Irritable bowel syndrome (IBS) is a pretty big deal. The most common gut disorder, IBS, costs the U.S. economy about $1 billion a year and occurs in a considerable number of people with chronic fatigue syndrome (ME/CFS) and/or fibromyalgia (FM).
It, ME/CFS and FM, have long been considered “functional” diseases e.g., diseases that can cause substantial reductions in functionality but without an apparent cause. Gut imaging studies that found nice, healthy-looking guts in the midst of considerable pain have left researchers puzzled – with some searching for a psychological cause.
The same scenario, of course, has been applied to ME/CFS, FM, and POTS – three “invisible” diseases without obvious structural abnormalities that are more likely to be diagnosed in women.
That psychological idea for IBS has never held much water. While it’s true that calming therapies can help reduce symptoms, the same is probably true for many conditions. The fact that some people can avoid or even eliminate their symptoms by avoiding some foods (carbohydrate-rich, gluten-containing, dairy, citrus, beans, cabbage/broccoli, and similar vegetables) or by going diets like the FODMAPS diet has suggested that a food connection is present.
We know that IBS is a hypersensitivity condition because inserting a balloon into the colon and slowly blowing it up causes pain in people with IBS but not in healthy controls. Why the pain is there has been unclear. A paper, “Local immune response to food antigens drives meal-induced abdominal pain“, that popped up in the Nature journal earlier this year may provide answers, – not just for IBS but for other “functional syndromes” as well.
It offers an explanation for several of the mysteries that have permeated the IBS, ME/CFS, FM, and other fields. It shows how an infection can lay the groundwork for a chronic disease, it demonstrates why standard measures of inflammation have never revealed much, it shows how easily the causes of diseases like these can be hidden, and it shows how the nerves come into play. Plus, it validates something ME/CFS experts consider to be a hot topic (mast cell activation syndrome (MCAS) but which the medical research field has yet to embrace.
The Infection Connection
The authors – all 45 of them (!) (from Belgium, Germany, Canada, and the U.S.) – started off by noting that about 20% of IBS patients report a gut infection sparked their illness, making IBS, at least in part, a post-infectious disorder.
They suspected that IBS is a food-triggered antigenic driven event; i.e. that certain foods are sparking an immune reaction in the gut. First, they infected one group of mice with a pathogen (Citrobacter rodentium) while exposing them to a known antigen (ovalbumin (OVA)); i.e. something they knew would also spark an immune response. Another group of mice were exposed to the antigen but not to the pathogen.
The mice which had been infected and exposed to the antigen cleared the infection but then developed an IBS-like condition; i.e. they experienced diarrhea, increased fecal water content, increased transit times, increased gut permeability, gut muscle contractions, and hypersensitive response (pain) in the gut. Antibodies to the antigen also showed up.
Re-exposing the mice to the antigen later resulted in another period of prolonged gut hypersensitivity. Exposing the mice to other antigens, interestingly, did not evoke an extended period of gut hypersensitivity. This indicated that the immune systems of the mice had been sensitized only to the antigen which had been introduced when they were fighting off the infection.
None of the above happened in the mice that had not been exposed to a pathogen. In an interview with Jane Brody of the New York Times, Dr. Marc Rothenberg explained what appears to have happened.
The infection temporarily disturbed the protective layer of cells lining the bowel that prevents allergy-inducing proteins from being absorbed. Losing that barrier – even for a short time – sensitized the immune system to those proteins – causing it to react to those foods.
Treating the mice with a monoclonal antibody that latched onto the suspect antibody stopped the whole thing in its tracks; i.e. it appeared that an antibody-triggered immune reaction was behind the whole thing. They explained it like this.
“Together, these data indicate that a gastrointestinal bacterial infection can break oral tolerance to a dietary antigen and result in an adaptive immune response towards food antigens, leading to increased permeability and abnormal pain signaling upon re-exposure to the antigen.”
Over a series of studies, they dug deeper and deeper. Exposing the mice to a gut pathogen and an antigen at the same time caused dramatic shifts in the mouse gut flora – but as neither antibiotic use nor the shift in the flora (at least at a macroscopic level) produced the gut hypersensitivity problem, they discarded an altered gut flora as a cause of the problem. (This may not be a particularly solid finding as the authors determined this using the two main genera driving the bacterial shift and did not take other bacteria into account.)
