CISRA’s Synergy Health Newsletter – Issue 10, Summer, 2007

Article III. Carbohydrate, Chlorogenic Acid and Benicar Sensitivity
in Relationship to the Marshall Protocol:
Preliminary Observations and Links to Theories of Chronic Disease

By J. C. Waterhouse, Ph.D.

Short Summary: A diet is proposed that appears to reduce allergic or sensitivity/intolerance reactions in certain susceptible people and help eliminate treatment-resistant bacteria by reducing an immunosuppressive class of substances (vitamin D receptor blockers). The diet consists of reducing consumption of a number of foods/beverages containing chlorogenic acid and closely related substances and reducing consumption of starches and certain sugars and fibers. The reasons that this diet is not suitable for certain people are given, along with the reasons this diet may help some people have greater success on the Marshall Protocol. Clinical observations, experiments and scientific studies are described that support this approach and link it to several theories of chronic disease.

Note on Translational Medicine: This article shows how insights from sophisticated, molecular modeling methods may help the chronically ill reduce symptoms and progress in bacterial killing, especially in cases of increased food/medication sensitivity/intolerance. This work arises from the understanding developed by Trevor Marshall, Ph.D., of the pathogenesis of a number of chronic inflammatory diseases (eg., sarcoidoisis, rheumatoid arthritis, fibromyalgia, chronic Lyme disease and others). This understanding has been incorporated into the Marshall Protocol (MP). The MP involves an antibacterial approach, which relies heavily on immune modulation to kill treatment resistant bacteria (cell wall deficient bacterial forms and bacteria in biofilms). These findings are an example of how clinical observations, when combined with the precise mechanistic knowledge gained from molecular modeling, can lead to useful revelations about treatment. (Disclaimer: What follows is for information only and is not intended as medical advice. Neither CISRA nor the author receives any funding or income from any organization or manufacturer connected with the topics discussed.)

Detailed Summary

The observations described below, suggest certain substances found in food, like chlorogenic acid (CGA), that are able to bind to the vitamin D receptor (VDR), appear to cause allergic or sensitivity/intolerance reactions in a small percentage of people. In highly susceptible people, CGA appears to be particularly effective at stimulating these immune sensitivity/intolerance reactions (through cross-reactions) to vitamin D, vitamin A, genistein, certain medications (e.g., Benicar), carnosic acid and a substance produced by bacteria that feed on certain carbohydrates (starch and certain sugars and fibers). CGA occurs in a diverse array of foods and beverages and is particularly high in coffee, tea, apples, soft drinks, prunes, lemon peel and pomegranate, among others. Sensitivity may manifest as negative and/or addictive reactions to various foods, supplements and medications.

As mentioned above, what all these cross-reacting substances appear to have in common is the ability to bind to the vitamin D receptor (VDR). The acronym is introduced here, VBS (VDR binding substance), to mean any substance that can bind to the vitamin D receptor, either blocking or activating it.

The fact that VBSs are all able to bind to the VDR means that at least some portion of the molecules are very similar. And VBSs appear to be similar enough in structure to cause immune sensitivity cross-reactions. Cross-reactions are well-known phenomena in allergy and immunology and are due to the similarity of structure of particular portions of sometimes diverse types of molecules. If the shapes of certain portions of the molecules are similar enough, patients may find increased sensitivity to one molecule increases sensitivity to the other similar molecules and thus causes the cross-reactions mentioned above.

The biological role of VBSs in binding to the vitamin D receptor is also very important. We now know that VDR binding substances can be important due to the vital role of the VDR in helping the innate immune system protect us from infection. In fact, blocking of the VDR by certain VBSs appears to be responsible for many chronic and autoimmune diseases (1, 2, 3, 6 Issue 10. "A Short Introduction to the Marshall Protocol"), while activation of the VDR by other VBSs can help us to heal.

