Research clearly suggests that digestive health in chronic fatigue syndrome is compromised, at least in a subset of patients. This is not surprising when we appreciate that chronic fatigue syndrome is not a single disease entity. The below two quotes provide a clear indication of the frequency of gastrointestinal imbalances in CFS patients:
There is a remarkably high frequency of IBS among chronic fatigue syndrome patients estimated at ninety-two percent (Aaron et al., 2000 cited in Fremont et al., 2013).
Evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in chronic fatigue syndrome
Research clearly shows that a subset of individuals with chronic fatigue syndrome have altered intestinal microbiota (dysbiosis), mucosal barrier dysfunction (leaky gut), and disturbed intestinal immunity.
Therefore, therapeutic efforts to modify the gut microbiome could be a means to modulate the development and/or progression of this disorder.
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
Let’s have a look at some of the research.
Dysbiosis & Chronic Fatigue Syndrome
In a study (Fremont et al., 2013) investigating differences in the microbiome of Norwegian and Belgian CFS patients compared to controls a difference of statistical significance was detected between Norwegian cases and controls but not of Belgians. These differences aren’t too surprising however. We cannot expect to find a biomarker that is going to hold true in all cases.
Dietary habits and genetic individuality are just two of the numerous factors that can help explain the individuality seen in research investigating the microbiome. One of the limitations in this study is that no causal relationship can be made. It is impossible to say whether changes in the microbiome are causes or consequences of CFS. Based on our understanding that the immune system has a role to play in regulating the microbiome, it could be the immune dysregulation detected in CFS is causing dysbiosis. Longitudinal studies investigating changes of the microbiome over an extended period, ideally with changes in the severity of symptoms during this time, and, with good baseline data, may help further our understanding.
A randomized, double-blind, placebo-controlled intervention may give us the greatest insight in to causality. Groeger et al. (2013) investigated the benefit of supplementing with the probiotic B. infantis 35624 for six to eight weeks on inflammatory markers. Inflammation reduced in CFS patients supplementing the probiotic.
Most importantly, all three inflammatory biomarkers were significantly elevated compared to controls at the beginning of the trial.
There are limitations to this study however including the sample size being low (forty-eight cases and thirty-five controls). While the numbers included were adequate to show statistical significance, larger sample sizes are needed to validate clinical efficacy. Also, only one dose of the probiotic was used within the trial and as a result no dose-dependent effect of the probiotic can be investigated. Future research building on this study is required.
It’s important to appreciate the complexity of how the gut microbiome is regulated though:
The microbiota of the human gastro-intestinal (GI) tract inhabits a complex ecosystem. Factors such as pH, peristalsis, nutrient availability, oxidation–reduction potential within the tissue, age of host, host health, bacterial adhesion, bacterial co-operation, mucin secretions containing Igs, bacterial antagonism and transit time influence the numbers and diversity of bacteria present in the different regions of the GI tract
In another study (Sheedy et al., 2009) a significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients was found compared to 177 control subjects. Some of the symptoms in CFS are strikingly similar to those of patients presented with D-lactic acidosis. D-lactic acidosis is a metabolic condition that originates from the bacterial fermentation of carbohydrates by gastrointestinal (GI) bacteria. These include Enterococcus and Streptococcus spp as well as Lactobacillus and Bifidobacterium which also produce ethanol and carbon monoxide.
This study showed that there was an overall increase of aerobic Gram positive intestinal bacteria particularly those of the Enterococcus and Streptococcus spp.
High count of lactic acid bacteria in the gastrointestinal tract may lower intestinal pH levels resulting intestinal permeability, and may perpetuate an increased absorption of microbial exometabolites such as D-lactic acid which may result in pathophysiological cognitive and neurological responses in CFS patients as reported in patients with D-lactic acidosis.
This suggests that when Enterococcus and Streptococcus spp. colonization in the intestinal tract is increased, the heightened intestinal permeability caused by increased lactic acid production may facilitate higher absorption of D-lactic acid into the bloodstream, henceforth perpetuating the symptoms of D-lactic acidosis. Increased intestinal permeability is also associated with endotoxin release from Gram negative enterobacteria, leading to inflammation, immune activation and oxidative stress, which are cardinal features in a large subset of CFS patients
Based on the findings described in this study, the authors concluded that “existing therapeutic tools such as short courses of an appropriate antibiotic, alkalinizing agents, a low carbohydrate diet and the restriction of glucose intake could become part of the therapy of CFS patients who suffer from D-lactic acidosis”.
The colon is protected from large influxes of carbohydrate, being regulated by gastric emptying and effective small intestinal digestion and absorption. Based on a large subset of patients with CFS having small intestine bacterial overgrowth, low pancreatic elastase 1 (a marker of pancreatic function and thus digestive ability), it would seem that larger than normal influxes of carbohydrate in to the large intestine may be common.
