Just as something in the blood reproduced FM, so did something in the gut.
Ed.
Canada can use some good news right now, and at least on the medical front, it got some with the fascinating “The gut microbiota promotes pain in fibromyalgia” study. The 40+ researcher study hailing from McGill and other Universities in Canada and one in Israel captured new ground.
Multiple studies suggest that something in the blood is causing or contributing to chronic fatigue syndrome (ME/CFS) and/or long COVID, but this is the first study to suggest that something lurking in the guts of fibromyalgia (FM) patients might have just as fundamental an impact.
Let’s not necessarily limit this finding to FM patients, though. This study was all about “nociplastic” pain – the kind of pain that also produces cognitive, sleep, sensory, and other problems, which means it may apply to other nociplastic pain diseases including ME/CFS, long COVID, irritable bowel syndrome, endometriosis, some subsets of rheumatoid arthritis, etc.
The gut, though, has always seemed kind of like a side issue. The authors, after all, started their explanation of FM with the central nervous system findings (altered neurotransmitter levels, neuroinflammation, dysregulated pain pathways) the condition is so well known for. The authors reminded us that the “gut-brain axis” affects the gut, immune system, and brain. The effects of gut flora on metabolites and metabolism and the high degree of nerve activity found in the gut indicate that the gut is a remarkably significant organ.
The gut is sometimes called “the second brain” because the “enteric nervous system” contained in it contains over 100 million nerve cells that operate independently of the brain. The gut makes its own serotonin and uses many of the neurotransmitters found in the brain to run itself. It’s in constant contact (and vice versa) with the brain via the vagus nerve.
The Study
Instead of transplanting serum, plasma, or antibodies from ME/CFS, fibromyalgia, or long-term COVID patients into mice or lab cultures, these researchers planted gut flora derived from fecal material donated by FM or healthy women into germ-free (bacteria-free) mice.
By the end of four weeks, the mice receiving the gut flora from healthy women were fine, but the mice whose guts were populated with FM flora displayed increased sensitivity to touch, heat, and cold. No signs of cognitive issues or muscle weakness were found. Surprisingly, the FM gut flora worked without producing any signs of leaky gut or inflammation. (Apparently, you don’t need to structurally damage the gut to cause these symptoms (at least in mice).)
Immune changes were reminiscent of what we’ve seen at times in ME/CFS and long COVID (increased classical monocytes, increased inflammation, decreased memory B-cells, and others.
Turning to metabolomics, increased spinal cord glutamine and brain glutamate levels suggested the FM patients’ gut flora had altered some fundamental nervous system metabolites. Decreased plasma medium—and long-chain fatty acids, branched-chain fatty acids, and dicarboxylate fatty acids fit perfectly with the fatty acid problems similar studies have found in ME/CFS.
A Bilious Problem?
- A brownish-greenish-yellow substance produced by the liver and discharged into the duodenum where it helps with digestion; also an important detoxifications and signaling agent.
- An excess of bile was believed in the Middle Ages to result in irascibility and ill humour.
- In Hindu medicine, a “bilious temperament” is associated with increased irritability, a susceptibility to sweets, and rapid alcohol intoxication. (It is, however, caused by increased bile production.)
Bile problems could affect many systems. The liver, showing the various bile ducts. (Image by T Sheasby CC; Wikimedia Commons).
It was the reduced bile acid levels (reduced plasma ursocholate, increased fecal lithocholic acid sulphate), though, that really sparked things.
Bile is a fascinating new entrant into the ME/CFS, fibromyalgia, and long-COVID fields. Bile acids are synthesized in the liver from cholesterol and then are modified by gut bacteria. Numerous potential connections between bile, ME/CFS, FM, and long COVID exist.
Because bile binds to receptors across the body, including in the brain, immune cells, and metabolic tissues, problems with bile production could contribute to things like neuroinflammation and inflammation in the gut. Bile acids can activate sensory neurons, causing pain, or downregulate pain-producing pathways by stimulating opioid activity. Reduced bile levels can impair detoxification, resulting in fatigue, pain, etc.
