Reprinted with the kind permission of Cort Johnson and Health Rising.
By Cort Johnson
It seems every week brings more news highlighting the surprising importance the gut has on our health.
A couple of years ago the Solve ME/CFS Initiative funded a pilot study on the effects of exercise on chronic fatigue syndrome (ME/CFS) patients gut flora. It was one of those multi-faceted studies that Suzanne Vernon loved funding. There was an exercise component, a gut component, a blood and stool component and a time component. It took quite a while to get published, but here it is.
PLoS One. 2015 Dec 18;10(12):e0145453. doi: 10.1371/journal.pone.0145453.Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Shukla SK1, Cook D2,3, Meyer J2, Vernon SD4, Le T1, Clevidence D3,Robertson CE5, Schrodi SJ1, Yale S6, Frank DN5.
In this small (n=20) study first they examined the gut flora (stool sample) and the bacterial component of the blood. Then they had people with chronic fatigue syndrome (ME/CFS) and healthy controls participants pedal themselves into exhaustion on a bicycle. Then15, 48 and 72 hours after the bicycle test stool and blood samples were taken again.
The idea was to get at a possible cause of post-exertional malaise. The study was driven by findings suggesting that the gut flora can be dramatically effected by exercise. The flora of the gut is so responsive to exercise that one review paper suggested that it “acts as an endocrine organ and is sensitive to the homeostatic and physiological changes associated with exercise.”
In healthy people exercise appears to improve their health by enhancing the diversity of their gut flora. Could the gut flora/exercise interaction be a double-edged sword, though? Could exercise trigger changes in the gut that produce exhaustion instead of health? In particular, could it cause gut microbes to spill into the blood – setting off a devastating immune response causing fatigue, pain, cognitive problems and other symptoms in ME/CFS.
Let’s see what they found:
These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.
It’s important to note first, that gut symptoms were not, repeat not, required for this study. The patients in the study reported few gut symptoms. The gut, it turns out, can be severely impaired without generating many symptoms or it can produce dramatic symptoms without it being severely impaired. Both celiac disease and non-celiac gluten hypersensitivity, for instance, can exist without significant gut symptoms being present.
Heart Rate – A Slight Digression
Except for heart rate (which was reduced) the VO2 max and other measures were similar between the healthy controls and the ME/CFS patients. An inability to ramp up heart rate to normal levels during exercise is called chronotropic incompetence (CI). While not as well-known as the reductions in VO2 max CI has been found ME/CFS – and it is associated with “exercise intolerance” in other diseases.
A 2011 review indicated that CI “produces exercise intolerance which impairs quality-of-life, and is an independent predictor of major adverse cardiovascular events and overall mortality” (ouch). CI appears to be caused by sympathetic/parasympathetic nervous system problems.
The study suggested that exercise may have major, even outsized effects on the gut flora in ME/CFS. Instead of being less responsive to exercise, the gut flora in ME/CFS was significantly more responsive to exercise than that of the healthy controls. Exercise increased the abundance of 6/9 of the gut phyla in the ME/CFS patients but only 2/9 major phyla of the healthy controls. The gut bacteria had bloomed in the ME/CFS patients.
Suzanne Vernon said they didn’t know why exercise was causing the bacteria to grow so much in the ME/CFS patients but likened it to a “bacterial bloom.”
“I hypothesize that it is akin to a “bacterial bloom” that is not healthy and potentially contributing to increased inflammation and other problems that occur when something (in this case bacterial growth) happens too fast and furious throwing the balance off.” Suzanne Vernon
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The increased abundance of bacteria in the stools of ME/CFS patients was reflected in their blood. Fifteen minutes after exercise species of Clostridium bacteria popped up in the blood of ME/CFS patients. Bacilli bacteria showed up at the 48-hour mark. While most bacterial loads declined in the blood of the healthy controls, they remained high in the ME/CFS patients three days after the exercise.
Clostridium are obligate anaerobes that thrive in oxygen-poor environments. Five species including C. botulinum, C. tetanus, and C. dificile cause the most severe problems in humans, but many others are involved in gut health. Suzanne Vernon said that the Clostridium complexes that showed up in the study were important regulators of gut health.