Molecular modeling indicates that chlorogenic acid blocks the VDR. Thus, reducing CGA will increase VDR activation, resulting in greater immune activation and bacterial killing (6). Molecular modeling and clinical evidence shows that 1,25D (the active form of vitamin D) and Benicar activate the VDR, while high levels of 25D, carnosic acid, capnine and CGA block the VDR.

The bacterial killing enhanced by an active VDR is a desirable goal, but may increase symptoms due to the immune system reaction that occurs when the immune system attacks the bacteria and cleans up toxins and cellular debris. This immune system reaction increases inflammatory cytokines (e.g., IFN gamma, TNF alpha), which can increase pain, fatigue and a diverse array of other symptoms (a.k.a. Jarisch-Herxheimer, “Herx” or immunopathology reactions). The reaction to bacterial killing can become intolerable and even life-threatening if not controlled properly (see "Cautions – Updated").

So, VBSs have significance in two different ways. They can be a source of sensitivity reactions in a small minority of people, who thus may need to avoid them with a low VBS diet. And their ability to bind the VDR, means they can play an important role in the ability of the innate immune system to kill pathogenic microbes. How to deal with the multiple effects of VBSs (in sensitivity reactions and in VDR activation) is discussed in detail in the sections on practical implications (Sections C, D, E).

This article first presents additional background on the new observations on CGA and VBS sensitivity (Section A, below) and then discusses the relationship of VBSs to several theories of chronic disease (Section B). As mentioned above, there appears to be at least one type of bacteria that inhabits the intestines of some chronically ill people that is able to produce a VDR binding substance (VBS). Some experiments are described that suggest that it is species in the bacterial family, Enterobacteriaceae, that produce this VBS in the intestines. Though not all bacteria in this family produce VBSs, the Enterobacteriaceae include pathogenic forms of Escherichia coli, which have been linked to Crohn’s disease. It also includes Klebsiella pneumoniae, a common pathogen that has been linked to ankylosing spondylitis and other rheumatic diseases. Also in this family, are bacterial species linked to various diseases in the genera, Shigella, Salmonella, Yersinia, Proteus, Enterobacter and Citrobacter.

The production of a VBS by intestinal pathogens, as proposed here, provides support for Marshall's explanation of many chronic inflammatory diseases (1, 2, 3, 4, 5, 6). The VBS production by these and other pathogens could inhibit innate immune system function and thus allow bacteria to cause these chronic conditions. Reversing this VDR blockage, as in the Marshall Protocol (MP), is therefore seen as key to treatment success. Molecular modeling and clinical research that support this view are discussed.

Other topics discussed in Section B include how VBSs and the MP may relate to new revelations in the journal, Nature, about how particular bacteria in the intestines may promote obesity. The role of the optimal diet predicted by evolutionary medicine (low in sugar and starches) is also discussed, as well as the potential role of VBSs in the Specific Carbohydrate Diet approach to treating certain intestinal diseases (e.g., Crohn’s disease, ulcerative colitis, irritable bowel syndrome).

Practical implications are discussed in detail in Section C, D and E, including the types of foods to be reduced in a low VBS diet, the ability of some probiotics to lower VBS production, the potential utility of enzymes (e.g., No Fenol), and the rare circumstances in which a break from Benicar might be appropriate for those on the MP.

Suggestions are also made about how people in various situations might apply this information to help determine what diet would be best for them, since individual needs will differ (see Section D and "Cautions – Updated"). A low VBS diet is not appropriate for everyone, particularly those who are having very intense immunopathology reactions due to bacterial killing. Section F provides the details about CGA/VBS levels in various foods, supplements and medications.

The multiple effects of various VBSs are not always easy to distinguish. However, one can tell that one is likely to have an immune sensitivity to a substance if one experiences a reaction in less than 10 -15 minutes (short cut test can be useful, see: Testing for Food/Chemical Reactions "Cautions – Updated" before doing any testing). This is a test that may help one to distinguish a sensitivity reaction from other responses. Changes in the intensity of bacterial die-off reactions that involve the VDR would take longer to occur.


