Wayne Persky

This is a glimpse of some of the information that will be discussed in my next book.  Please be aware that the details of this text are subject to change in the final version when the book is published.  This post is for informational purposes only, and should not be considered to be medical advice.  While this information is thought to be correct, some of it may be incomplete, and at this point it may not be verified by published medical research data.

Histamine is responsible for most of the classic allergy symptoms that we experience if we have a pollen allergy or some other type of allergy. The runny nose, watery eyes, itching, and in severe reactions, the anaphylactic symptoms such as airway restriction and breathing difficulties are caused by the release of histamine from mast cells, basophils, and eosinophils. The redness and swelling that develop following a mosquite bite or a wasp sting are due to the release of histamine in the tissues surrounding the bite or sting.

Histamine causes increased permeability of the small blood vessels (capillaries) in the area in order to allow white blood cells to pass from the capillaries into the surrounding tissues to engage any pathogens or toxins that might be present. The inflammation resulting from the histamine and the white cells, along with the fluids from the bloodstream that also flow into the area, cause the redness and swelling.

In the body, histamine is derived from histidine, which is an essential amino acid. Because humans cannot produce histidine, it must be present in the diet. However, certain species of gut bacteria can produce histidine, and it’s conceivable that the evolutionary changes that have taken place in our gut bacteria profiles in recent decades due to increased antibiotic use and the expanded use of ingredients and chemicals in processed foods may play a part in the trend toward increasing histamine problems.

Many authorities have long suspected that MC may be caused by gut bacteria imbalances.
But to date, no researcher or research team has ever been able to verify that this is even a valid possibility, let alone likely. What follows is a theory (my own) — a description of a mechanism by which this might occur.

If histamine can cause increased permeability of blood vessels, then it doesn’t take much of a stretch of the imagination to recognize that it may well also be capable of causing increased permeability of the intestines, because the epithelial lining of both blood vessels and the intestines are quite similar. And because the intestines are specifically designed so that nutrients can pass from the lumen (the interior volume of the intestines) into the blood vessels present in the intestinal walls, for distribution throughout the body, similarity of design of the 2 interfaces in order to accommodate this vital function would be expected.

We learned in the first edition of Microscopic Colitis that increased intestinal permeability is a side effect of gluten sensitivity that leads to the development of food sensitivities, so now we can see how excess histamine in the intestines could easily trigger existing food sensitivities, or possibly promote the development of additional food sensitivities. So now all that is lacking in this scenario in order to provide the potential for excessive histamine levels capable of causing a leaky gut and triggering intestinal inflammation is a gut bacteria population shift toward higher percentages of histidine-producing species, and a mechanism for promoting the conversion of histidine to histamine.. And it just so happens that such a mechanism happens to be very, very common in IBD patients — a magnesium deficiency.

Many MC cases that are unresponsive to treatment may be associated with an undiagnosed magnesium deficiency.
Magnesium deficiency is very common in the general population. In fact, many authorities insist that a majority of the population in developed countries are magnesium-deficient. And magnesium deficiency is even more likely among MC (and other IBD) patients because not only do both the malabsorption problem and diarrhea associated with the disease deplete magnesium, but the most common medical treatment used to suppress the inflammation, corticosteroids, also depletes magnesium.

Histidine decarboxylase is the enzyme used by the body to convert histidine into histamine. It’s known that a magnesium deficiency increases the activity of histidine decarboxylase, thereby increasing the conversion of histidine into histamine. But a magnesium deficiency can lead to a double whammy in this situation, because it also reduces the activity of diamine oxidase enzyme (DAO). As we discussed in the first edition of Microscopic Colitis, DAO is the enzyme primarily used by the body to purge unused or excessive amounts of histamine in circulation, in order to prevent the possibility of a potentially harmful histamine buildup.

So with the potential for a significant increase in histamine production, and a reduced ability to remove excessive amounts of histamine from the body, clearly a magnesium deficiency is likely to significantly increase the risk of a histamine buildup that can lead to various problems with the digestive system and elsewhere. And this can occur with or without a shift in the gut bacteria population balance to an increased percentage of histidine-producing bacteria. Obviously if gut bacteria begin to promote an increase in histidine production concurrent with a magnesium deficiency, this could create the potential for a perfect storm of inflammation due to an inappropriate level of mast cell activity. And the likelihood that this would become a chronic condition means that it would impose a significantly increased risk of triggering and/or perpetuating a microscopic colitis flare.

