This concordance raises the possibility that sympathetic dysfunction could be their common underlying pathogenesis that brings on overlapping clinical features. The recognition of sympathetic predominance in these 4 syndromes may have potential clinical implications. It may be worth exploring the use of nonpharmacological measures as well as drug therapies aimed to regain autonomic balance.

 

Source: Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014 Apr;20(3):146-50. doi: 10.1097/RHU.0000000000000089. https://www.ncbi.nlm.nih.gov/pubmed/24662556

 

Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is accompanied by a) systemic IgA/IgM responses against the lipopolysaccharides (LPS) of commensal bacteria; b) inflammation, e.g. increased plasma interleukin-(IL)1 and tumor necrosis factor (TNF)α; and c) activation of cell-mediated immunity (CMI), as demonstrated by increased neopterin.

METHODS: To study the relationships between the IgA/IgM responses to the LPS of microbiota, inflammation, CMI and the symptoms of ME/CFS we measured the IgA/IgM responses to the LPS of 6 different enterobacteria, serum IL-1, TNFα, neopterin, and elastase in 128 patients with ME/CFS and chronic fatigue (CF). Severity of symptoms was assessed by the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in CF patients. There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.

CONCLUSIONS: The findings show that increased IgA responses to commensal bacteria in ME/CFS are associated with inflammation and CMI activation, which are associated with symptom severity. It is concluded that increased translocation of commensal bacteria may be responsible for the disease activity in some ME/CFS patients.

Copyright © 2011 Elsevier B.V. All rights reserved.

 

Source: Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012 Feb;136(3):909-17. doi: 10.1016/j.jad.2011.09.010. Epub 2011 Oct 2. https://www.ncbi.nlm.nih.gov/pubmed/21967891

 

Somatic comorbidities in irritable bowel syndrome: fibromyalgia, chronic fatigue syndrome, and interstitial cystitis

Abstract:

Fibromyalgia, chronic fatigue syndrome, and interstitial cystitis frequently overlap with irritable bowel syndrome (IBS). There is a positive correlation between the incidence of these comorbidities and increased health care seeking, reduction in quality of life, and higher levels of mood disorders, which raises the question of a common underlying pathophysiology. A possible central hypersensitization disorder seems to be particularly involved in the dysfunction of bidirectional neural pathways and viscerovisceral cross-interactions within the CNS, thus explaining these many extraintestinal manifestations in IBS.

 

Source: Mathieu N.Somatic comorbidities in irritable bowel syndrome: fibromyalgia, chronic fatigue syndrome, and interstitial cystitis. Gastroenterol Clin Biol. 2009 Feb;33 Suppl 1:S17-25. doi: 10.1016/S0399-8320(09)71521-0. [Article in French] https://www.ncbi.nlm.nih.gov/pubmed/19303534

http://www.em-consulte.com/article/206075/alertePM (Full article)

Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study in primary care

Abstract:

BACKGROUND: Fatigue syndromes and irritable bowel syndrome (IBS) often occur together. Explanations include being different manifestations of the same condition and simply sharing some symptoms.

METHOD: A matched case-control study in UK primary care, using data collected prospectively in the General Practice Research Database (GPRD). The main outcome measures were: health-care utilization, specific symptoms and diagnoses. Risk markers were divided into distant (from 3 years to 1 year before diagnosis) and recent (1 year before diagnosis).

RESULTS: A total of 4388 patients with any fatigue syndrome were matched to two groups of patients: those attending for IBS and those attending for another reason. Infections were specific risk markers for both syndromes, with viral infections being a risk marker for a fatigue syndrome [odds ratios (ORs) 2.3-6.3], with a higher risk closer to onset, and gastroenteritis a risk for IBS (OR 1.47, compared to a fatigue syndrome). Chronic fatigue syndrome (CFS) shared more distant risk markers with IBS than other fatigue syndromes, particularly other symptom-based disorders (OR 3.8) and depressive disorders (OR 2.3), but depressive disorders were a greater risk for CFS than IBS (OR 2.4). Viral infections were more of a recent risk marker for CFS compared to IBS (OR 2.8), with gastroenteritis a greater risk for IBS (OR 2.4).

CONCLUSIONS: Both fatigue and irritable bowel syndromes share predisposing risk markers, but triggering risk markers differ. Fatigue syndromes are heterogeneous, with CFS sharing predisposing risks with IBS, suggesting a common predisposing pathophysiology.

 

Source: Hamilton WT, Gallagher AM, Thomas JM, White PD. Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study in primary care. Psychol Med. 2009 Nov;39(11):1913-21. doi: 10.1017/S0033291709005601. Epub 2009 Apr 15. https://www.ncbi.nlm.nih.gov/pubmed/19366500

 

General practitioners’ perceptions of chronic fatigue syndrome and beliefs about its management, compared with irritable bowel syndrome: qualitative study

Abstract:

OBJECTIVES: To compare general practitioners’ perceptions of chronic fatigue syndrome and irritable bowel syndrome and to consider the implications of their perceptions for treatment.

