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Histamine as an inducer of symptoms in IBS

Shanti1

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Clinical studies support the hypothesis that histamine is an inciting factor in IBS for a sizable cohort.

Antihistamine reduces pain in irritable bowel syndrome
In a 12-week randomised trial, the team gave 28 patients the H1 antihistamine ebastine and 27 patients a placebo. Ebastine treatment significantly reduced the mean pain score, while no change was observed in the placebo group. Nearly half of ebastine-treated patients reported considerable symptom relief.


Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patient
Symptoms related to the irritable bowel syndrome improved in 60% of patients treated with elimination diet and in 67% of those treated with oral cromolyn sodium (1500 mg/day) for 1 month. Moreover, in both groups clinical results were significantly better in the patients positive to the skin prick test than in the negative ones.


Gut Microbes that Release Histamine Worsen IBS Pain
In this study, patients were assessed over several months. High levels of histamine were found in fecal samples when patients were also feeling severe pain, and when they were free of pain, histamine levels in stool were low, revealed senior study author and gastroenterologist Premysl Bercik, a professor at McMaster.

The researchers also colonized mice that had no gut microbiota with gut microbes from IBS patients. Control mice were colonized with gut microbes from healthy human volunteers. With this model, the scientists determined that K. aerogenes converts an amino acid called histidine, which is found in the diet, into histamine, which is known to be involved in pain signaling. The immune system in the gut is also activated by that bacterially converted histamine, where the histamine-4 receptor binds to it, attracting mast cells. The mast cells can can trigger additional inflammation and pain by producing more histamine and other molecules.

"Now that we know how the histamine is produced in the gut, we can identify and develop therapies that target the histamine producing bacteria," said first study author Giada de Palma, an assistant professor at McMaster.

If mice that had been exposed to K. aerogenes were given a diet with low levels of fermentable carbohydrates (sometimes known as a low FODMAP diet), the production of histamine was significantly reduced. There were changes in acidity and fermentation by bacteria in the gut, inhibiting an enzyme that generates the bacterial histamine.

This work has shown why diets that are low in fermentable carbohydrates are helpful for IBS patients, who are known to carry abnormally high levels of mast cells in their gastrointestinal tracts. Treatments that target mast cells or histamine may, therefore, be beneficial as well.

"Although mast cell treatment in IBS has been explored, a novel approach based on our research would be targeting the bacterial histamine production or H4R pathways," Bercik said.

"Many, but not all IBS patients, will benefit from therapies targeting this histamine driven pathway," noted co-first study author David Reed, an assistant professor at Queen's. Biomarkers might be helpful to identify the patients that would probably respond to the treatment, added Reed.

Sources: McMaster University, Science Translational Medicine

(Note: Title of thread edited from Histamine as an inciting factor in IBS to current title for clarity)
 
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Pyrrhus

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Clinical studies support the hypothesis that histamine is an inciting factor in IBS for a sizable cohort.

Histamine, or other mast-cell activators, can increase intestinal pain, but the phrase "inciting factor" sounds like you're claiming that mast cell activation is a cause of IBS, which I don't believe is supported by the literature.

I think what you meant to say is "pain-producing factor", not "inciting factor".


Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patient
Symptoms related to the irritable bowel syndrome improved in 60% of patients treated with elimination diet and in 67% of those treated with oral cromolyn sodium (1500 mg/day) for 1 month. Moreover, in both groups clinical results were significantly better in the patients positive to the skin prick test than in the negative ones.

This is a seriously flawed study that mixes up food intolerance with Irritable Bowel Syndrome (IBS).
As far as I know, food intolerance is not even mentioned in the Rome Criteria.

There was another seriously flawed study last year that made the same mistake:

Local immune response to food antigens drives meal-induced abdominal pain (Aguilera-Lizarraga et al., 2021)
https://forums.phoenixrising.me/threads/irritable-bowel-syndrome-caused-by-mcas-new-report.83001/
 

Shanti1

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I think what you meant to say is "pain-producing factor", not "inciting factor".
Yes, you are right, the histamine is not the underlying cause of the IBS, but may be causative of symptoms in some people.

