Gut Inflammation in Chronic Fatigue Syndrome

Shaheen E Lakhan; Annette Kirchgessner

Disclosures

Nutr Metab. 2010;7(1) 

In This Article

Abstract and Introduction

Abstract

Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood. Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis.
Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease. In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut.
If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder. For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.

Introduction

Chronic fatigue syndrome (CFS) is a clinical condition characterized by persistent and unexplained relapsing fatigue that is worsened by physical and mental exertion.[1,2] According to the Centers for Disease Control (CDC) report, the overall prevalence of CFS in the USA is as many as 4 million people.[3,4] Up to 80% of those affected are women.[5] These individuals suffer from severe fatigue that impairs daily activity, diminishes quality of life (QOL) for years, and has no known cure. CFS represents an economic burden for society and healthcare institutions.[6]

The CDC originally proposed the term CFS in 1988. In 1994, the International CFS Study Group published a revised and more inclusive case definition which defines CFS on the fulfillment of two major criteria: chronic fatigue of at least 6 months duration, which is accompanied by various rheumatologic, infectious and neuropsychiatric symptoms.[7] Although considerable progress has been made in recent years, a major gap in the knowledge of the pathogenesis of CFS remains and has precluded the discovery of effective forms of treatment. Moreover, the diagnosis of CFS is highly problematic since no biological markers specific to this disease have been identified. Thus, CFS is a diagnosis of exclusion.[7]

Along with disabling fatigue, CFS is characterized by neuropsychological disturbances such as headaches, myalgia, arthralgia, and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; un-refreshing sleep; and mood changes, such as depression and anxiety.[8] In addition, many CFS patients complain of gastrointestinal (GI) disturbances, including abdominal pain or discomfort and an alteration in bowel habit. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gastrointestinal tract, and experience IBS-related symptoms.[9] Although the precise pathophysiology of CFS is yet to be fully elucidated, the high frequency of co-morbidities in CFS suggests that the underlying pathophysiological mechanisms cannot be confined to an organ (e.g., the brain), but rather must involve an integrating system or mechanism such as the brain-gut axis and the autonomic nervous system.

There is a growing body of literature describing immune dysfunction in CFS.[10] A possible involvement of the immune system is supported by the observation that the onset of CFS is often preceded by virus infections and a "flu-like" illness. For example, infectious mononucleosis has been shown to be a risk factor for developing CFS.[11] Immune activation is also suggested by an elevation of pro-inflammatory cytokines, an increased expression of T lymphocyte activation markers, such as CD26 and CD38[12] and decreased function of natural killer (NK) cells (for review see [13]).

Both physical and psychological stressors have been found to activate the hypothalamic-pituitary-adrenal (HPA) axis, an important link between the brain and the immune system.[14] Corticotrophin-releasing hormone (CRH) produced in the hypothalamus, is the primary hypothalamic regulatory peptide of the HPA axis and its release has been shown to be controlled by circulating pro-inflammatory cytokines, especially interleukin (IL)-6.[15] Thus, the increase in pro-inflammatory cytokines seen in CFS patients may be involved in an exaggerated activation of the HPA axis.[14]

The frequent association between CFS and IBS could also be governed by elevated circulating pro-inflammatory cytokines acting either locally or on the brain-gut axis. Patients with IBS were shown to have increased plasma levels of IL-6 and IL-8.[16] Moreover, patients with both IBS and CFS were found to have, in addition, increased levels of two other pro-inflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α.[16] Given that other studies have shown a variety of findings (mast cell activation, increased lymphocytes) suggesting a state of low-grade inflammation or immune activation in the mucosa and lamina propria of the bowel,[17] increased serum concentrations of cytokines have been interpreted as evidence of spill-over from a primary focus in the gut. Thus, pro-inflammatory cytokines may be involved in the exaggerated activation of the HPA axis and thereby promote a coordinated central response to stress, such as GI inflammation and dysfunction.

There is now evidence that CFS is associated with marked alterations in the gut microbiota, with lower levels of Bifidobacteria and higher levels of aerobic bacteria.[18] Gut pathogens can communicate with the CNS and influence emotional behaviors such as anxiety and depression, even at extremely low levels and in the absence of an immune response.[19,20] In addition, probiotics or live microorganisms which confer a health benefit on the host, have the potential to decrease mood-regulating systemic pro-inflammatory cytokines, decrease oxidative stress and improve nutritional status when orally consumed (see below[18]). Probiotic lactic acid producing-bacteria have been shown to prevent and alleviate GI disturbances and to normalize the cytokine profile which might be of an advantage for patients suffering from CFS.[21]

In the case of CFS, evidence for a synergism between aberrant gut microbiota, mucosal barrier dysfunction, and altered mucosal immunity contributing to the disorder's pathogenesis has begun to evolve. Research shows that patients with CFS have alterations in gut microbiota.[22] Moreover, emerging studies have demonstrated that pathogenic and non-pathogenic gut microbiota may influence mood-related symptoms and even behavior in animals and humans. These findings lend further support to the presence of a gut-brain interface, one that may be modulated by gut microbiota.

Experimental data also show that inflammation, even if mild, can lead to persistent changes in GI nerve and smooth muscle function, resulting in dysmotility, hypersensitivity, and dysfunction. Furthermore, alterations in gut function are observed after the resolution of an acute intestinal inflammation.[23,24] The enteric nervous system (ENS), the intrinsic innervation of the bowel, controls virtually all GI functions (e.g., motility, secretion, blood flow, mucosal growth and aspects of the local immune system). Whether the persistent alterations in gut function observed in the majority of CFS patients are due to inflammation-related changes in the properties of enteric nerves is unknown.

This review will provide a brief overview of the current understanding of the role of gut inflammation in CFS. Despite advances in the understanding of the pathophysiology of CFS, therapeutic options for combating the symptoms of CFS are still not available.

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