Note: The findings presented here are not a part of the Marshall Protocol at this time, just preliminary observations until more data is gathered. The current position of the MP website is that one should try to avoid consuming excessive amounts of chlorogenic acid on the Marshall Protocol, primarily through drinking too much coffee, and to avoid too much genistein from soy products. The reason discussed on the MP site is the possibility that chlorogenic acid will block the VDR and interfere with the ability of the immune system to kill bacteria. It should be remembered that most people do not have a problem with a sensitivity to Benicar or chlorogenic acid and do not need to avoid the foods discussed here. The MP website also suggests a low carbohydrate diet, but not of the specific type or for the specific reasons discussed here. (Note: Readers of this article who have experiences that relate to what is reported here are encouraged to contact the author at jcwat101@aol.com)

Note to MP patients – this information is aimed primarily at a small minority of individuals who have had difficulties and most people do not need to be concerned about the issues discussed here.

Caution on the Use of the Marshall Protocol: The power of the antibiotics used on the Marshall Protocol is so greatly enhanced by the immune system modulation of the MP that patients may have serious or even life threatening reactions if they do not start at low enough antibiotic dosages and do not proceed according to the guidelines (see Autoimmunity Research Foundation - Phase One Guidelines and Issue 10. "A Short Introduction to the Marshall Protocol"). Health Care providers are responsible for the use of this information. Neither the Autoimmunity Research Foundation nor the author assumes responsibility for the use or misuse of this protocol.


Advice to the Reader: This article is meant for doctors and health professionals as well as patients, so it contains practical suggestions, along with more technical material and some may choose to skip or skim some sections.

Before changing one’s diet, one should read Sections D and E and "Cautions – Updated," and consult a health professional, because what is suggested for one person may be the opposite of what would be beneficial to another due to differing individual situations. These are preliminary observations and it is suggested that you watch the website for updates.


Section A. Background

Chlorogenic Acid Allergy/Sensitivity/Intolerance (CGA)

The Marshall Protocol (MP) is a treatment that combines immune modulation with very low dosages of pulsed antibiotics to kill treatment-resistant bacteria. These cell wall deficient (CWD) and biofilm bacteria are seen as the cause of many autoimmune and chronic diseases (See Issue 10. "A Short Introduction to the Marshall Protocol")

I have experienced a number of improvements in my own long-standing chronic Lyme disease/chronic fatigue syndrome/fibromyalgia/irritable bowel syndrome in the more than two years I have been on the MP. In the last six months, I have made a number of observations with regard to food/chemical sensitivities/intolerances and the MP. In this section, I will give a history of how I made these observations and will also describe how they have led me to some preliminary conclusions about the role of chlorogenic acid (CGA) and related substances in allergy/sensitivity/intolerance, including their effects on the ability of the body to kill treatment-resistant bacteria.

I have discussed in previous articles (e.g., Marshall Protocol -- Talk Transcript), how my food sensitivities were severe and extensive over many years, and how this initially remained unchanged on the MP. After about two years, however, my food reactions began to lessen, presumably due to the progress I have made in lowering my bacterial load and improving my immune function through the MP. I began to tolerate a number of foods I did not tolerate before. And those foods I did react to, caused fewer and milder symptoms. So, I began widening my diet and testing my reactions to many different foods (See Issue 10. Article IV. "Detecting Food Allergies/Sensitivities/Intolerances: Beyond the Pulse Test").

Interestingly, after I began trying some new foods, I found that a few began to cause a much greater increase in certain symptoms than I expected, including a high pulse increase. It turned out that these foods were all high in CGA. For example, I became highly sensitive to apples, coffee, tea, melon, prunes, which all have high levels of CGA. I also discovered that as I widened my diet, I was becoming much more sensitive to anything containing vitamin D, vitamin A, carnosic acid, genistein and certain medications and supplements.