This is a seriously flawed study that mixes up food intolerance with Irritable Bowel Syndrome (IBS).
As far as I know, food intolerance is not even mentioned in the Rome Criteria.
It is true that the Rome Criteria does not mention food reactions as a diagnostic criteria for IBS, so it is not correct that the study abstract states, "In a significant number of patients affected by the irritable bowel syndrome, an adverse reaction to food is proposed to be a causative factor".

However, IBS is widely recognized to be triggered by food choices. It is now know that SIBO is highly associated with (sometimes misdiagnosed) as IBS, and is also highly impacted by food choices. I took a peek at the full text and this multi-center study did not use food intolerance as a diagnostic criteria, but used similar criteria to what we have today. In addition to the criteria linked to, the study authors made some specifications around BM frequency and consistency for the classification of IBSD.

So the study took verified IBSD patients and compared two different treatment options, elimination of offending foods and cromolyn sodium. While not your double-blind placebo controlled study, I think it still has value in adding to cumulative evidence for a role of histamine in symptomatology of IBS.
 

Rebeccare

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Clinical studies support the hypothesis that histamine is an inciting factor in IBS for a sizable cohort.
That was actually my mother's experience. After a series of serious illnesses she became allergic to just about everything. She also started having GI issues, which didn't seem to be connected to the allergy issues at first. She was on the verge of being diagnosed with IBS when one day she happened to run out of bananas. She usually had a banana each morning for breakfast with her oatmeal, and on the day she didn't have that banana, she felt great! That's when she put two and two together.
 

Pyrrhus

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However, IBS is widely recognized to be triggered by food choices.

I have not heard of any such recognition, at least not in a scientific setting. If people are saying this, then it sounds like people are trying to lump all possible gastrointestinal disorders into a single diagnosis, which would be very unwise. The Rome Criteria are overly broad as it is, and we need to be getting more specific with our diagnoses, not less specific. Lumping the various types of food intolerance in with IBS may ultimately result in another unfortunate wastebasket diagnosis.

In my own personal case, I have had IBS for decades without any association to any particular food, the size of any meal, or even whether or not I have eaten anything. My IBS symptoms are naturally "triggered" by only one thing: physical/cognitive exertion. There is, however, a strong correlation between my IBS symptoms and my orthostatic intolerance symptoms.

It is now know that SIBO is highly associated with (sometimes misdiagnosed) as IBS

My understanding is that SIBO is a symptom of IBS-C, but this symptom is not seen so much in IBS-D. Although, as @kangaSue likes to remind us, diagnostic testing for the SIBO symptom of IBS is currently problematic at best.

So the study took verified IBSD patients and compared two different treatment options, elimination of offending foods and cromolyn sodium. While not your double-blind placebo controlled study, I think it still has value in adding to cumulative evidence for a role of histamine in symptomatology of IBS.

Yes, assuming the patients were correctly diagnosed. :)
 
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Shanti1

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I have not heard of any such recognition, at least not in a scientific setting. If people are saying this, then it sounds like people are trying to lump all possible gastrointestinal disorders into a single diagnosis, which would be very unwise. The Rome Criteria are overly broad as it is, and we need to be getting more specific with our diagnoses, not less specific. Lumping the various types of food intolerance in with IBS may ultimately result in another unfortunate wastebasket diagnosis.

In my own personal case, I have had IBS for decades without any association to any particular food, the size of any meal, or even whether or not I have eaten anything. My IBS symptoms are naturally "triggered" by only one thing: physical/cognitive exertion. There is, however, a strong correlation between my IBS symptoms and my orthostatic intolerance symptoms.

To clarify, I should have said, IBS symptoms are know to be triggered by food choices. This is, of course, not true for everyone as IBS, like ME/CFS probably has more than one etiology. I certainly have met others, like yourself, where food did not seem to have any influence. I have also met people where dietary changes greatly improved symptom control.