Bile acid production problems appear associated with reducing butyrate-producing bacteria, intestinal inflammation, and fatty acid metabolism problems in ME/CFS. Reduced bile production has been speculated to impair tryptophan metabolism in these diseases, resulting in increased levels of neurotoxic metabolites (quinolinic acid), which produce fatigue and cognitive problems as well as serotonin synthesis (mood). In Germain’s study, the pathway with the highest “impact factor” was taurine, part of the primary bile acid biosynthesis pathway.
In the end, bile issues could reflect liver problems—a possible emerging issue in these diseases. Interestingly, mitochondrial issues that negatively impact the liver may also be implicated (more on that later).
Possible bile acid problems showed up in a 2023 paper, “Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity“. The study found substantial bile acid changes in both bile-metabolizing gut bacteria and serum bile levels.
Alterations in one bile acid, α-muricholic acid, whose levels were highly correlated with pain and fatigue, appeared particularly significant. These detailed analyses, which uncover specific molecular entities that may have thrown major systems off, could lead to targeted treatments.
Fibromyalgia isn’t alone in its possible bile acid problems. Germain’s 2017 metabolomic study highlighted bile reductions in ME/CFS and signs of liver problems. After Xiong’s 2023 microbiome study found a reduction in bile acids, his 2025 BioMapAI study highlighted bile acids (among other factors). Turning to long COVID, both metabolomic and lipidomic analyses have found dysregulated bile acids.
Treatment Possibilities
With their own and the 2023 bile findings in hand, the Canadian researchers suggested that ursodiol—an FDA-approved formulation of the bile acid ursodeoxycholic acid—might help. When they gave it to the mice, it partially eliminated their pain sensitivity.
Interestingly, primary biliary cholangitis (formerly cirrhosis) (PBC) is one of the most fatiguing diseases known. In fact, Julia Newton, a UK ME/CFS researcher, came to ME/CFS via primary biliary cholangitis. The bile problems in PBC—where bile and toxin buildup cause scarring of the liver (fibrosis) and destruction of the bile ducts—far exceed those found in fibromyalgia, ME/CFS, and long COVID-19.
Still, the bile and liver problems that may be emerging in these diseases and the enormous fatigue in PBC suggest it’s worth a look. Like ME/CFS, addressing the fatigue in PBC has been difficult, but a recent drug called Iqirvo has recently helped both with fatigue and sleep. Iqirvo’s ability to reduce bile production may not fit in FM, ME/CFS, and long COVID, but with its ability to increase peroxisome activation via peroxisome receptors and enhance lipid metabolism – both of which have been implicated in ME/CFS – one wonders if there’s a fit somewhere.
Supplements such as TUDCA, ox Bile or bile Salts, taurine, choline, milk thistle, artichoke extract, dandelion root, and betaine (trimethylglycine) might also help with bile production. Bile acids are metabolized in the gut to ursodiol. During his recovery, Efthymios started with 250 mg and gradually increased the dose to 750 mg to support his liver and ameliorate endoplasmic reticulum stress.
Open Label Fecal Transplant Study Provides Some Benefits
Whether or not to first use antibiotics to clear the gut microflora prior to recolonizing the gut has been controversial. In this study, the FM-like mice given antibiotics first did much better than the mice simply given new flora. For example, the attempt at flora recolonization stuck and their pain sensitivity improved. FM-like mice given new flora alone did not show reductions in pain sensitivity.
Recolonizing the gut with healthier bacteria helped. Bigger studies are needed, and one is on its way.
The next step was obvious – give fecal bacteria from healthy women to women, each of whom had “severe, refractory,” (i.e., treatment-resistant) FM characterized by high levels of pain and fatigue. After being given oral antibiotics for 3 days (vancomycin 500 mg (Mylan, France) q6h and neomycin 1000 mg (Ma’ayan Haim, Israel); 24h clear liquid diet and bowel irrigation using polyethylene glycol 255 g (PEG, Taro, Israel), each participant received 30 healthy donor FMT capsules, the equivalent of 15 g. This was followed by four maintenance doses of 15 capsules each, taken 2 weeks apart, for a total duration of 8 weeks.
Stool samples indicated that the new bacterial flora had taken hold. Importantly, even nine weeks later, each participant’s gut flora still closely resembled their donor’s gut flora. Bile acids improved, and amino acids showed substantial changes.