One medication I became more sensitive to was Benicar, the medication that is an integral part of the Marshall Protocol. This was indicated by a variety of symptoms and a pulse increase of over 20 beats per minute, which began 1- 2 minutes after chewing even 2 mg of Benicar and allowing it to remain in my mouth for a few minutes ( Issue 10. Article IV. "Detecting Food Allergies/Sensitivities/Intolerances: Beyond the Pulse Test" and "Cautions – Updated"). The reaction was most reliable when I was fasting, and when it was at least 6 to 7 hours after last taking Benicar. The very high degree of reactivity to Benicar only began after consuming foods high in chlorogenic acid.

Fortunately, around the time I was having these reactions, Dr. Marshall used molecular modeling (6) to identify chlorogenic acid as a substance that could bind to the vitamin D receptor (VDR). It became clear that all the substances I had suddenly become sensitive to contained VDR binding substances (VBSs) that he had previously identified.

Apparently, aside from its effects on the VDR, CGA can also be a potent source of allergy/sensitivity/intolerance responses. The increase in sensitivity to Benicar that occurred following the increase in CGA now made sense because it became clear that these substances cross-react due to their similarity in structure revealed by molecular modeling research (2, 3, 4, 6).

Cross-Reactions, Allergy, Immune Sensitivities/Intolerances (non IgE), Haptens, Bacteria

It seems appropriate to give a little background on cross-reactions and some related topics. Cross-reaction means that the structures of the molecules are similar enough that the immune system regards them as nearly the same. Consuming one to the point of becoming sensitive to it, causes one to also become sensitive to the other cross-reacting substances. It appears that foods with a large amount of chlorogenic acid are particularly potent at stimulating this type of sensitivity reaction.

My emphasis is not on the classical Type I allergy (IgE mediated), but on reactions that involve another mechanism, such as a Type II, III or IV sensitivity responses (7). Partly this is because both blood tests and intradermal testing has indicated these are the types of reactions I experience, but also because these types of reactions are often harder to detect and therefore overlooked, despite being common and important (see Issue 5 Food Sensitivity Article).

I currently have data on another patient who had a similar experience as mine. He had begun consuming more CGA while on the MP and had a similar pattern of sensitivities develop, which then declined with a dietary change similar to the one I describe here.

In my research, I found that chlorogenic acid is recognized as a potent allergen for some people (8) and it is included on one of the ALCAT food/chemical intolerance test panels (www.ALCAT.com). It should be noted that substances may be quite different chemically, but have a particular area of their molecule that is very similar and thus can have the same effect upon a receptor or immune cell and thus cause similar sensitivity reactions.

Also, it is now recognized that even very small molecules, and even substances like metals, can bind with a large molecule and create what are called haptens. Recently, it has been shown that nickel allergy can occur when a nickel ion bonds to a lipopolysaccharide from a bacteria to form a hapten, thus showing a possible link between nickel sensitivity and bacterial infection (9). These haptens can stimulate immune allergy/sensitivity reactions, even though the original small molecule could not.

I had become mildly sensitive to Benicar previously and took a break from it in the first year of the MP. But the sensitivity declined and I went back on it. Now, I realize that dietary factors can affect this tendency toward Benicar sensitivity.


Vitamin D, Supplements and Sun Exposure

As mentioned above, when I included high CGA foods in my diet, I also become very sensitive to foods with vitamin D in them. Vitamin D binds the vitamin D receptor, so is similar in structure to the other VBSs, like CGA, and thus cross-reacts with them. As a result, based on my reactions, I have also learned that many supplements probably do have either hidden vitamin D in them, or other substances, like CGA. For instance, I tested one high quality fish oil supplement whose manufacturer claimed the vitamin D had been removed and my level of reaction indicated it still had significant levels of vitamin D and/or Vitamin A, though it was likely that much of it had been removed.

I had similar reactions with most supplements, even a number of high quality, expensive ones. I think this is due to very small amounts of vitamin D or A contaminating the supplement or due to small amounts of CGA or carnosic acid that is extracted along with the nutrient, from the plant product that is used to make the supplement (Section F).