Next, they turned to inflammation and mast cell activation. Although the low-grade inflammation found during the acute phase of the illness resolved itself an intriguing uptick in the expression of a mast-cell gene (tryptase α/β-1 gene (Tpsab1)) showed up. That suggested that the mast cells had become sensitized – and were just waiting for an opportunity to activate.
Next, they linked the increased gene expression to the increased production of the main mast cell mediator – histamine. That indicated that the mast cells had degranulated and released their immune mediators. Validation of the mast cell connection occurred when treatment with the mast cell stabilizer doxantrazole turned off the gut hypersensitivity problems completely.
The B-cell connection was validated when eliminating B and plasma cells also reduced the levels of the pathogen-specific antibodies and prevented the development of gut hypersensitivity. It appeared that the original antibody response that had popped up during the infection/antigen overload was driving the mast cell response.
More evidence that IBS is, at least in some people, a mast cell-induced disorder was forthcoming. Studies showed that histamine-containing fluids from people with IBS and colonic liquids from the mice were able to produce pain hypersensitivity (central sensitivity). Adding a different histamine antagonist called pyrilamine once again turned off the pain.
The researchers have even identified ion channels (TRPV1) in the sensory nerves that get turned on during this process. They’ve also shown that other pathogens can – in the presence of an antigen – reproduce the whole process; i.e. the infection/antigen/antibody/mast cell connection seems broad indeed.
(Note that an infection is not necessarily required to start this process – anything that wipes out that protective gut lining could do that. Although the authors discarded an altered gut flora as a cause, their gut flora analysis was rather primitive. The inflammation-promoting and gut lining damaging gut flora found in ME/CFS could presumably do the same damage as an infection, and probiotics and other gut flora influencing treatments can help.)
Next, they looked at indicators of increased mast cell activity in people with IBS. Tryptase activity was higher both under baseline conditions and when exposed to 4 common allergens (soy, wheat, gluten, and histamine). AEBSF – a broad-spectrum serine protease inhibitor – also completely stopped the trypsin-like activity.
Some doctors test for MCAS by assessing how many mast cells are found in gut biopsies but this group didn’t find an increase in the total number of mast cells. Instead, people with IBS had more IGE+ mast cells close to their nerve fibers. In fact, the closer they were to the nerve fibers, the more pain the IBS patients were in – suggesting that this entire reaction is very localized (and quite hidden from sight).
The fact that the antibodies are only found in colonic tissues – not in the circulation – underscores that this is not a typical allergic process that occurs systemically. The authors noted that a similar process has been found in allergic rhinitis and chronic rhinosinusitis.
They proposed that IBS, at least in some patients, is at one end of a spectrum of food-induced disorders, all of which, they believe, are driven by mast cell activation. Systemic food allergy is at the other. The lead author, Professor Guy Boeckxstaens, stated:
“At one end of the spectrum, the immune response to a food antigen is very local, as in IBS. At the other end of the spectrum is food allergy, comprising a generalized condition of severe mast cell activation, with an impact on breathing, blood pressure, and so on.”
They also proposed that people who are more genetically inclined to have more allergic reactions (allergic rhinitis, asthma, allergic eczema) are probably more likely to develop IBS.
It’s easy to see why Nature – perhaps the most read scientific journal in the world – was happy to publish this work. It reports on a very methodical, step-by-step process that may have tracked down at least one of the sources of a very mysterious disease. Its main shortcoming concerns the small number of humans in the human study – something which is surely being remedied now.
The model helps explain why IBS has been such a mystery. The infection sweeps through, exposing the gut to elements that it reacts to – setting up a long-term immune reaction. The immune reaction is quite localized, however – it only sparks a reaction in the gut itself (making blood tests iffy) and then, and perhaps most importantly, only affects the nerves. That makes it hidden.
All the time the nerves are going bananas the tissue apparently looks perfectly healthy. This is, if memory serves, exactly the process that mast cell proponents have proposed is happening. All you need to bake this pie is to have activated mast cells close enough to the nerves to make them scream.
Professor Guy Boeckxstaens, the lead author of the paper, summed up how this work should change doctors’ ideas about IBS.
“Very often these patients are not taken seriously by physicians, and the lack of an allergic response is used as an argument that this is all in the mind, and that they don’t have a problem with their gut physiology. With these new insights, we provide further evidence that we are dealing with a real disease.”
A Fit for ME/CFS/FM and Long COVID?