Nonetheless, the association between food and exacerbation of IBS is documented in the literature and medical websites (mayo, webmd, Harvard etc) routinely post "avoid" lists (coffee, high fructose foods, spicy foods, etc) or suggest low FODMAP. If you do a quick search, you will see many studies supporting the association, but here are a few:


Dolan R, Chey WD, Eswaran S. The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs. Expert Rev Gastroenterol Hepatol. 2018 Jun;12(6):607-615.

Altobelli E, Del Negro V, Angeletti PM, Latella G. Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-Analysis. Nutrients. 2017 Aug 26;9(9):940.

Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.

Vazquez-Roque MI, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013 May;144(5):903-911.e3.

Kamal A, Pimentel M. Influence of Dietary Restriction on Irritable Bowel Syndrome. Am J Gastroenterol. 2019 Feb;114(2):212-220. (nice review if you pull the full text)

Singh R, Salem A, Nanavati J, Mullin GE. The Role of Diet in the Treatment of Irritable Bowel Syndrome: A Systematic Review. Gastroenterol Clin North Am. 2018 Mar;47(1):107-137.
 

Shanti1

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My understanding is that SIBO is a symptom of IBS-C, but this symptom is not seen so much in IBS-D. Although, as @kangaSue likes to remind us, diagnostic testing for the SIBO symptom of IBS is currently problematic at best.

IBS-C is typically associated with methane SIBO and IBS-D is more commonly seen in hydrogen SIBO (ref)(ref). This has also been my experience in looking at SIBO tests, although mixed is also common with hydrogen. Hydrogen sulfide predominate SIBO is usually described by practitioners as associated with diarrhea, but I recently saw a study where they associated it with constipation, so not really sure on that one. Anyhow, which gas is produced is dependent on the bacteria present.

There are now multitudes of studies associating IBS-D and IBS-C with SIBO, they are easy to find, so I won't bother posting them.

Regarding SIBO breath testing:

Siddiqui I, Ahmed S, Abid S. Update on diagnostic value of breath test in gastrointestinal and liver diseases. World J Gastrointest Pathophysiol. 2016 Aug 15;7(3):256-65.
"A diagnosis of SIBO is made on glucose hydrogen BT if there is an upsurge in breath hydrogen by 12 ppm above the base line levels. Reportedly sensitivity and specificity of this test are 62% and 83% respectively, when compared with culture from jejunal aspirate[7]. "

I personally think these rather poor statistics (some studies do report better test performance) can be improved by measuring methane as well as hydrogen because significant proportion of SIBO is methane SIBO. Hydrogen sulfide can now be measured as well, which would increase the ability to identify SIBO patients who are negative for methane and hydrogen and improve false negatives. Lactulose and glucose both have pros/cons as testing substrates, however, if someone gets a negative with one substrate and SIBO is still strongly suspected, the test should be repeated with the other substrate. Testing duration of 3 hours instead of two can help with accuracy. Having individuals with slow transit time do the prep diet for 48 instead of 24 hours can also increase accuracy and limit false positives. Anyhow, I think all of these measures would greatly improve specificity and sensitivity.

The way SIBO test results come back, they are not always black or white. Even through there are criteria for SIBO diagnosis (see North American Consensus), on borderline tests, much is left to the interpretation of the clinician. Improvement with antibiotics, history of food poisoning, worse with FODMAP foods, worse with pre-biotics, and other questions can help with accurate test interpretation.

Estimations on the occurrence of SIBO in IBS are all over the place, but those who are better with high protein diets and antibiotics and worse with fiber and carbs may want to consider it. While it is always ideal to have testing, I have seen people who strongly fit the "SIBO picture" treat presumptively without testing and come out the other end much better for it. SIBO is one of the few conditions where there is good clinical evidence for effectiveness of non pharmaceutical treatment using low-FODMAP, herbal preparations, and/or elemental diet.
 
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Pyrrhus

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To clarify, I should have said, IBS symptoms are know to be triggered by food choices.

