We’ve all heard about the gut-brain axis. That’s where problems in the gut can translate to inflammation in the brain and vice versa but a gut-muscle connection? That’s entirely new. One wonders much further can the gut after all reach? It turns out quite a bit further than we thought. Like so many fascinating discoveries, it took a bit of serendipity to uncover this one. (Thanks to Neilly for the tip.)
- We’ve all heard of the gut-brain connection where inflammation in the gut can cause inflammation of the brain and vice versa but a gut-muscle connection? That’s something entirely new.
- It showed up when, to their surprise, Harvard researchers found gut-derived immune cells called T regulatory cells or Tregs in the muscle tissues of mice. Tregs regulate the functioning of the immune system; in particular, they’re the cells that swoop in and turn off the immune response when it’s time to do so. Regarding the gut, they’re the main immune cells involved in the gut’s regulation of the immune system. They’re a big deal.
- It turns out that exercise produces inflammation and produces small amounts of damage to the myofibrils found in muscle cells. This is usually quickly and easily resolved in healthy people…but what about exercise-challenged ME/CFS, long-COVID, etc. patients?
- The late Ron Tompkins proposed that exercise was damaging the myofibrils in ME/CFS patients, and several studies suggest that damage is indeed being done.
- Exercise, for instance, produced higher-than-usual amounts of inflammation in ME/CFS. It also appears to produce higher-than-normal rates of bacterial leakage from the gut (another source of inflammation). Reduced levels of protective substances (heat shock proteins) could be leading to more muscle damage.
- Finally, Maureen Hanson’s NIH-funded research groups recently found that exercise is not provoking nearly as much of a metabolite or protein response as expected, i.e. the “healthy metabolic response” to exercise, in other words, had disappeared.
- But what about those gut Tregs? Although they’ve never been studied in ME/CFS, some indirect evidence suggests they could be affected. Tregs, it turns out, are produced by the same factors – small chain fatty acids such as butyrate – that gut studies indicate are low in ME/CFS. It’s possible, then, that butyrate depletion in ME/CFS patients’ guts results in low levels of Tregs – too low to turn off the already very vigorous inflammatory event we know that exercise is producing.
- Could problems in the gut have kicked off ME/CFS? Lenny Jason’s studies of college students who came down with infectious mononucleosis suggests so. People who later developed a more severe form of ME/CFS experienced more gut symptoms when they were healthy – and get this – people who had IBS prior to coming down with infectious mononucleosis had an 80% chance of coming down with ME/CFS later on.
- Maybe the alternative health practitioners who have been saying for years that it all starts in the gut were right.
It turns out that gut Tregs play an absolutely essential role in the gut’s effect on the immune system. A recent study reported that, “Although the mechanisms are still unclear, the immunomodulatory effects of gut microbiota are mostly realized through the Th17/Treg axis”. Poor Treg functioning could result in inflammation in the gut, and if leaky gut is present – and we know it is in ME/CFS – outside it.
The Harvard researchers proceeded to validate their findings. Mice that had been genetically modified to lack this special class of Tregs had more trouble recovering from exercise, exhibited higher levels of inflammation, more muscle injury, and developed muscle scarring. It was clear that without the Tregs there to snuff out the inflammation, the muscle repair mechanisms simply weren’t up to the job.
Going to the nuclear option and knocking out the mice’s entire gut flora provided the same result – making it clear that the gut flora did indeed play a role in exercise recovery. Digging deeper, the researchers found that these colon-derived Tregs enhance the muscle repair process by suppressing an immune factor called IL-17. In, “How gut microbes help mend damaged muscles”, Bola Hanna, the lead author of the study, told Ilima Loomis:
“When muscles are healing, you need a certain dose of inflammation within a certain time frame… in the absence of these gut-derived regulatory T cells, we found that the degree of inflammation gets higher and extends for longer, and you end up having inferior repair.”
Muscle Repair Problems in ME/CFS?
What about ME/CFS? We know plenty of gut problems exist in ME/CFS but what about muscle repair? Is that damaged? Could gut-associated Tregs be failing to calm the fires, so to speak, in the muscles after exercise in ME/CFS? Other than a hypothesis that Tregs are failing to reign in herpesvirus infections, we have little information on the role they play in ME/CFS.
The late Ron Tompkins proposed, though, that exercise may doing lasting damage to the small myofibrils which make up our muscle fibers. Stress to the muscles from exercise does, in fact, damage those myofibrils even in healthy people, but the damage is quickly resolved, and Tompkins believed that the muscle repair processes may be broken in ME/CFS.
Indeed, studies that have found that exercise invokes higher than usual amounts of inflammation in ME/CFS would clearly put a premium on the muscle repair process. Shukla, for instance, found high rates of bacterial leakage into the bloodstream (aka inflammation) which were still present 72 hours after an exercise bout. In several small studies, Jammes found high levels of oxidative stress and reduced levels of protective factors after exercise. In a review article, he proposed that high levels of oxidative stress may be preventing muscle cells from responding properly to exertion in ME/CFS.
Maureen Hanson’s NIH-funded research group recently suggests that little is going right in people with ME/CFS after exercise. While the healthy controls showed a veritable explosion of metabolite alterations, the metabolites in the ME/CFS group basically flatlined. The “healthy metabolic response” to exercise, in other words, had disappeared. A proteomic study from her group found much the same thing – a much subdued proteomic response to exercise – in ME/CFS. Men, in particular, appeared to show dramatic changes in gene expression during the muscle repair period that occurs after exercise.
While it won’t tell us anything about Tregs, the OMF’s fascinating skeletal muscle study underway at the Harvard Collaborative ME/CFS Center should give us a ground-level view of what’s going on in the muscles. The unique study methodology involves using muscle biopsies to compare the expression between younger and older people undergoing 2 weeks of bedrest and then rehabilitation – with those of ME/CFS patients. Thus far, the study has found that 2 weeks of bedrest produces profound differences in gene expression. Ultimately, the study should be able to show that deconditioning produces a different impact on the muscles than seen in ME/CFS.
Back to Butyrate
Back to these gut-derived Tregs. We don’t know if missing gut Tregs are causing a problem in ME/CFS or not – so far the muscle-gut finding has only been explored in mice – but some other factors suggest they just might be. It turns out the Treg production in the gut needs the very substances – short-chain fatty acids (butyrate, propionate, and acetate) – that recent studies indicate are lacking in ME/CFS patients’ guts.
It should be noted that low butyrate levels are not just a problem in ME/CFS. The fact that butyrate and short-chain fatty acid problems are found in a host of other diseases (Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, stress, anxiety, depression, autism, vascular dementia, schizophrenia, stroke, diabetes, lupus, myasthenia gravis) makes one wonder if the gut dysregulation really could be the source of many diseases.
Indeed, Lenny Jason’s study that tracked college students after they came down with infectious mononucleosis found that people who later developed a more severe form of ME/CFS – the kind that most of the people reading this blog probably have – experienced more gut symptoms when they were healthy.
People who had irritable bowel symptoms (bloating, pain, etc.) when healthy, and severe gastrointestinal symptoms when they came down with mononucleosis (and low levels of IL-13 and/or IL-5 at baseline), had nearly an 80% chance of developing severe ME/CFS six months later.
Functional and alternative health doctors have been saying for years – it all starts in the gut… They may be right.
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