Coffee, GERD, stomach ulcers and Vitamin U






Drinking our morning coffee is one of life's little pleasures. Unfortunately, coffee is notorious for inciting acid reflux, GERD, and worsening peptic ulcers. This is especially the case with more heavily roasted coffees and instant coffee. 

What is it about coffee that makes it so problematic? The underlying reasons for the irritability of coffee are a little mysterious. People often cite the acidity of coffee, and it does seem that coffee that tastes less acidic is less harsh on the stomach. However, considering the stomach has a pH that makes coffee appear comparatively mild, there is likely more to this than meets the eye. Furthermore, there are many foods that taste acidic that don't elicit the same response. Malic acid in green apples is very tart and lemons are barely edible for the amount of citric acid they contain, yet eating these fruits doesn't typically cause acid reflux (they may make ulcers sting, but that's another story).

The classic stimulant caffeine almost certainly contributes to acid reflux to some extent. Caffeine definitely relaxes the esophageal sphincter, which is a muscle whose function is to separate stomach acid from the esophagus. The stomach is full of concentrated HCl, which would damage the lining of the stomach except for the presence of a thick alkaline mucus bilayer maintained by prostaglandins and certain nutrients such as Vitamin U. However, decaffeinated coffee can still cause acid reflux so there's more to it than just caffeine.

Stomach acid has several functions, from inhibiting the growth of bacteria to unraveling dietary protein and providing the right pH for the proteolytic actions of pepsin. What isn't widely known is that the stomach isn't full of acid at all times. In fact, eating stimulates the production of the hormone gastrin, which via a chain of events results in the secretion of HCl into the stomach. The key dietary component that stimulates gastrin release is protein. Scientists were curious to understand what is it about protein that triggers this response. Protein consist of 20 types of amino acids that have different properties. The aromatic amino acids phenylalanine and tryptophan were by far the most stimulatory (the other aromatic amino acid tyrosine was not tested due to solubility issues).

The fact that aromatic amino acids were most stimulatory may be quite revealing. Other amino acids all have an acidic group (in fact, some even have two), so it's not acid per se that is the issue. It would seem that the aromatic side chain is the effector (chemically, aromatic simply means that it has a benzene ring). This is where coffee comes in. Coffee has over 2000 compounds, some of which have benzene rings just like the aromatic amino acids. These are collectively referred to as cinnamic acids, and are present in many vegetables, fruits and other plant-based products. Examples include caffeic acid, p-coumaric acid, ferulic acid, and esters thereof. Though it hasn't been demonstrated conclusively, one may wonder whether some of the adverse gastronomical effects of coffee may in part be due to the fact that coffee is an extract containing a wide array of compounds that bear an uncanny resemblance to known acid producers. As extracts, cinnamic acids in coffee are easily accessible. Furthermore, it has been estimated that coffee is the richest sources of cinnamic acids in the Western diet at up to 1 g per day.

Can Vitamin U help with acid reflux? As the mode of protective action afforded by Vitamin U is via the stimulation of mucus secretion in the stomach, Vitamin U should protect the lining of the stomach to some extent. There is evidence that Vitamin U can help maintain mucosal integrity in other parts of the alimentary canal such as the esophagus. However, the mucus lining the esophagus is thin and not built to withstand concentrated hydrochloric acid. The protective effects conferred by mucoprotectants such as Vitamin U are most effective when used in conjunction with dietary modification that avoids the worse offenders like coffee. Drinking lightly roasted low-acid coffees still have plenty of caffeine and are less likely to cause problems.


Further reading



Allergies and Vitamin U





At this time of the year, allergies are a seasonal problem for many people. With the coming of pollen also comes itchy eyes, a runny nose, an annoying cough and maybe more serious conditions such as asthma or hives. Cells in our immune system called mast cells produce histamine, which triggers an inflammatory response by binding H1 receptors. Our blood vessels dilate and fill with fluid to help get rid of allergens and to counteract the narrowing causes by the build up of mucus. Unfortunately, our bodies tend to overreact and produce way too much histamine. Antihistamines like loratadine (Claritin), cetirizine (Zyrtec), diphenhydramine (Benadryl) work by blocking the binding of histamine to these receptors.