Ah yes, since some food intolerances share the same symptoms with IBS, it makes absolutely perfect sense that food choices can influence those symptoms.

These darn overlapping diagnoses can be quite annoying to try to disentangle! :sorry:


Dolan R, Chey WD, Eswaran S. The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs. Expert Rev Gastroenterol Hepatol. 2018 Jun;12(6):607-615.

Altobelli E, Del Negro V, Angeletti PM, Latella G. Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-Analysis. Nutrients. 2017 Aug 26;9(9):940.

Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.

Vazquez-Roque MI, et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. Gastroenterology. 2013 May;144(5):903-911.e3.

Kamal A, Pimentel M. Influence of Dietary Restriction on Irritable Bowel Syndrome. Am J Gastroenterol. 2019 Feb;114(2):212-220. (nice review if you pull the full text)

Singh R, Salem A, Nanavati J, Mullin GE. The Role of Diet in the Treatment of Irritable Bowel Syndrome: A Systematic Review. Gastroenterol Clin North Am. 2018 Mar;47(1):107-137.

Thanks for the great selection of studies! I'll definitely take a look at them. :monocle:

Interestingly, none of the IBS studies I have read had mentioned food intolerance. (except for that horribly flawed study from last year!)


Regarding SIBO breath testing:

Siddiqui I, Ahmed S, Abid S. Update on diagnostic value of breath test in gastrointestinal and liver diseases. World J Gastrointest Pathophysiol. 2016 Aug 15;7(3):256-65.
"A diagnosis of SIBO is made on glucose hydrogen BT if there is an upsurge in breath hydrogen by 12 ppm above the base line levels. Reportedly sensitivity and specificity of this test are 62% and 83% respectively, when compared with culture from jejunal aspirate[7]. "

You make some quite excellent points about SIBO testing!

You may also be interested in @kangaSue 's unique perspective on SIBO testing:
https://forums.phoenixrising.me/thr...intestinal-motility.81362/page-2#post-2394099
 

Shanti1

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You may also be interested in @kangaSue 's unique perspective on SIBO testing:
https://forums.phoenixrising.me/thr...intestinal-motility.81362/page-2#post-2394099

Thanks @Pyrrhus I clicked on the link, but I don't have enough brain power left to read it today, will take a look at it tomorrow.
Breath testing is definitely not a perfect tool, someone brought this study to my attention last week:

Erdrich S, et al. Hydrogen-methane breath testing results influenced by oral hygiene. Sci Rep. 2021 Jan 8;11(1):26.

Administration of a chlorhexidine mouthwash resulted in significantly (p ≤ 0.05) reduced breath hydrogen in 67% and/or methane gas in 93% of those consenting to inclusion. In some cases, this modified the diagnosis.

Anyhow, my current thought is that the breath test is an imperfect tool, but useful in the right hands and when used in conjunction with clinical presentation. I'll see if my thoughts change after reading KangaSue's info :monocle:
 
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Pyrrhus

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Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.

This paper was particularly interesting. I was surprised that of the 176 patients evaluated for this study, 150 had some detectable IgG antibody to at least one of 29 different food antigens.

I found this especially surprising because IgG antibodies generally develop in response to internalized antigens, whereas the intestinal lining generally produces IgE antibodies in the case of acquired food intolerance...

I am including the abstract below for the benefit of others:

Background: Patients with irritable bowel syndrome (IBS) often feel they have some form of dietary intolerance and frequently try exclusion diets. Tests attempting to predict food sensitivity in IBS have been disappointing but none has utilised IgG antibodies.

Aims: To assess the therapeutic potential of dietary elimination based on the presence of IgG antibodies to food.

Patients: A total of 150 outpatients with IBS were randomised to receive, for three months, either a diet excluding all foods to which they had raised IgG antibodies (enzyme linked immunosorbant assay test) or a sham diet excluding the same number of foods but not those to which they had antibodies.

Methods: Primary outcome measures were change in IBS symptom severity and global rating scores. Non-colonic symptomatology, quality of life, and anxiety/depression were secondary outcomes. Intention to treat analysis was undertaken using a generalised linear model.

