Gut Inflammation in Chronic Fatigue Syndrome

Shaheen E Lakhan; Annette Kirchgessner


Nutr Metab. 2010;7(1) 

In This Article

Cytokines and Inflammation

CFS is typically characterized by a chronic, low-grade inflammation. Although fatigue severity appears to correlate with inflammatory disease activity and is therefore consistent with an immunological model of CFS,[12] it is not known whether inflammation causes fatigue. Results from a population-based study indicate that people with CFS had increased markers of peripheral inflammation when compared to healthy controls, but had a similar inflammatory profile when compared to unhealthy subjects who did not meet the criteria for CFS.[56]

It is unlikely that CFS "causes" increased inflammation. Rather people with fatiguing conditions are likely to exhibit "unwellness" symptoms for a variety of reasons. One such reason may be an increase in peripheral pro-inflammatory signaling based on overwhelming evidence that pro-inflammatory cytokines are capable of inducing all the cardinal symptoms of CFS in humans.[57,58] Thus, factors that increase inflammation, such as stress and depression can increase peripheral inflammation, significantly increasing the risk in individuals with CFS of subsequently developing vascular disease, metabolic disease and dementia.

Several groups have reported evidence of chronic immune dysfunction in CFS although the exact nature of this dysfunction remains unclear. While initial studies generally suggested immunosuppression,[59] recent years have seen increased interest in the possibility that activation of the innate immune response might contribute to symptom development in CFS.[59,60] Studies have reported increased plasma concentration of the acute phase reactant c-reactive protein (CRP) in patients with CFS. Other findings include higher frequencies of various autoantibodies. A significant increase in the numbers of B cells with CD20+ CD5+ phenotype which is correlated with autoantibody production and with CD21 markers that is a ligand for retroviruses was also found in patients with CFS.[61]

CFS has a propensity to over-produce pro-inflammatory cytokines (e.g., TNF-α coupled with a decreased production of anti-inflammatory cytokines. A principal avenue of investigation has been the measurement in blood of immune signals conducted by cytokines. In animal studies, administration of pro-inflammatory cytokines (IL-1, TNF-α, and IL-6) directly into the brain can induce "sickness behaviors" that strongly resemble the symptoms of CFS. In particular, decreased motor activity, altered food and water intake, sleep and cognition have been linked to increases in the levels of IL-1b, IL-6 and TNF-α.[57] Furthermore, in humans, systemically administered pro-inflammatory cytokines, such as IL-6 and TNF-α typically induce a systemic inflammatory response where one of the major symptoms is intense fatigue.

The sensation of fatigue or exhaustion is prevalent in a number of infectious and chronic inflammatory disease states including IBD, systemic lupus erythematosus and ankylosing spondylitis.[62] In rheumatoid arthritis and IBD, in which TNF-α plays an integral role, fatigue is markedly improved by treatment with anti-TNF-α agents. Thus, amelioration of fatigue is mediated through an anti-inflammatory effect showing that the CNS is extremely susceptible to immunological reactions that occur during disease and injury.

The TNF-α inhibitors are a group of drugs that may provide benefit in CFS. One TNF-α inhibitor, etanercept, has been used with considerable benefit in the treatment of six patients with CFS in a pilot study.[63] Unfortunately, this trial was not published as a paper but only as a meeting abstract. The use of TNF-a inhibitors in CFS is strongly supported by data on the immune responses in CFS, and data from gene expression studies.[64,65] Thus, it is important to repeat this work and carry out a larger clinical trial of etanercept in patients with CFS.

On the basis of the results of gene expression studies, a clinical trial of IFN-β was proposed in CFS patients. IFN-β is associated with the regulation of humoral immune responses and immune responses against viral infections. IFN-β stimulates the activity of NK cells, which are considered to be inefficient in patients with CFS. It selectively inhibits the expression of some mitochondrial genes that are implicated by gene studies in patients with CFS.[65] Finally, IFN-β is a licensed treatment for multiple sclerosis, helping in reduction of fatigue. The pathogenesis of multiple sclerosis is also thought to be cytokine mediated, as has been shown in CFS.[65]

Broderick et al. recently demonstrated that CFS is associated with a profound imbalance in the regulation of immune function.[66] In this study, instead of analyzing immunological markers individually, network analysis was applied to study the co-expression of 16 cytokines in CFS subjects and healthy controls. Analysis showed consistent and significantly attenuated patterns of Th1 and Th17 immune responses in CFS in the context of a well-established Th2 inflammatory milieu. These patterns would have escaped detection had the analysis focused solely on differential expression of individual cytokines.

Interestingly, the cytokine co-expression patterns described in this study, were consistent with the disruptive effects of latent viral infection by pathogens such as EBV. Viral triggers such as EBV have long been suspected of involvement in the onset and persistence of CFS. However, this virus is not consistently detected in all patients.[25] While other causes may underlie the cytokine expression pattern observed in CFS patients many of these are at least consistent with some of the disruptive effects of chronic viral infection.


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