The gut may seem distant from the main source of action in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) but more and more studies suggest that gut problems can affect everything from the cardiovascular system to the immune system to the brain.
The gut is far more than the seat of digestion. It has its own special nervous system (the enteric system) which produces hormones, neurotransmitters, and immune factors. Seventy percent of the cells that produce inflammation are associated with gut tissues. Gut dysbiosis and gut inflammatory factors have been linked to everything from arthritis to major cardiovascular events to anxiety to the amyloid plaques found in Alzheimer’s disease. Reduced gut biodiversity has even been associated with poor sleep.
Numerous studies have uncovered gut issues in ME/CFS and FM. At least five studies, including one published this year, have found evidence of gut dysbiosis (harmful gut bacteria) in ME/CFS, and several have pointed a finger at the gut microbiome in FM. Reduced gut biodiversity – found in both ME/CFS and FM – has been associated with chronic widespread pain as well. One hypothesis proposes that a sort of “dysbiotic march” begins with irritable bowel-like syndromes and ends up with fibromyalgia and/or ME/CFS.
While we don’t know how much of a problem the gut causes in ME/CFS and FM it’s clearly a player. Given that t’s no surprise to learn that it’s also a player in Gulf War Illness (GWI). In fact, GWI gut researchers are plowing ahead and uncovering new treatment possibilities that may help restore the gut to health in ME/CFS and FM as well.
A Gut-Brain Connection in Gulf War Illness
Saurabh Chatterjee in South Carolina has a knack for publishing intriguing papers. In 2017, Chatterjee used a Gulf War Illness (GWI) animal model to show that the combination of an anti-nerve agent (pyridostigmine bromide), an insecticide (permethrin) – plus a nice dose of stress (corticosterone) as a mixer – did a number on the guts of GWI mice.
As their healthy gut flora tanked, their nasty gut flora (Firmicutes and others) pried apart the junctions in their gut lining allowing bad bacteria to spill into their bloodstream. That, not surprisingly, agitated the immune system, which responded with a pro-inflammatory response (toll-like receptor 4 (TLR4)) that reached all the way to the brain. Given the systemic response that had originated, apparently, in the gut, the authors suggested boosting gut health of GWI patients with antibiotics like minocycline and probiotics.
A small chronic fatigue syndrome (ME/CFS) study found that a different stressor – exercise – also increased Firmicutes bacteria. Given the small size of the study, the authors were surprised at how clearly the differences in the gut flora jumped out. While exercise dramatically altered the gut flora in people with ME/CFS it affected the gut flora of healthy controls hardly at all.
Much as did Chatterjee et. al., the authors noted that gut flora manipulation, including probiotics, prebiotics, dietary fiber, and fecal microbiota transplantation, was a possibility as they’ve proven helpful in “other chronic, inflammatory, non-communicable diseases.”
Antivirals for the Gut?
Chatterjee’s next study, “Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness“ (Nancy Klimas was a co-author), attempted to explain how a chemical exposure, an anti-nerve agent, and stress had impacted the gut of all places. It opened an entirely new window on what might be happening in GWI, as well as chronic fatigue syndrome (ME/CFS) and other diseases.
The study found that viruses in the gut – known as bacteriophages – thrived on the chemicals the mice had been exposed to. While bacteriophages haven’t received nearly the study that gut bacteria have, they’re considered the great regulators of our gut flora.
Since the gut virome appeared to be the core player in the gut dysbiosis found, Chatterjee turned not to an antibiotic but to a broad-spectrum antiviral called Ribavirin. Ribavirin is mostly used to treat hepatitis C and viral hemorrhagic fever but, in this case, not only did it return the gut virome to health, but it also stopped the leaky gut and reduced the inflammation in the brain…
The authors, one of whom was Nancy Klimas, suggested that antivirals like Ribavirin, by themselves or in combinations with “complementary and alternative compounds and probiotics”, might “form the basis of a novel treatment strategy for GWI and similar disorders.”