Carbohydrates reach the colon in an undigested form. Colonic bacteria ferment the carbohydrate, producing organic acids that lower the intestinal pH. This acidic environment favors the suppression of normal gut microflora and allows for the overgrowth of acid-resistance flora. Lactobacillus contains an enzyme that produces D-lactate.
As you can see, or will see if you read my articles on SIBO, this concept clearly ties in with SIBO (which may case suboptimal digestion of food for example). Also we at Conquering Fatigue frequently see clients stool/breath results showing these imbalances (small intestine bacterial overgrowth and dysbiosis in the large intestine).
Leaky Gut & Chronic Fatigue Syndrome
Bifidobacteria species can contribute to maintaining intestinal epithelial integrity
It should come as no suprise, based on the above findings, that leaky gut has been associated with CFS and resolution of the leaky gut has coincided with resolution of symptoms.
Normally, the gut lining acts as a barrier to avoid bacteria and other products from translocating in to circulation where they can trigger immune activity and inflammation. Chronic stress, a poor diet, antibiotics, hypothyroidism, among other factors, are all potentially able to contribute to a leaky gut.
Thus, mucosal barrier function is a key component in the arsenal of defense mechanisms required to prevent infection and inflammation.
Maes and Leunis (2008) investigated forty-one patients with CFS who had serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria (breakdown products from certain bacteria). The participants were placed on a ‘leaky gut diet’ and were supplemented with glutamine, N-acetyl cysteine and zinc, for ten to fourteen months. The authors concluded that:
In this study we report that the normalization of the increased LPS translocation during treatment with specific NAIOSs and the leaky gut diet is accompanied by a clinical improvement or remission of CFS. The results of the present support the view that leaky gut is a novel pathway in CFS
In an interesting case report (Maes et al., 2007) a thirteen-year-old girl experienced remission of her CFS with normalisation of intestinal permeability and oxidative stress pathways. However we can’t say with absolute certainty that the CFS was caused by the increased translocation of bacteria and reactive oxygen species production. The nutritional and lifestyle interventions recommended which included:
- Antioxidants – L-carnitine, CoQ10, lipoic acid, taurine
- Gut lining support -L-glutamine, gamma oryzanol, and zinc
- A leaky gut diet – low carb, gluten and dairy free
- Intravenous immunoglobulins – 6g/day during 1 month, and thereafter 6 g each two weeks for the following months.
The authors concluded that:
the normalisation of the increased translocation of gram-negative enterobacteria – obtained with a specific diet, specific antioxidants and IVIg – is accompanied by an attenuation or normalization of IRS activation and O&NS and by a clinical remission
Additionally, studies have shown certain Bifidobacteria species to have a significant impact on functional improvements in NK cell activity and to lower levels of IL-4, IL-5 and IL-10 cytokines. These effects support the presence of Th1 directed cell-mediated immunity (see our article entitled is CFS – Th2 dominant condition – click here)
Gut Infections & Chronic Fatigue Syndrome
recent studies have suggested that infection with gut pathogens could be related to CFS onset
SIBO & Chronic Fatigue Syndrome
You may like to read our series of articles on small intestine bacterial overgrowth.
77% of CFS patients have been found to have small intestinal bacterial overgrowth [SIBO], which displays some similar clinical symptoms to CFS
In a double-blind randomised study (Pimental et al.) the authors concluded:
SIBO is associated with CFS and eradication of SIBO decreases symptoms.
Exercise & Digestive Health in Chronic Fatigue Syndrome
post-exertion worsening of chronic fatigue syndrome symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation….
While we need to be mindful this hypothesis comes from a study whereby patients had to perform maximum intensity exercise and therefore may not be relevant to all cases of symptom exacerbation through exercise, and had other limitations including a very small sample size, it does further the argument for gastrointestinal and immune involvement in chronic fatigue syndrome.
Interestingly, the dysbiosis reported in this study was consistent with the dysbiosis reported in patients with CFS in Norway and Belgium – changes in relative abundance of Firmicutes and Bacteroidetes.
The research presented on gastrointestinal disturbances in CFS does suggest that the frequent inflammatory and oxidative stress findings in CFS patients may be caused by these imbalances.
The Virome in Digestive Health
The virome evidently plays a powerful part within the microbiome
Yes as well as the bacteria, so frequently spoken about, we have the virome – the viral components of the microbiota which we know very little about. What we do know suggests they are an important aspect of the digestive environment and immune function though.
Gut Inflammation & Chronic Fatigue Syndrome
Based on all the above information it comes at no surprise that patients with both IBS and CFS were found to have, in addition to elevated IL-6 and IL-8, increased levels of two other pro-inflammatory cytokines, IL-1b and tumor necrosis factor (TNF)-a. Given that other studies have suggested a state of low-grade inflammation or immune activation in parts of the digestive tract, increased serum concentrations of cytokines have been interpreted as “evidence of spill-over from a primary focus in the gut”.
There is an excellent article from Medscape on gut inflammation and chronic fatigue syndrome that can be found here.