Results: After 12 weeks, the true diet resulted in a 10% greater reduction in symptom score than the sham diet (mean difference 39 (95% confidence intervals (CI) 5–72); p =  0.024) with this value increasing to 26% in fully compliant patients (difference 98 (95% CI 52–144); p<0.001). Global rating also significantly improved in the true diet group as a whole (p = 0.048, NNT = 9) and even more in compliant patients (p = 0.006, NNT = 2.5). All other outcomes showed trends favouring the true diet. Relaxing the diet led to a 24% greater deterioration in symptoms in those on the true diet (difference 52 (95% CI 18–88); p = 0.003).

Conclusion: Food elimination based on IgG antibodies may be effective in reducing IBS symptoms and is worthy of further biomedical research.
 

Shanti1

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You make some quite excellent points about SIBO testing!

You may also be interested in @kangaSue 's unique perspective on SIBO testing:
https://forums.phoenixrising.me/thr...intestinal-motility.81362/page-2#post-2394099

Yes, a very informative post. I actually pulled the full text give it a read. Can't really argue about Glucose being a better substrate choice than Lactulose. It is said (not in the article, in general) that Glucose will give more false negatives because it can be absorbed early in the small intestine, and Lactulose will give more false positives because it can speed up transit time and cause a rise thought to be in the small intestine, but that is really in the cecum or colon. However, it seems that in most cases, glucose is preferable since the false positive from lactulose seems beyond a reasonable margin.

I think SIBO is probably both under-diagnosed and over-diagnosed, depending on the medical setting and practitioner. Many GI docs will never consider it and some "functional" docs will try to pin everything on it!
 

Shanti1

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This paper was particularly interesting. I was surprised that of the 176 patients evaluated for this study, 150 had some detectable IgG antibody to at least one of 29 different food antigens.

I found this especially surprising because IgG antibodies generally develop in response to internalized antigens, whereas the intestinal lining generally produces IgE antibodies in the case of acquired food intolerance...

I actually have a collection of about 10 studies or so evaluating the connection between IgG antibodies to foods and IBS, Migraine, arthritis, and other conditions. Most of these studies show a small to moderate but statistically significant correlation with intake of IgG reactive foods and symptoms.

Not surprisingly, IgG food antibody panels are available for people who would like to identify food triggers for symptoms. Unlike IgE symptoms, systemic IgG symptoms are thought to me more delayed in onset and harder to intuitively relate to the food. I personally think the best method for identifying food sensitivities is an elimination diet with structured reintroduction of foods, but I think there is some value in IgG food testing. However, like SIBO breath test, it is far from perfect. Many foods that show IgG reactivity don't actually seem to bother the person and, since there are many ways, known and unknown, that we can react to foods, many foods that may be a problem, won't show up.

When someone shows up with a large number of IgG reactive foods, it is generally assumed that there is intestinal permeability, either through the gap junctions or actual intestinal lining breakdown. This goes with your comment of IgG developing in response to internalized antigens. Another interesting observation is that most tests I see come back with elevated IgG to egg albumin. I have always wondered if this is due to egg albumin being a vaccine ingredient.

Another fun-fact, most studies on IgG food reaction look at total IgG, but IgG4 antibodies are thought to calm down IgE response and are not associated with the same reactions elicited by food antibodies of IgG1,2,3.

James LK, Till SJ. Potential Mechanisms for IgG4 Inhibition of Immediate Hypersensitivity Reactions. Curr Allergy Asthma Rep. 2016 Mar;16(3):23.
IgG4 is the least abundant IgG subclass in human serum, representing less than 5 % of all IgG. Increases in IgG4 occur following chronic exposure to antigen and are generally associated with states of immune tolerance. In line with this, IgG4 is regarded as an anti-inflammatory antibody with a limited ability to elicit effective immune responses. Furthermore, IgG4 attenuates allergic responses by inhibiting the activity of IgE.
 

Pyrrhus

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