CFS & gut function (dysbiosis, leaky gut & inflammation)

A role for general gut dysfunction in the CFS pathophysiology is steadily increasing (for review see [1]). Changes reported in the gut in CFS include those relating digestive function, microbial balance, gut-barrier function and general inflammation.

Dysbiosis

Various studies have shown changes to the gut microbiota in CFS, such as lowered levels of healthful probiotics (e.g. bifidobacteria & e.coli) and increased growth of potentially pathogenic organisms (e.g. aerobic bacteria) [1-3]. Furthermore, overgrowth of certain anaerobic bacteria (e.g. streptococcus, enterococcus & prevotella) may also be a major part of the CFS pathophysiology [2-5]. These bacteria may produce large amounts of toxic substances such as D-lactate, which can then be absorbed through the cells in the intestine. D-lactate (not to be confused with endogenously produced L-lactate) cannot be efficiently metabolised in humans and may produce symptoms of lactate acidosis, which includes neurological complaints. Overgrowth of these bacteria was also associated with high H2S (hydrogen sulphide) levels in CFS [5], although this could be of endogenous metabolic origin. H2S is toxic through suppression of aerobic energy metabolism, and has a vasodilative effect on the circulatory system. For more information on H2S and D-lactate production see my H2S and Lactate posts.

Some of the bacterial overgrowth seen in CFS may be quite similar to the well-recognised medical condition SIBO (small intestine bacterial overgrowth), so research relating to the pathogenesis and treatment of this condition may also be relevant to CFS. Research suggests high risk factors for developing SIBO include hypochloridia (low stomach acid), immunodeficiency, poor motility/peristalsis and morphological/anatomical changes amongst other factors [6]. Treatments for SIBO include antibiotics and natural antimicrobials such as peppermint oil [7,8]; other plant 'essential oils' with antimicrobial activity may also have therapeutic potential. With regards to CFS, a couple of studies have shown some significant benefit of probiotic supplementation on neurocognitive function and mood in CFS [9,10].

Leaky gut

There is consistent evidence for leaky gut and LPS (lipopolysaccharide)-induced immune activation in CFS [5,11-14]; related treatment has been associated with significant improvement and even remission in some cases. In particular research by Maes et al. has implicated translocation of gram-negative bacteria (as detected via serum IgA and IgM) and subsequent gut-derived systemic inflammation in CFS [12-14]. These findings corroborate with other studies documenting increased basal expression of inflammatory pathways in CFS such as iNOS, COX2, NF-kB and several inflammatory cytokines [1,15-20]. Treatment of leaky gut with various NAIOs (e.g. glutamine, NAC, zinc, curcumin etc) and a ‘leaky gut diet’ is associated with normalisation of serum antibody responses to gram-negative bacteria and correlating symptom improvement in CFS [13].

References

[1]         S.E. Lakhan, A. Kirchgessner, Gut inflammation in chronic fatigue syndrome., Nutrition & Metabolism. 7 (2010) 79.

[2]         A.C. Logan, A. Venket Rao, D. Irani, Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value., Medical Hypotheses. 60 (2003) 915-23.

[3]         J.R. Sheedy, R.E.H. Wettenhall, D. Scanlon, P.R. Gooley, D.P. Lewis, N. McGregor, et al., Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome., In Vivo (Athens, Greece). 23 (2009) 621-8.

[4]         M.D. Lemle, Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism., Medical Hypotheses. 72 (2009) 108-9.

[5]         K. De Meirleir, C. Roelant, M. Fremont, Research on Extremely Disabled M.E. Patients Reveals the True Nature of the Disorder., (2009).

[6]         J. Bures, J. Cyrany, D. Kohoutova, M. Förstl, S. Rejchrt, J. Kvetina, et al., Small intestinal bacterial overgrowth syndrome., World Journal of Gastroenterology : WJG. 16 (2010) 2978-90.

[7]         A.R. Gaby, Treatment with enteric-coated peppermint oil reduced small-intestinal bacterial overgrowth in a patient with irritable bowel syndrome., Alternative Medicine Review : A Journal of Clinical Therapeutic. 8 (2003) 3; author reply 4-5.

[8]         G. Cappello, M. Spezzaferro, L. Grossi, L. Manzoli, L. Marzio, Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial., Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 39 (2007) 530-6.

[9]         A.V. Rao, A.C. Bested, T.M. Beaulne, M.A. Katzman, C. Iorio, J.M. Berardi, et al., A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome., Gut Pathogens. 1 (2009) 6.

[10]      A. Sullivan, C.E. Nord, B. Evengård, Effect of supplement with lactic-acid producing bacteria on fatigue and physical activity in patients with chronic fatigue syndrome., Nutrition Journal. 8 (2009) 4.

[11]      M. Maes, F. Coucke, J.-C. Leunis, 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 (2007) 739-44.

[12]      M. Maes, I. Mihaylova, J.-C. Leunis, 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 (2007) 237-40.

[13]      M. Maes, J.-C. Leunis, 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 (2008) 902-10.

[14]      M. Maes, F.N.M. Twisk, M. Kubera, K. Ringel, J.-C. Leunis, M. Geffard, 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. (2011).

[15]      M. Maes, I. Mihaylova, E. Bosmans, 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., Neuro Endocrinology Letters. 28 (2007) 456-62.

[16]      M. Maes, I. Mihaylova, M. Kubera, E. Bosmans, Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome., Neuro Endocrinology Letters. 28 (2007) 463-9.

[17]      P. Scully, D.P. McKernan, J. Keohane, D. Groeger, F. Shanahan, T.G. Dinan, et al., Plasma cytokine profiles in females with irritable bowel syndrome and extra-intestinal co-morbidity., The American Journal of Gastroenterology. 105 (2010) 2235-43.

[18]      N. Carlo-Stella, C. Badulli, A. De Silvestri, L. Bazzichi, M. Martinetti, L. Lorusso, et al., A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles., Clinical and Experimental Rheumatology. 24 (2006) 179-82.

[19]      V.A. Spence, G. Kennedy, J.J.F. Belch, A. Hill, F. Khan, Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome., Clinical Science (London, England : 1979). 114 (2008) 561-6.

[20]      M. Maes, F.N.M. Twisk, M. Kubera, K. Ringel, 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., Journal of Affective Disorders. (2011).