Tuesday, 28 May 2013

The gut in CFS - dysbiosis, infection & translocation

A role for the gut in the pathophysiology of ME/CFS is initially implied by the prevalence of IBS-like symptoms experienced by patients 1–3. Consistent with this biological findings describing gut dysfunction are steadily increasing 1. Changes which may occur in the gut in ME/CFS include altered digestive function, microbial balance, gut barrier function and immuno-inflammatory activity. Furthermore, altered gut function is increasingly being linked to systemic biological changes and core ME/CFS symptoms. Major findings will be briefly reviewed below.

Welcome to the gut
The gut is a large organ endowed with the primary function of nutrient-waste exchange. Anatomically the gut represents a major host-environment interface immediately withheld by the gut barrier, a single layer of epithelial cells and the mucus that coats them. Below this barrier lies the largest reservoir of immune tissue in the body, the gut associated lymphoid tissue (GALT). The gut is further enwrapped in nervous tissue which makes up the enteric nervous system (ENS). This immune and neurological tissue in the gut serves to maintain functional homeostasis and protect from environmental threats. Also crucial to an appreciation of the gut is the vast microbial community which lies within it, collectively known as the gut microbiota or gut microbiome. These microbes have coevolved with us and now perform a myriad of functions mostly of benefit to the host. Gut bacteria digest food, maintain barrier integrity, protect against pathogens and modulate immune function.

The functioning of these various systems and processes is altered in primary intestinal disorders such as celiac disease, IBD and IBS. In addition other extra-intestinal conditions, which often feature inflammatory components and high comorbidity, are also increasingly being associated with altered gut function. One such condition is CFS.

Gut microbiology in CFS
A small number of studies have looked at gut bacteria levels in CFS and several notable findings have emerged. Early studies by Butt et al. reported that levels of Bifidobacteria and (non-pathogenic) E.coli are lowered in CFS and patients with persistent fatigue; while there was an overabundance of Prevotella and Enterococcus. Overabundance of aerobic Enterococcus in particular associated with various neurological symptoms 1,2. Similarly a later study reported that Streptococcus and Enterococcus are increased in CFS 4 and also associated with various symptoms 5. It was considered these bacteria may produce increased amounts of toxic substances such as D-lactate and hydrogen sulphide (H2S) 4,5. Small intestinal bacterial overgrowth (SIBO) was also found to occur in the majority of CFS patients, and its eradication associated with symptom improvement 2. Notably SIBO is often a consequence hypochlorhydria (low stomach acid) 6 which may also occur in CFS.

In addition to shifts in bacterial balance in the gut, chronic viral infections have also been reported in CFS. Increased incidence of Parvovirus B19 infection was found in the gastric and intestinal mucosa of CFS patients 7. Chronic enterovirus infection has also been reported in CFS 8 and may occur at illness onset 9. Interestingly a small study recently found that human endogenous retrovirus (HERV) expression was increased in duodenal biopsies of 8/12 CFS patients 10. HERV expression was localised to putative plasmacytoid dendritic cells (pDCs); these are antigen presenting cells which initiate and determine the polarity of immune activity in response to gut antigen/bacteria.

In light of early studies finding changes to the gut microbiota associate with symptoms in CFS Logan et al. suggested lactic acid bacteria (LAB) probiotics may be of therapeutic value 2. Since then a few studies have trialled probiotic supplementation in CFS patients. One small unblinded study reported that supplementation with a three-strain LAB probiotic improved neurocognitive function 11. Another study found that supplementation with lactobacillus casei shirota led to significant increases in fecal lactobacillus and bifidobacteria, and decreased anxiety symptoms 12. Most recently an unpublished double-blind pilot study found that treatment with bifidobacteria infantis 35624 lowered blood pro-inflammatory cytokines (i.e. TNFα and IL6) and C-reactive protein (CRP) levels 13.

