Two medical practitioners/researchers, Dr. Bested and Alan Logan, with a long history of involvement in chronic fatigue syndrome (ME/CFS), have written a series of three review papers suggesting gut flora and gut issues impact the fatigue, pain and mood issues present in ME/CFS and fibromyalgia. In this blog we complete the review of those papers.
How important is the gut in ME/CFS/FM? Clinicians specializing in ME/CFS appear to think its very important – at least in a significant subset of patients. A recent Jason survey that combined frequency and severity symptom scores to get a single all encompassing symptom score found that gastrointestinal symptoms were in the second tier of symptoms; not as prominent as unrefreshing sleep or post-exertional malaise but occurring with a similar degree of frequency and severity to concentration problems and muscle pain, and more important than symptoms such as tender lymph nodes, dizziness and fever and chills.
Now for the overview of the review papers.
From Bottom Up to Top Down
By 1930, the authors indicated that the idea that gut issues could cause depression, fatigue and other problems was mostly dead, replaced by the notion that depression and anxiety were the source. Not for another seventy years, until Logan’s proposal in 2003 and 2005 that chronic fatigue syndrome and depression could be effected by gut flora and other gut issues was the idea of gut manipulation broached.
The authors propose gut caused inflammation may be play a key role in some fatigue, pain and mood disorders. The idea that inflammation may play an important role in these disorders is not new; the authors are simply proposing that the gut could be a prime source of that inflammation.
Studies involving the administration of small amounts of bacterial endotoxins, many of which can be formed in the gut, paved the way for the modern recognition that leakage of materials out of the gut into the bloodstream could have significant effects. Very low levels of toxins produced by Staphylococcus, for instance, have been shown to cause acute anxiety, depression, cognitive problems and increased pain.
Some toxin leakage across the intestinal walls may always be present, and healthy blood typically contains small amounts of bacterial endotoxins (lipopolysaccharides – LPS), but higher endotoxin levels are associated with increased cardiovascular risk and the development of diabetes. (Several cardiovascular risk factors are increased in ME/CFS as well). These endotoxins can trigger elevations of cytokines that are associated with ‘excitotoxic neuronal overstimulation’ which sounds very much like the glutamate imbalance Marco has been proposing in his neural inflammation blogs.
LPS-induced inflammation has been shown to increase the activity of a tryptophan-degrading enzyme that has been associated with depressive symptoms and indirectly, anxiety. LPS, in fact, doesn’t need to elevate cytokines to make an impact on the brain; simply by damaging the blood-brain barrier LPS have been shown to allow all manner of toxins and pathogens entry to the brain. (Dr. Mady Hornig suggested the blood-brain barrier may be impacted in ME/CFS). In fact, LPS can inhibit the process of removing neurotoxins from the brain and can potentiate future cytokine releases in reaction to stress.
Several studies by Maes suggest increased endotoxin levels are present in chronic fatigue syndrome and treatment protocols designed to reduce them can be helpful. Maes has also found increased endotoxin levels in depression and believes gut derived inflammation plays a role in both disorders. He describes a complete remission of chronic fatigue syndrome using antioxdants and a ‘leaky gut diet’ in a young girl with high levels of IgM antibodies against enterobacterial LPS in this case report.
Given that LPS are common in the gut, it’s perhaps not surprising that increased intestinal permeability is associated with fatiguing, pain producing and sometimes mood altering illnesses such as ME/CFS, fibromyalgia, complex regional pain syndrome, insulin resistance, autism and obesity.
Remarkably, and this is something we’re going to focus on later, studies have found that exercise can induce a small amount of gut dysfunction even in healthy people. Not surprisingly, given the predominance of females in most of these disorders, women are more prone to experience increased gut permeability after stress than men.
Small Intestine Bacterial Overgrowth (SIBO)
Small intestinal bacterial overgrowth (SIBO) is just what it says – higher than normal levels of bacteria in the small intestine. Low gastric (stomach) acid levels are found in depression and increase the risk for small intestinal bacterial overgrowth (SIBO). SIBO has been found in ME/CFS, FM, IBS, insulin resistance and a disease called erosive esophagitis (reflux disease). The authors suggested that depressed gastric reflux patients respond poorly to traditional remedies because their gastric reflux is driven by bacterial overgrowth in the intestines.