Just last week, Chatterjee and his South Carolina team (and Nancy Klimas) took a different crack at restoring the wounded microbiomes of their unfortunate GWI mice. This time they used something much more accessible than an antiviral – an herbal supplement called andrographolide.
Andrographolide (AG) is not just any herb. In fact, it’s not an herb at all. It’s a chemical compound that comes from an herb called Andrographis paniculata found in India, China, and Australia. Andrographolide is used extensively in Chinese and Indian medicine. While its anti-inflammatory, antibacterial, antivirus, antitumor, and cardiovascular protecting properties have excited many, its low bioavailability has been a problem. That problem has prompted much work to create more potent derivatives.
AG has been well studied, leaving the medical literature studded with reviews. Over the past couple of decades, hundreds of derivatives have been developed and bioavailability has been improved. A 2020 review of the many efforts made to improve the usefulness of this unique compound demonstrated how active the andrographolide field is. There’s clearly still work to be done, though. While lauding the “ancient mighty herb” – and its perhaps mighty compound – a 2018 Chinese review asserted that better forms are needed.
In its current form andrographolide is still pretty potent. A 2017 review of andrographolide’s antiviral and immune properties reported that it does something that might be quite helpful in ME/CFS – boosts cytotoxic T cell and natural killer (NK) cell functioning. Two more recent reviews lauded it for its antioxidant, anti-inflammatory properties, and neuroprotective properties.
To wit – andrographolide has generated a lot of interest. This is the first time, though, this “wonder compound” has shown up in Gulf War Illness, ME/CFS, or fibromyalgia. (Quite a few studies have been focused on its potential effects on the coronavirus, though).
Chatterjee’s latest study “Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk“, was a mouthful – and for good reason – it was quite a complex effort.
The authors (which again included Nancy Klimas) found that AG restored the mouse microflora, and improved it by increasing the abundance of two bacteria species (Lachnospiraceae, Akkermansia, Bifidobacterium), which are both “immensely helpful in maintaining robust gut and immune health”.
Significant decreases occurred in two virome families (Siphoviridae, Myoviridae) known to negatively impact gut health. As that happened, the leaky gut tightened up, and inflammatory cytokine levels in the blood decreased. In a result they called “very significant”, microglial activation – potentially the source of so much misery – decreased as well. Some evidence suggested that that other crucial barrier – the blood-brain barrier – tightened up as well.
Their examination of the “microglial secretome”, via harvesting the microglial conditioned medium (MCM), found that AG reduced the phosphorylation of the tau protein in the brain. Tau phosphorylation produces “neurofibrillary tangles” and “neuropil threads” that interfere with nervous system functioning. These tangles and threads have been implicated in the progression of Alzheimer’s disease.
Increased levels of phosphorylated tau have not been found in GWI (it doesn’t appear that anyone has looked for them), but significantly elevated levels of Tau antibodies have been found – and suggest phosphorylated tau could be present.
It was remarkable to see this plant compound possibly reverse levels of phosphorylated tau, rebalance the gut flora, heal the gut lining, and reduce inflammation in the body and neuroinflammation in the brain. Sometimes we forget what a potent source of effective drugs plants are. While more and more drugs are being synthesized in the lab, more than 60% of clinically approved anticancer drugs come from medicinal plants.
In conclusion, the authors stated that the:
“AG treatment mitigated the Gut–Brain-Axis associated pathology in GWI and may be considered as a potential therapeutic avenue for the much-needed bench to bedside strategies in GWI.”
Placebo-controlled trials in humans will hopefully be next. AG is readily available in supplement form in the U.S.and WebMD has prepared a section on it. Check out several reviews of the best AG supplement to take.
The GWI mouse-gut story doesn’t end here. Ample Department of Defense funding has produced an integrated and well-organized effort that has clearly has helped the field take rapid steps towards human trials. Another nutraceutical that I’ve never heard of also produced some nice gut harmonization in a GWI mouse.