Some translocation from the gut to the blood occurs even in the healthy people, but it occurred to a greater degree in the ME/CFS patients in this study. The findings suggested that exercise was, either by altering the gut flora or by some other means, compromising the integrity of ME/CFS patients gut lining.
Once the gut bacteria escaped into the blood, it was sure to be attacked by the immune system.
Maes may have been the first ME/CFS researcher to glom onto this potential problem. His 2008 study described what was at that time a “novel pathway” of ME/CFS causation: weakened gut junction barriers allowing allowed the escape of gut materials into the blood.
Finding evidence of increased immune responses (IgA/IgM) to those gut materials Maes had his ME/CFS patients embark on a year-long leaky gut diet and anti-inflammatory supplements program containing glutamine, N-acetyl cysteine and zinc. The diet/supplements reduced the levels of the pro-inflammatory factors in their blood and many patients improved.
Maes later showed that immune responses to gut material that leaks into the blood can cause depression, and in ME/CFS are associated with increased symptoms. He recently produced a grand schema that proposes that many factors including gut bacterial translocation underpin a wide variety what he calls inflammatory and oxidative and nitrosative stress disorders including depression, inflammatory bowel disease (and ME/CFS).
Given the increased abundance of Firmicutes species found in ME/CFS in this study, it’s intriguing that Rifaximin, an antibiotic sometimes used in irritable bowel syndrome (IBS) preferentially reduces Firmicutes species including Clostridium.
Anecdotally, some ME/CFS patients have reported remarkable mood and other changes after altering their gut flora. Esther was able to go off her antidepressants, cut out Xanax and Ambien, half her dose of Trazodone, and say goodbye to her shrink after Rifaximin treatment for some gut problems.
I asked Suzanne if she’d had any expectations what the study would find. She didn’t know what to expect with this study – except that she expected to find something. The gut is so large and complex, and there is so much we don’t know that it was impossible for her to predict what they might find.
The fact, though, that they were able to detect significant changes with such a small sample set (10 patients and ten healthy controls) was “pretty exciting” to her, and indicates that the microbiome might indeed be very important in ME/CFS.
Has Shukla or is Shukla trying for an NIH grant using the findings? She said he did submit a grant proposal in 2010 or 2011 which was not rewarded but hoped that with these “exciting results” and the recent NIH promise of more research funding that Shukla would try again and be successful.
She noted that larger studies able to pinpoint individual species and determine microbial diversity are greatly needed. We are just at the beginning of learning what is happening in the guts of ME/CFS patients.
There are many unknowns with the gut microbiome in ME/CFS, and so there is a lot of room for well-designed scientific exploration of the gut microbiome. As my friends (who also happen to be patients remind me) remind me the most important research for them is the kind that is going to bring treatment sooner rather than later. Suzanne Vernon
The authors noted that gut flora manipulation including probiotics, prebiotics, dietary fiber, and fecal microbiota transplantation has proven helpful in “other chronic, inflammatory, non-communicable diseases.”
Much more clearly needs to be done. This study was too small to be able to pluck out individual species or to assess the abundance of groups of rarer phyla. It was a pilot study; a preliminary look at the effects of exercise on the guts of ME/CFS patients, but it did suggest that something different is happening and that something is showing up in their blood as well. Hopefully it will translate into a larger study or studies.
In the meantime you can add the gut to a growing list of systems (cardiovascular, immune, nervous system) studies indicate are effected by exercise in ME/CFS.
We are a long, long way from understanding the role the gut plays in ME/CFS. The initial findings are, however, promising. At least five gut studies are currently underway in ME/CFS: two (maybe three) by Dr’s Lipkin and Hornig, a Maureen Hanson study, the UK’s ME/CFS microbiota project and the Open Medicine Foundation’s severely ill study.
Hanson’s NIH funded gut study hasn’t gotten much press but it’s impressive, has been underway for awhile and may be finishing up soon. It won’t have an exercise component but it looks like Hanson’s study may be able to identify the individual species in the gut. The study will determine the bacterial diversity and composition of the gut flora in ME/CFS patients and healthy controls. She’s working with Dr. Susan Levine and an experienced gut researcher, Dr. Ruth Ley.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.