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SIBO, which may very well be common in ME/CFS/FM, can interfere with the absorption of proteins, fats, carbohydrates and nutrients, can produce toxic elements and can increase gut leakage. Small wonder, then that gut researchers assert SIBO is associated with fatigue and mood changes along the with diarrhea and bloating. But the authors noted that the body-mind connection goes both ways; stress has been found to encourage the overgrowth of bad bacteria and increase intestinal wall permeability as well.
(A small 2008 study found of SIBO was present in about 30% of people with fibromyalgia and a 2004 study found 20% prevalence and noted that SIBO was associated with increased pain. )
The Modern Diet and the Gut
Diet may have a crucial impact on the gut. Modern diets with their low variety, low levels of fermented foods, high proportions of fat and sugar, and low fiber may be particularly hard on the gut. Studies have found greater bacterial diversity (the more diverse the bacteria in your gut the better) and higher counts of good bacteria in rural Japanese populations eating traditional diets featuring fermented foods than in urbanites. African children living in traditional subsistence cultures also have more good gut bacteria and a greater diversity of bacteria than Western European children. The authors propose that our modern diets create ‘inflammatory microbiomes’ in our gut flora.
One interesting study using a dye found that high saturated fat diets allowed the dye entry into the hippocampus of the brain (!), suggesting that this type of diet both increased gut leakage and reduced blood-barrier permeability. Rodents fed Western type diets have been shown to spring leaks in their blood-brain barriers as well. Several studies finding reduced depression and anxiety levels in people switching to the Mediterranean diet with its high proportion of vegetables, olive oil/nuts and fiber, and low intake of red meat and processed foods, demonstrate the power of diet to influence mood and well-being. (Mediterranean-type diets are also associated with reduced cardiovascular risk, which, of course, is associated with inflammation.) Studies indicate that high fiber, low saturated fat diets can reduce endotoxin levels in the gut in as little as one month.
- Dig Deeper: The Best Diet For ME/CFS/FM
Fermented foods (sauerkraut, kimchee, fermented pickles, kombucha, miso, etc.) contain Lactobacillus strains that can prevent intestinal permeability, increase antioxidant levels, and reduce stress-induced LPS levels. L. plantarum, for instance can reduce the pain of IBS and reduce oxidative stress levels in smokers. Providing L. plantarum to animals increased their gut diversity and had anti-obesity effects later in life.
The Missing Link? D-Lactic Acid
A gut study found significantly higher levels of enterococcus and streptoccocus species in the fecal samples of chronic fatigue syndrome patients vs controls. Interestingly, upon exposure to glucose, these bacteria produce a form of lactic acid called D-lactic acid that is more difficult to break down and more prone to leak through intestinal membranes. D-lactic acid also appears to be able to move through the blood-brain barrier and interfere with neuronal energy supply. Animals with carbohydrate intolerance and high levels of D-lactic acid exhibit anxiety, aggression and poor memory. All these problems occur at D-lactic acid levels previously thought to be innocuous.
Given its ability to penetrate the blood-brain barrier, the authors suggest D-lactic acid may be the missing link in correlation between gut issues and fatigue, cognitive and mood problems. They propose that SIBO and increased intestinal permeability in a variety of disorders (including ME/CFS/FM) boost D lactic acid levels in the bloodstream and subsequently in the brain.
Gut Manipulation – Sometimes A Tricky Business
In short, the well-meaning lay advice to supplement with prebiotics , or the wrong types of probiotics, may have unintended consequences to sub-groups of patients within the modern day ‘entersothenia’ spectrum.
Like the immune system, the gut is a complex area and altering it can have unintended consequences. Different species of Lactobacillus have different effects, and some may be harmful. If D-lactic acid is an important player in gut-induced fatigue and mood changes, then probiotics should be selected for Lactobaccillus species that produce reduced D-Lactic acid levels and higher L-lactic and stay away from Lactobacillus species that do the opposite, such as L. delbruecki.
Too much prebiotic fiber, in the wrong person, could produce fermentation that produces higher D-lactic acid levels. They note that one popular prebiotic compound – beta glucans- was recently shown to increase not decrease intestinal permeability (woops). Increased intestinal propionate production due to prebiotics can result in locomotor slowing and induce a neuro-inflammatory response in the brain. People who have trouble with fiber or bran might be warned to stay away from these substances.