My reaction to sun exposure also greatly increased during this period of CGA sensitivity due to vitamin D production that occurs in the sun. The reaction occurred within 2-3 minutes of exposure of even a very small area of unprotected skin. Patients on the MP have sun reactions for a variety of reasons, including increased bacterial killing and hormonal reactions. However, my observations indicate that for some people, whose reaction occurs almost immediately (within the first 10-15 minutes), the reaction may be at least partly due to a sensitivity to vitamin D (Section M. "Methods").

When I changed my diet to reduce VBSs, my short-term sun reaction was also reduced. This supports the view that the dramatic effect of sun exposure on my pulse and other symptoms was similar in nature to my VBS sensitivity and that the ability to bind the VDR was what all my very reactive substances had in common. The same changes in sun reaction intensity were confirmed in another patient who made the same dietary changes.


Role of Carbohydrates – Pathogenic Bacteria and the Innate Immune System

For several weeks, as I avoided the CGA and vitamin D containing foods, and took a break from Benicar, my sensitivities declined gradually. Then I decided to stop eating oats and was surprised to find my reactivity declined even more, even though oats do not contain CGA. Then, when I reduced my consumption of grains altogether, by reducing my white rice consumption to about 2/3 cup per meal, there was an even more dramatic decline in my sensitivity to chlorogenic acid, vitamin D, Benicar and other similar substances.

Soon after this diet change, I was able to resume Benicar and tolerate sun exposure much better. Even after I resumed the Benicar, my sensitivities to these substances has continued to decline on the low starch and low chlorogenic acid diet. The same reduction in sensitivity/intolerance was confirmed to occur in two other people, who made similar changes.

Based on these observations, I have hypothesized that certain bacteria in the intestines that feed on starch and certain sugars and fibers can produce a substance similar to CGA. This substance is another VBS that also stimulates cross-reactions with other substances that bind the VDR. Reducing the sugars/starches/fibers that feed these bacteria thus decreases the sensitivities to all VBSs, including CGA, vitamin D and Benicar, due to their cross-reactivity.

As discussed previously, the VDR is an important regulator of the immune system and its activation has profound effects on innate immunity. Thus, besides inducing sensitivity reactions in a small percentage of people, some VBSs activate the VDR (eg. 1,25D and Benicar) and some block the VDR (e.g., 25D and chlorogenic acid). The exact details of their structure determine how tightly they will bind to it and whether they will activate the VDR or block it. If they bind to it without activating it, they can prevent other substances from activating it and thus block it. If they activate it, a series of processes will begin that fulfill the function of the VDR. Activation of the VDR results in facilitation of the activity of certain immune cells (macrophages) and the production of anti microbial peptides that kill bacteria, viruses and fungi.

Thus, besides the relevance to CGA and other sensitivities, the production of a VDR binding substance (VBS) by certain starch-feeding bacteria would be expected to have consequences for bacterial killing.

These consequences have, in fact, been observed. In addition to my own repeated experiments (see below and Section M. "Methods"), several other people on the Marshall Protocol have noted increases in bacterial die-off reactions when they lower starchy carbohydrates in their diet. This provides more support for the hypothesis that a VBS is produced by certain intestinal bacteria and that it blocks the VDR.

And as might be expected, some people who have experienced excessive bacterial die-off reaction have found that consuming carbohydrates or high CGA foods or beverages has relieved their symptoms related to the bacterial killing. My findings indicate that this is because there is a VBS produced by the starch-feeding bacteria in their intestines that is able to block the VDR and thus block the innate immune system’s attack against the bacteria. However, as discussed below, there is evidence that not all people have this effect from starch consumption, probably due to differences in the particular bacteria in the intestines of different individuals.

Section B. Theoretical Links
Section C, D, E. Practical Implications
Section F. CGA/VBS Sources -- Lists
Section M. Methods
References

Cautions - Updated

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