Note that this can happen independently of any T cell-based inflammation that might currently be present. Theoretically it can occur even if no T cell-based inflammation is present. Or it can occur when a combination of the 2 modes of inflammation exceed the threshold at which a reaction is triggered. It’s possible that there might even be a synergistic effect between the 2 types of inflammation. And in such a situation, logic dictates that as long as the total sum of the inflammation exceeds the threshold at which a reaction is maintained, remission cannot occur.

And because diamine oxidase enzyme requires vitamin B-6 for activation, the deficiency of B vitamins that so commonly occurs over the long term because of the malabsorption problems associated with MC and other IBDs can significantly add to the problem of histamine buildup by preventing DAO from functioning properly. Laboratory experiments have shown that increased vitamin B-6 intake can result in higher DAO activity levels. Whether or not this correlates with improved performance in the real world remains to be seen.

Could it be that the combination of antibiotic use and a magnesium deficiency is the real key in many cases?
As mentioned earlier in chapter 3 (in the new book — Edition II), many antibiotics and various other drugs tend to significantly deplete magnesium. And many MC patients point to antibiotics as the cause of their disease. So according to my theory, here is how this cascade of events unfolds to explain why antibiotics trigger microscopic colitis for so many people:

Antibiotics not only disrupt gut bacteria populations to provide the potential for histidine-producing bacteria to become better established, but they also severely deplete magnesium. And as we discussed earlier in this article, magnesium deficiency not only increases the activity of histidine decarboxylase, thereby increasing the conversion of histidine into histamine, but it also reduces the activity of diamine oxidase enzyme thereby compromising the ability of the body to purge excess histamine from the body This sets up an ideal environment for significantly increased mast cell activity and and an inflammatory histamine condition.

Forbes et al. (2008) has demonstrated that when stimulated by interleukin-9, increased mast cell activity can cause increased intestinal permeability that leads to food sensitivities.2 Note that this basically mimics the action of gliadin peptides in wheat gluten, which activate zonulin to cause increased intestinal permeability independent of genetics associated with autoimmunity (Drago et al., 2006).3 In other words, gluten causes increased intestinal permeability in all individuals, not just in those who have a gene associated with celiac disease.

Likewise, the conditions described above appear to provide another mechanism that can lead to leaky gut.  This opens the door to a totally independent way for food sensitivities to not only develop, but to be perpetuated, and this is essentially unexplored by medical researchers.  And while this may occur independent of any genetic limitations, it seems likely that genetics may play a role due to the fact that MC tends to run in families. It’s also possible that MC may run in families because of similar environmental associations, rather than genetic links.

But remember that a magnesium deficiency can promote the conversion of histidine to histamine without a gut bacteria population shift. Obviously a much more robust effect would occur if the use of an antibiotic promoted the proliferation of histidine-producing bacteria, but it also appears apparent that this mechanism should be capable of triggering MC independent of an event associated with the use of an antibiotic.

If this theory can be verified, it appears to define a mechanism by which MC can be triggered independently of T cell inflammation, which is currently considered to be the cause of the inflammation that’s associated with the disease. Because lymphocyte-induced inflammation is a diagnostic marker for the disease (LC), this raises an interesting question. “Are there any undiagnosed cases of MC that involve only mast cell-induced inflammation (apart from mastocytic enterocolitis), or do all cases involve T cell inflammation?”

Lymphocytic infiltration is a diagnostic prerequisite for lymphocytic colitis, and it is virtually always present even in collagenous colitis cases.  And if it is absent, and no collagen band  thickening can be detected in colonic biopsy  samples under the microscope, then neither LC nor CC can be diagnosed.  But does that mean that MC cannot exist in such a situation?  What if the mechanism I have described above is an alternative source of inflammation that can lead to the clinical symptoms normally associated with MC?

If all cases of MC involve lymphocyte-promoted inflammation (by definition), then either all cases initiated by mast cell inflammation soon lead to lymphocytic infiltration, or mast cell-based inflammation (as described above) is secondary to the lymphocyte-based inflammation typically attributed to MC.  Otherwise, there is no way that it could be diagnosed under the current diagnostic criteria.

Here are references 2 and 3 for this post:

2. Forbes, E. E., Groschwitz, K., Abonia, J. P., Brandt, E. B., Cohen, E., Blanchard, C., . . . Hogan, S. P. (2008). IL-9– and mast cell–mediated intestinal permeability predisposes to oral antigen hypersensitivity. Journal of Experimental Medicine, 205(4), 897–913. Retrieved from http://jem.rupress.org/content/205/4/897

3. Drago, S., El Asmar, R., Di Pierro, M., Grazia Clemente, M., Tripathi, A., Sapone, A., . . . Fasano A. (2006). Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scandinavian Journal of Gastroenterology, 41(4), 408-19. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16635908