Could this general model help explain ME/CFS, FM, POTS, and long COVID? Might the endothelial cells lining the blood vessels in ME/CFS/FM and long COVID present a similar scenario? A different pathogen disrupting the protective layer lining another important roadway in the body? Time will tell but one thing is for sure – mast cell activation syndrome (MCAS) – long ignored by the traditional research community – has just been shown to provide a plausible answer for a medical mystery.
Could activated mast cells be tweaking the nerves in FM? Something is doing that, after all, and that something has not been identified. Nor does that something, similar to IBS, appear to be producing much of a systemic reaction or causing any tissue swelling or damage. Instead, in its hidden way it’s going straight for the nerves. It’ll be interesting to see if this IBS study sparks studies that start looking for mast cell activation in FM.
At the 2018 Dysautonomia Internationa Conference Brent, MD. asserted that the gut problems in POTS were caused by mast cell activation syndrome (MCAS) and described how a panoply of treatments returned a very ill POTS/MCAS/IBS patient to health.
- Irritable bowel syndrome (IBS) has long been considered a “functional disease”; i.e. a disease that substantially impairs functioning – but which doesn’t have a clear cause. The mystery is deepened by the fact that while people with IBS often experience severe gut pain, bloating, etc. the guts appear pink and healthy.
- A recent publication is one of the most prestigious scientific journals – Nature – may change all that. Through years of work several research teams that have slowly picked away at IBS findings using rodent studies and most recently human ones have come to a realization – IBS, they believe, is a mast cell disorder.
- First, an infection wipes out the protective layer lining the gut – exposing it to food proteins or antigens it usually doesn’t encounter. The immune system leaps to the rescue – attacking the proteins – and causing gut cramping (the muscles contracting in response to the antigens), bloating, constipation, etc.
- The infection clears – leaving the mast cells activated and ready to pounce once the suspect food is introduced again. Importantly, only the food proteins introduced when the gut lining was damaged are able to spark an immune reaction. Even after the gut lining is restored, though, the immune system still senses an invader is present and rises to the attack. It’s that immune response that’s causing IBS.
- Interestingly, mast cell numbers did not seem to be increased. Instead, the mast cell location made the difference. Mast cells found near the nerves provoked the reaction while mast cells more distant from the nerves did not.
- This indicated that the mast cell activation is VERY localized and explains why tests of mast cell activation or inflammation often don’t explain much. The authors believe that the mast cell activation in IBS is akin to that found in food allergies except that food allergies provoke a systemic immune response while the mast cells in IBS provoke a very localized mast cell response – leaving them mostly hidden from sight.
- The mast cell activation is the end product of the immune response. The process is begun, however, when B-cells produce antibodies to the offensive proteins of the foods.
- The paper’s weak point was the small sample size used in the human studies. That needs to be rectified but the evidence leading up to the human studies seemed overwhelming. Step by step, the researchers have produced an impressive body of research that appears to have tracked down a cause of IBS that could explain much.
- Of course, if immune and mast cell activation explains IBS could it also explain its sister diseases like ME/CFS, fibromyalgia, and POTS? In their lack of structural damage and overt physical findings, the diseases all resemble each other. Each can be triggered by an infection and each seems likely to be immune-mediated but evidence of significant inflammation (except perhaps in the brain) is lacking. Could mast cells be producing very localized reactions that are tweaking the nerves and escaping detection in these diseases as well? (VanElzakker has proposed that small, localized infections affecting the vagus nerve may be being missed in ME/CFS).
- The authors of the Nature paper suggested that antihistamines and drugs that reach further upstream of the mast cell activation may be helpful and cited some. Other, hopefully, more effective mast cell inhibiting drugs are in the final stages of the drug approval process and could provide more help for IBS and perhaps for ME/CFS and FM patients as well.
- Some mast cell treatments are described in the blog – check the treatment section for those.
Dr. Klimas has called it one the most interesting immune diseases going.
A larger trial using antihistamines is underway but the lead author believes antihistamines present just the beginning of a potentially effective treatment regimen. Professor Guy Boeckxstaens hoped the studies will spark the development of more effective mast cell treatments.
“But knowing the mechanism that leads to mast cell activation is crucial, and will lead to novel therapies for these patients. Mast cells release many more compounds and mediators than just histamine, so if you can block the activation of these cells, I believe you will have a much more efficient therapy.”