The gut barrier in CFS
Recent research suggests the gut barrier is compromised in CFS. Increased intestinal permeability to bacteria is implied by increased blood levels of lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria which elicits strong immune responses. Initial findings by Maes et al. reported that CFS is accompanied by immune responses (serum IgA and IgM) to the LPS of enterobacteria, implicating a state of increased intestinal permeability. These findings correlated with various symptoms and especially heavily with irritable bowel symptoms 14. Another group also found that CFS severity correlated with serum LPS levels 5. Further studies have reported that bacterial translocation in CFS correlates markers of systemic inflammation and immune activation (i.e. IL1, TNFα, neopterin and elastase) 15, and auto-immune responses to serotonin 16.

Treatment of leaky gut with various supplements (e.g. glutamine, zinc, NAC and curcumin) and a leaky gut diet (i.e. gluten/casein-free and low-carb) is associated with normalisation of serum antibody responses to gram-negative bacteria and correlating symptom improvement in CFS 17. Such treatment was reported to induce remission in one case 18.

Summary
Several studies now suggest the gut is altered in CFS and changes may correlate systemic disease activity and symptoms. Dysbiosis and infections may be expected to disrupt gut barrier function, promote local inflammation and alter systemic immune function 1. Bacterial translocation occurs in a large subset of CFS patients and correlates particularly strongly with irritable bowel symptoms 14,15. Furthermore bacterial translocation has been linked to other key systemic elements of CFS pathophysiology such as inflammation and auto-immunity, consistent with these process being driven in part by bacterial translocation 15,16. Taken together it seems likely that changes in the gut play a major role in the pathogenesis of ME/CFS for at least a large subset of patients.

References
1.         Lakhan, S. E. & Kirchgessner, A. Gut inflammation in chronic fatigue syndrome. Nutrition & metabolism 7, 79 (2010).
2.         Logan, A. C., Venket Rao, A. & Irani, D. Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value. Medical hypotheses 60, 915–23 (2003).
3.         Carruthers, B. M. et al. Myalgic encephalomyelitis: International Consensus Criteria. Journal of internal medicine 270, 327–38 (2011).
4.         Sheedy, J. R. et al. Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome. In vivo (Athens, Greece) 23, 621–8 (2009).
5.         De Meirleir, K., Roelant, C. & Fremont, M. Research on Extremely Disabled M.E. Patients Reveals the True Nature of the Disorder. (2009).at
6.         Bures, J. et al. Small intestinal bacterial overgrowth syndrome. World journal of gastroenterology : WJG 16, 2978–90 (2010).
7.         Frémont, M., Metzger, K., Rady, H., Hulstaert, J. & De Meirleir, K. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In vivo (Athens, Greece) 23, 209–13 (2009).
8.         Chia, J. K. S. & Chia, A. Y. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. Journal of clinical pathology 61, 43–8 (2008).
9.         Chia, J., Chia, A., Voeller, M., Lee, T. & Chang, R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. Journal of clinical pathology 63, 165–8 (2010).
10.       DE Meirleir, K. L. et al. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In vivo (Athens, Greece) 27, 177–87 (2013).
11.       Sullivan, A., Nord, C. E. & Evengård, B. Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome. Nutrition journal 8, 4 (2009).
12.       Rao, A. V. et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut pathogens 1, 6 (2009).
13.       Quigley, E. M. M. et al. Oral Administration of the Probiotic Bifidobacterium Infantis 35624 to Humans Induces Immunoregulatory Responses In Vivo. (2011).at
14.       Maes, M., Mihaylova, I. & Leunis, J.-C. 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. Journal of affective disorders 99, 237–40 (2007).
15.       Maes, M. 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. Journal of affective disorders 136, 909–17 (2012).
16.       Maes, M. et al. In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. Journal of affective disorders (2013).doi:10.1016/j.jad.2013.03.029
17.       Maes, M. & Leunis, J.-C. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro endocrinology letters 29, 902–10 (2008).
18.       Maes, M., Coucke, F. & Leunis, J.-C. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuro endocrinology letters 28, 739–44 (2007).

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