Animal studies suggest that gut dysbiosis results in anxious, cognitively challenged states in animals and probably humans. Brain studies suggest that gut toxins activate the limbic system of the brain (including the fear center of the brain, the amygdala), probably via the vagus nerve, the center of parasympathetic nervous activity in the body. (Anxious behavior in rodents exposed to gut pathogens disappeared after their vagus nerve was cut.) Bifidobacterium longum prevented anxiety behavior in these animals. Lactobaccilus rhamnus induced reductions in anxiety behavior associated with changes in GABA levels in the brain, suggesting again that the brain is much closer to the gut than we think. The fact that vagus nerve excision extinguished those changes suggests the gut-vagus nerve-brain connection is a key one.
With their massive effects on gut flora, antimicrobials (antibiotics) have been shown to reduce anxiety behaviors in mice, and the authors suggested that the effectiveness of the antibiotic minocycline in depression may be due to its ability to rejigger gut composition. Minocycline and probiotics are more effective at reducing intestinal inflammation and permeability than either alone.
Animal studies have provided substantial evidence that probiotics can help reduce stress and enhance health.
Bifidobacterium infantis and lactis have been shown in rodent studies to reduce pain and even to reduce the level of pain nerve signaling from the body to the brain. B. lactis, moreover, reduced intestinal permeability and blood endotoxin levels. As L. farciminis ‘abolished’ hyperalgesia (hyper-sensitive pain states) in an animal model, it reduced limbic activation (amygdala, PVN) as well. L. paracasei‘s ability to prevent antibiotic-caused pain states without restoring Lactobacilli levels overall indicated that small changes in gut flora can have significant effects. Not only did L. farciminis reduce both gut permeability and endotoxin levels in one study, but it also reduced neuroinflammation
Bifidobacteria reduced cytokine levels and normalized brain hormone levels in an animal exposed to psychological stress. Forced exercise studies seeking to drive laboratory animals into a chronically fatigued state found that L. acidophilus reduced immobility and fatigue while reducing oxidative stress levels in the brain and TNF-a levels in the blood.
People with fibromyalgia should note that alterations in the normal gut microflora can increase the release of substance P, a key pain mediator in the brain. Even slight elevations of substance P in the blood are associated with increased anxiety, depression and aggression.
Research into cannabinoid effectiveness in pain relief is dismally low, but it’s clear that cannabinoid receptors affect anxiety and pain and can even limit endotoxin-produced blood-brain permeability. That’s noteworthy given preliminary findings that probiotics appear to affect cannabinoid receptor expression.
In what may be of special relevance to ME/CFS/FM, L. rhamnos us IMC 501 and L. paracasei IMC 502 reduced oxidative stress associated with intense physical activity. A psychological stress test found that women taking probiotics had reduced ‘emotional arousal’ and reduced activity in their insula, a part of the brain implicated in ME/CFS/FM.
While researchers have isolated probiotic strains that appear to be able to lower endotoxin levels, reduce oxidative stress and inflammatory cytokines, improve ones resilience to stress, affect neurotransmitter levels, reduce gut permeability and lower toxin levels, the field is still in its infancy. For one thing, animal trials are the norm and cannot mimic the complexity found in humans. The bad news was that the authors projected that decades of work will be needed to determine how specific probiotic strains may interact with each other and the gut to affect health. The good news is they believe experimental evidence had been gathered to warrant extensive human trials.
Much more data on the effects of specific strains is needed, although they cautioned that an ecologic approach to microbial manipulation is also needed. The gut is home to many types of bacteria and they warned that supplementation with a single or a couple strains of bacteria, no matter how beneficial they are, could ultimately diminish microbial diversity. A focus on a few commercially patented strains ignores the microbial richness that accrues from good dietary choices. They noted that fully 35% of lactic acid bacteria found in raw food survives the acid bath in the stomach. There is no substitute for good dietary practices, which apparently include a sufficient quantity of raw and fermented foods.
Probiotics are not a be-all and end-all. They are not going to replace antidepressants; nor did the authors envision them as first-line treatment for many conditions. They’re simply part of a complex mix of options for patients that need to be explored further. Diet, for instance, may play a large role in how effective probiotics may be. The authors did not anticipate that probiotics would significantly help a sedentary person with depression living on a fast food diet and taking pharmaceuticals that blasted the gut microbiome. The odds, they felt, of a single strain of probiotics providing ‘clinically meaningful and longlasting benefits’ was probably not high, and they cautioned against the unsubstantiated claims of probiotic businesses regarding anti-aging and anti-stress effects.
The authors closed the paper stating that probiotics are not a panacea, but the experimental evidence is encouraging and they deserve and hopefully will receive much more focus in the future.