DESIGN: Qualitative analysis of transcripts of group discussions.

PARTICIPANTS AND SETTING: A randomly selected sample of 46 general practitioners in England.

RESULTS: The participants tended to stereotype patients with chronic fatigue syndrome as having certain undesirable traits. This stereotyping was due to the lack of a precise bodily location; the reclassification of the syndrome over time; transgression of social roles, with patients seen as failing to conform to the work ethic and “sick role” and conflict between doctor and patient over causes and management. These factors led to difficulties for many general practitioners in managing patients with chronic fatigue syndrome. For both conditions many participants would not consider referral for mental health interventions, even though the doctors recognised social and psychological factors, because they were not familiar with the interventions or thought them unavailable or unnecessary.

CONCLUSIONS: Barriers to the effective clinical management of patients with irritable bowel syndrome and chronic fatigue syndrome are partly due to doctors’ beliefs, which result in negative stereotyping of patients with chronic fatigue syndrome and the use of management strategies for both syndromes that may not take into account the best available evidence.

Comment in: Patient organisations in ME and CFS seek only understanding. [BMJ. 2004]

 

Source: Raine R, Carter S, Sensky T, Black N. General practitioners’ perceptions of chronic fatigue syndrome and beliefs about its management, compared with irritable bowel syndrome: qualitative study. BMJ. 2004 Jun 5;328(7452):1354-7. Epub 2004 May 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC420289/ (Full article)

 

Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review

Abstract:

OBJECTIVE: Our objective was to review and compare, with meta-analytic methods, observational studies on the association of medically unexplained physical symptoms, anxiety, and depression with special emphasis on healthy and organically ill control groups and on different types of symptoms, measures, and illness behavior.

METHODS: A search of MEDLINE and PsycLIT/PsycINFO for abstracts from 1980 to April 2001 was performed; principal investigators in the field were contacted and article reference lists were used to retrieve additional relevant articles. Two hundred forty-four studies were included on the basis of consensus ratings if they fulfilled seven of eight inclusion criteria pertaining to diagnostic accuracy and statistical appropriateness. Five hundred twenty-two studies were deferred or excluded. We focused specifically on the four functional somatic syndromes for which there were sufficient numbers for meta-analytic integration: irritable bowel syndrome (IBS), nonulcer dyspepsia (NUD), fibromyalgia (FM), and chronic fatigue syndrome (CFS). Data were extracted independently by two authors according to a prespecified coding manual with up to 70 parameters per study.

RESULTS: Effect sizes for the association of the four functional somatic syndromes with depression and anxiety were of moderate magnitude but were highly significant statistically when compared with healthy persons and controls with medical disorders of known organic pathology. Moreover, this association was significant whether depression was measured with or without somatic items. Chronic fatigue syndrome is characterized by higher scores of depression, fibromyalgia by lower scores of anxiety than irritable bowel syndrome. Consulting behavior and severity of somatization is related to higher levels of anxiety and depression.

CONCLUSIONS: Meta-analytic integration confirms that the four functional somatic syndromes (IBS, NUD, FM, CFS) are related to (but not fully dependent on) depression and anxiety. At present, there is only limited meta-analytic evidence for the same sort of association for medically unexplained physical symptoms in general. In view of the relative independence from depression and anxiety, classification and treatment of these symptoms and syndromes as “common mental disorders” does not seem fully appropriate.

 

Source: Henningsen P, Zimmermann T, Sattel H. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003 Jul-Aug;65(4):528-33. http://www.ncbi.nlm.nih.gov/pubmed/12883101

 

Chronic diffuse musculoskeletal pain, fibromyalgia and co-morbid unexplained clinical conditions

Abstract:

This chapter reviews our current knowledge on the presence of overlapping syndromes in one form of chronic diffuse pain, fibromyalgia. Patients with fibromyalgia often present with signs and symptoms of other unexplained clinical conditions, including chronic fatigue syndrome, irritable bowel syndrome, temporomandibular disorders, and multiple chemical sensitivities. The high prevalence, impact on function and opportunities for treatment underscore the need for clinicians and researchers to screen routinely for co-morbid unexplained clinical conditions among persons with fibromyalgia. We, therefore, describe a simple approach to screening for such conditions in accordance with published criteria. Interventions should directly address both fibromyalgia symptoms and co-morbid unexplained clinical conditions, as well as the multiple factors that propagate pain, fatigue and limitations in function.

 

Source: Aaron LA, Buchwald D. Chronic diffuse musculoskeletal pain, fibromyalgia and co-morbid unexplained clinical conditions. Best Pract Res Clin Rheumatol. 2003 Aug;17(4):563-74. http://www.ncbi.nlm.nih.gov/pubmed/12849712