Sparstolonin B (SsnB)
A study (with Nancy Klimas as a co-author) found that Sparstolonin B (SsnB) – another compound with a difficult name – which was derived from a Chinese herb, increased the abundance of butyrogenic bacteria, helped tighten up the crucial junctions lining the gut, and reduced inflammation and neuroinflammation. Sparstolonin B (SsnB), which has also recieved quite a bit of study, interestingly, appears to be able to protect the blood vessels from harm – a possibly key need in ME/CFS.
Note that similarly reduced levels of gut-protecting butyrogenic bacteria have been found in both ME/CFS and fibromyalgia (FM).
- The gut is far more than the seat of digestion. Studies indicate that the gut affects many systems and plays a role in many diseases including chronic pain disorders like fibromyalgia, cardiovascular diseases, and central nervous system diseases like Alzheimer’s.
- Numerous studies have implicated bad gut flora in ME/CFS and fibromyalgia. Others have linked reduced gut diversity to chronic pain and problems with sleep.
- Behind substantial federal support, Gulf War Illness (GWI) studies have been plowing new ground. A 2019 paper showed that the gut virome was severely disturbed in a GWI mouse model, and that an antiviral called Ribivarin was able to restore the gut to health.
- In the latest study, South Carolina researchers found that a plant compound called andrographolide not only restored the gut bacteria to health, it also readjusted the gut virome, repaired leaky gut, and knocked down inflammation in the body and brain. It even appeared to reduce the phosphorylation of the tau protein which produces threads and tangles which have been implicated in Alzheimer’s.
- In another study, another plant compound called Sparstolonin B (SsnB) produced much the same effects.
- The Gulf War researchers are benefitting from a well-funded and organized approach to GWI that is spinning off clinical trials right and left. ME/CFS has never received that kind of approach but long COVID surely will. At some point, we will likely be awash in long COVID treatment trials.
- While mice are not humans, disease mouse models can provide crucial insights into diseases and can pave the way for human trials.
- Meanwhile, GWI research is uncovering treatment possibilities that may benefit it and ME/CFS and FM as well.
Piggybacking Off the GWI Field
How nice it must be to have funding – and an animal model. Unfortunately, the ME/CFS field has never received the kind of support that would allow it to take an integrated, multidisciplinary stab at the disease and produce clinical trials. Walter Koroshetz warned that, based on his experience, it was too early for the NIH to fund clinical trials, as unsuccessful trials can sink future efforts. He may be right, but it’s clear that the NIH’s refusal to adequately fund and support ME/CFS is the driving force behind that situation.
While that fact will, no doubt, continue to rankle for quite a while, Congress’s willingness to send over a billion dollars to the NIH to study long COVID means that, at some point, we should have long COVID treatment trials coming out of our ears.
In any case, it’s clear that the generous GWI funding the DOD is providing is potentially having some nice spillover effects for ME/CFS – including new treatment possibilities.
These are mouse studies that may or may not translate to humans, but as mouse studies are often the first step to human drug trials, there’s clearly enough overlap between humans and mice for researchers to use them, again and again, to suss out possibilities.
The studies illuminated once again, what a powerful influence the gut – in particular, a leaky gut – can have on both the body and the brain. While one might have expected the combination of a stressor, an anti-nerve agent, and an insecticide to give the central nervous system a good whack, it was surprising to see how much it also affected the gut. It now appears, as well, that the gut microbiome is much more than about the gut bacteria – the gut virome must be studied as well. In fact, if the gut virome is the great gut flora regulator, it may take central place at some point.
With similar gut findings showing up in ME/CFS and FM, and the GWI field producing new treatment possibilities for the ME/CFS and FM fields to mull over, the GWI field is clearly a field to keep an eye on. Nancy Klimas, by the way, is beginning a clinical trial using a novel probiotic that’s found only in Europe.