The authors suggested using mast cell inhibitors like the H1R-antagonist ebastine which target the upstream mechanisms behind the mast cell activation should be more effective. Ebastine is a non-sedating HI antihistamine that studies show can help IBS. The authors also plugged omalizumab, a monoclonal antibody against IgE26, which in two case reports completely resolved severe cases of IBS, as well as treatments like IgE neutralization, and drugs that can inhibit spleen tyrosine kinase.
In an interview, Rothenberg also noted that new mast cell inhibiting drugs are now in the very last stage of approval (Phase 3 trials).
Check out how two informed MD’s treat MCAS.
Dr. Chheda on Treating MCAS
High doses of antihistamines are, of course, one possibility for this situation. Dr. Bela Chheda explained how she diagnosed and treated MCAS a couple of years ago.
Citing their inaccuracy, she doesn’t run 24-hour urine tests but does run a mast cell panel (tryptase, chromogranin, histamine, prostaglandins, IgE). (The tests leave something to be desired – using them to form a diagnosis is rather problematic.)
- Tryptase – a small percentage of people have elevated tryptase. When tryptase levels are elevated, they’re usually borderline elevated (13-20).
- Chromogranin – another small percentage of patients have high chromogranin. (She noted that low stomach acid can also cause elevated chromogranin).
- Prostaglandins – The two main MCAS markers she uses involve the prostaglandins. Prostaglandin D2 is the most helpful marker, but because it can have diurnal variations, it may take several tests to capture the elevation. F2 alpha – which is a breakdown product from other cells as well as mast cells – is moderately diagnostic.
- IgE is not diagnostic, but high IgE levels suggest that something may be going on with the mast cells.
Biopsies of the GI tract or from colonoscopies can provide another clue if they find high numbers of mast cells. If a patient already has a biopsy, she tries to get it stained and counted for mast cells. While it’s not clear yet what constitutes an abnormal number of mast cells, in her experience >30 is probably abnormal.
With the diagnostic testing lacking accuracy, often a trial of MCAS medication – which is usually well-tolerated – is called for.
Dr. Chheda referred to a recent patient with a classic case of ME/CFS who did not appear at first blush to have MCAS. An antihistamine trial told the tale, though; while neither 1-2 antihistamines a day made a difference, adding a third one did – it completely removed the patient’s anxiety!
Dr. Chheda suggests starting with non-sedating antihistamines such as Claritin or Allegra. (She doesn’t recommend patients trying more than 2 antihistamines at a time on their own without supervision.) She also can use an herbal mast cell stabilizer called Quercetin (500 mg twice a day) and ketotifen, a compounded antihistamine that is also a mast cell stabilizer,
If someone thinks they may have MCAS, Dr. Chheda recommends reading Dr. Afrin’s book “Never Bet Against Occam: Mast Cell Activation Disease and the Modern Epidemics of Chronic Illness and Medical Complexity” which contains more detailed information on treatments.
Dr. Carnahan on Treating MCAS
Dr. Jill Carnahan reports that the following over-the-counter drugs or supplements can block MCAS symptoms. If you experience MCAS symptoms and these make you feel better, it stands to reason that you may have MCAS. (Not responding to these treatments, on the other hand, does not mean that you don’t have MCAS.)
- Diphenhydramine (Allergy Relief, Allermax, Banophen, Benadryl, Compoz Nighttime Sleep Aid, Nytol QuickCaps, PediaCare Children’s Allergy, Q-Dryl, QlearQuil Nightitme Allergy Relief, Simply Sleep, Sleepinal, Sominex, Tranquil, Twilite, Unisom Sleepgels Maximum Strength, Valu-Dryl, Vanamine PD, Z-Sleep, ZzzQuil and many others)
- Loratidine (Claritin, Claritin Liqui-Gels)
- Cetirizine (Zyrtec, All Day Allergy)
- Famotidine (Pepcid, Pepcid AC); Cimetidine (Tagamet, Tagamet HB); Ranitidine (Zantac)
Mast Cell Stabilizers
- Cromolyn, Ketotifen, Hyroxyurea
Natural anti-histamines and mast-cell stabilizers
- Ascorbic Acid, quercetin, Vitamin B6 (pyridoxal-5-phosphate), Omega-3 fatty acids (fish oil, krill oil), Alpha Lipoic Acid, N-acetylcysteine (NAC), Methylation donors (SAMe, B12, methyl-folate, riboflavin)
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