As mentioned in the article by Medscape:
People with CFS were shown to have higher concentrations of intestinal bacteria than normal, which probably leads to higher levels of H2S. Professor Kenny De Meirleir of the Brussels Free University and his team say high levels of H2S caused by an intestinal overgrowth of Gram positive D/L lactate-producing bacteria play a major role in CFS and lead to a series of reactions in your body that leave cells devoid of oxygen and energy.
Too much hydrogen sulphide, produced by the overgrowth of harmful, pathogenic bacteria causes the intestinal epithelial barrier to break down. Increased levels of bacterial hydrogen sulphide stimulate the production of destructive compounds called reactive oxygen species, which inhibit mitochondrial function directly (see our articles on glutathione and immune dysregulation)
The TLR4 Radical Cycle
activation of the TLR4 complex may underpin chronic inflammatory diseases
Pattern recognition receptors, such as toll-like receptors (TLRs – an example being TLR4), play a key role in the immune system. Immune responses are initiated when damage-associated molecular patterns (DAMPs – such as oxidises LDL) and pathogen-associated molecular patterns (PAMPs) are recognized by these pattern recognition receptors.
A classical PAMP that stimulates TLR4 is lipopolysaccharide (LPS) from gram-negative bacteria. Others include viruses and fungi.
Once TLR4 is activated an inflammatory response is initiated. This leads to enhanced amounts of reactive oxygen species (ROS) being produced. Inflammation and oxidative stress (elected levels of ROS) are frequently found in chronic fatigue syndrome.
This can become vicious cycle however whereby the oxidative stress feeds further inflammation and the inflammation creates further oxidative stress.
There is evidence showing that mucosal bacteria growing in biofilms on surfaces lining the gut differ from luminal populations, and that due to their proximity to the epithelial surface, these organisms may be important in modulating the host’s immune system and contributing to some chronic inflammatory diseases (MacFarlane et al., 2011)
In general, bacteria have two life forms during growth and proliferation. In one form, the bacteria exist as single, independent cells (planktonic) whereas in the other form, bacteria are organized into immobile mass. The latter form is commonly referred to as a biofilm. Acute infections are assumed to involve planktonic bacteria, which are generally treatable with antibiotics, although successful treatment depends on accurate and fast diagnosis.
However, in cases where the bacteria succeed in forming a biofilm within the human host, the infection often turns out to be untreatable and will develop into a chronic state. The important hallmarks of chronic biofilm-based infections are extreme resistance to antibiotics and many other conventional antimicrobial agents, and an extreme capacity for evading the host defences (Bjarnsholt, 2013).
This is why we sometimes recommend biofilm disruptors within our protocols.
Mindset And Digestive Health
“The literature suggests that early interdisciplinary diagnostic cooperation between gastroenterologists and body-‐mind therapists is necessary.”
The appreciation of the significance of the mind in IBS has led to the cognitive–behavioural model of IBS. This model proposes that gastrointestinal symptoms are affected and maintained by interactions between psychological (e.g. emotions, cognitions and behaviour), social (e.g. modelling, support) and physiological factors (e.g. cramps, bloating).
Within this model, the way in which the individual reacts cognitively to recurrent gastrointestinal symptoms (e.g. catastrophising, hyper-vigilance), and life events (e.g. relationship break-up), will in turn affect emotional responses (e.g. fear, anxiety, depression), the severity of gastrointestinal symptoms and coping ability.
Catastrophising: a term that refers to a bias towards prediction of a high likelihood of worst outcomes. This measure strongly correlates with the severity of pain symptoms and is a primary treatment target in Cognitive Behavioural Therapy.
Hyper-vigilance: the more attention we place on our gut health the more aware of it we are and, potentially, the worse it becomes.
How we at Conquering Fatigue Successfully Incorporate This Information In to Practice
a cycle of chronic intestinal dysfunction and instability of the microbiota certainly characterizes a subset of patients with CFS
Based on a the research and the above quotes, all from recently published papers on chronic fatigue syndrome, we perform functional lab tests on all our 1-2-1 clients to investigate digestive health. Used alongside the clients health history, family health history, previous experiences and current symptoms this allows us, as best we can, to create a personalised programme to help our clients achieve their goals. We frequently see dysbiosis (imbalances in bacterial populations), infections (parasitic, bacterial, viral), leaky gut and food sensitivities in our clients. While some of these can potentially be seen as consequences of other imbalances, it is our belief that these still need to be focused on within protocols to restore health and vitality to the individual.
As well as performing testing on our 1-2-1 clients we also go in to considerable detail on the topic of digestive health in our online educational programme (download our information pack for more details). We discuss how we can restore health to the digestive system via nutrition, lifestyle and supplement interventions.
This is a great short video (more suitable for fellow practitioners) on the mucosal immune system in the gut: video here.
One thing to appreciate I feel is that even today, due to the difficulty of obtaining samples from the different regions of the intestine, much of the work done in relation to the ecology and activity of bacteria within the GI tract is carried out using faecal samples. However, the faecal microbiota is not representative of that of the GI tract as a whole. Something to consider when interpreting results perhaps.