Symptomatically, recolonizing their gut flora with healthier flora wasn’t a magical cure, but it did help. Pain intensity reduced by about 20%, and anxiety, depression, sleep quality, and physical quality of life scores improved. There was a trend towards improved hypersensitivity to heat. A larger, placebo-controlled study is underway.
Overall, fecal transplants are just beginning to be assessed in FM. A 6-month open label trial resulted in significantly improved symptom scores (widespread pain Index, symptom severity, hospital anxiety and depression scale, and Pittsburgh Sleep Quality) score as well as significant increases in serotonin (5-hydroxytryptamine) and gamma-aminobutyric acid levels (P < .001), and decreased levels of the neurotoxic neurotransmitter glutamate.
Small FMT trials in ME/CFS and long COVID have had mixed results, and key factors such as how many treatments are optimal are far from clear.
Fecal transplants appear to use a similar “flood the system” approach as IVIG; i.e. insert lots of healthy bacteria or antibodies in an attempt to reset the system. Far better, perhaps, to identify the specific bacterial and/or metabolic imbalances that need to be repaired and focus on those, and efforts to do that are underway.
In the end, personalized treatment may be the ticket. Ken Lassesen – a mathematician, software engineer, and citizen scientist with an MS in Operations Research and Statistics argues that the “One treatment treats them all” is the stuff of fantasy writers. After looking at dozens of microbiomes from ME/CFS and Long COVID, he’s found that each one is different and that gut changes over time must be addressed. (Studies suggest consistently broad alterations, such as butyrate depletion, exist.) Lassesen, who is not a doctor, created MicrobiomePrescription.com to provide more detailed treatment options.
The Starting Place…
Perplexity AI suggested that problems in the gut or elsewhere could explain the “something in the blood or gut” findings.
Perplexity AI suggested that problems in the gut or outside of the gut could start the process.
The million-dollar question is where it all starts – the gut or the rest of the body. Just for the heck of it, I asked Perplexity AI, “What is the likely source of a disease that can be transmitted to laboratory animals through blood, serum, or gut transplants?” Its suggestion—various viruses—didn’t seem particularly helpful.
Next, I asked, “How could gut microbiome alterations affect the blood so as to produce disease when the blood or serum is transplanted into laboratory animals?”, and got a more helpful response. Perplexity AI proposed that toxic metabolites, inflammatory factors, and autoantibodies that are produced in the gut could find their way into the blood or serum and produce disease when transplanted into laboratory animals.
On that note, Jason and Katz’s prospective study following college students who came down with infectious mononucleosis strongly implicated the gut. College students who experienced severe gut symptoms (pain, bloating, irritable bowel) at the time of their illness and low levels of IL-13 and IL-5 had nearly an 80% chance of coming down with ME/CFS 6 months later (!).
Lastly, I asked Perplexity AI: “How could factors not produced by the gut but are found in the serum or blood replicate disease by transferring the gut microbiome to laboratory animals?“. It stated that inflammatory factors, altered bile acids, autoantibodies, uremic toxins, and cortisol could all influence the gut flora in such a way as to cause it to produce disease when transplanted.
The gist is that Perplexity AI believes the process could start from either direction – the blood or the gut.
Conclusion
It’s really something! Studies have found that something in the blood and now the gut can reproduce the symptoms seen in FM, ME/CFS, and long COVID in laboratory animals and in the lab! Perhaps this is not surprising, given how intense and debilitating these diseases can be, but still… (What’s next—spinal fluid transplants?).
It was heartening to see how the immune and metabolic changes in the mice (B-cells, monocytes, inflammation, fatty acids, lipid dysregulation) mirrored so much of what we know about these diseases. While these diseases are very complex, and there are no easy answers, many of these studies—whether in FM, ME/CFS, or long COVID—seem to end up in familiar places—hovering around a simuilar suite of dysregulations, and that’s good to see as well.
I left an in-depth comment about my experience with TUDCA but when I submitted it said ‘duplicate comment – looks like you’ve already said that’ and erased it 🙁
Short version: TUDCA may also help ME directly due to immunomodulatory and mitochondrial effects…