Our body has a few mechanisms that can remove excess histamine from our body. One of the most important is the enzymatic action of histamine N-methyltransferase. HNMT catalyzes the methylation of histamine using the universal methyl donor S-adenosylmethyltransferase (SAM) as its source of methyl groups. Methylated histamine can no longer bind to the H1 receptor and cannot trigger more inflammation. Methylhistamine is removed from our body in our urine. People with polymorphisms in the gene encoding HNMT often present with a runny nose, hives and peptic ulcer disease.

Vitamin U is a natural support for decreases in methylation capacity caused by allergies. Vitamin U carries two methyl groups that contribute to the formation of SAM. Taking Vitamin U in the form of fresh cruciferous or stalky vegetables, or as a supplement, helps replenish methylation capacity when you are struck by allergies. Allergens can have a draining effect on the whole body, with low methylation capacity reducing our ability to maintain good health and can lead to low methylation conditions such as peptic ulcers and histamine intolerance.

Vitamin U is not a drug: it will not stop a runny nose dead in its tracks like antihistamines can. Nor will Vitamin U be effective in treating anaphylactic shock. If you have a severe allergic reaction, please immediately rush to the hospital for treatment. Vitamin U simply aids our body's natural mechanism for removing excess histamine. Ensuring your dietary intake of Vitamin U is adequate will complement drugs in your battle with seasonal and persistent allergies.

Further reading

Neural tube defects and Vitamin U



By Centers for Disease Control and Prevention - Centers for Disease Control and Prevention, Public Domain, https://commons.wikimedia.org/w/index.php?curid=30509337


 
Summary - Vitamin U may play a supportive role in correct neural tube formation, a process that depends on the methylation of dUMP to form dTMP via the folate cycle. The folate and methionine cycles work together to meet the methylation needs of the body. Low cellular methylation status diverts methyl groups from the folate cycle to the methionine cycle, thereby decreasing dTMP synthesis and increasing the risk of neural tube defects. Dietary methyl donors that enter the methionine cycle directly (e.g. methionine, betaine, Vitamin U) support neural tube formation by reducing this methyl group drain. While folate is the most important factor affecting neural tube formation, folate intake may not be sufficient in and of itself due to other factors such as polymorphisms within these two pathways and intake of other components that contribute to methylation homeostasis. Talk to your dietitian before conception about designing a diet that reduces the risk of neural tube defects in your baby.


Neural tube defects (NTDs) are a collection of medical conditions in which the neural tube of the baby does not form completely during early development, exposing the spinal cord and/or brain with permanent disability resulting. Two common neural tube defects are spina bifida (spine) and anencephaly (brain). 

What causes NTDs? Like many conditions, NTDs result from a combination of environmental and genetic factors. The most common environment factor is the insufficient intake of folate by the mother just before and during the first few weeks of pregnancy. Folate is a vitamin (B9), and is therefore an essential component of one's diet. In the 1950s it was noted that pregnant women taking anti-folate drugs to treat cancer gave birth to babies afflicted with congenital abnormalities like NTDs (Safi 2012). It was established that folate is essential for embryonic development, that women whose folate levels were low were at greater risk of having babies with NTDs, and that supplementation by the mother-to-be with folate substantially reduced the risk of NTD occurrence (Smithells 1980Wald 1991). Folate supplementation is the most effective way to prevent NTDs, reducing risk by 50-70%. Consequently, medical authorities recommend young women ensure their diet contains 400 ug of folate per day through food and supplements in case they become pregnant.

How does folate prevent neural tube defects? The function of folate is to transfer methyl groups generated from serine to a range of molecules throughout the cell. In embryos, these methyl groups are essential to make nucleotides required for DNA synthesis. There are many compounds that are methylated as a result of the action of folate. However, there is one for which there is evidence that a shortage of results in neural tube defects - dTMP (deoxythymidylate). There are four nucleotides used to make DNA - abbreviated to A, T, C, G. dTMP is a precursor in the formation of dTTP, usually shortened to T. In humans, the nucleotide dTMP is made from dUMP by the transfer of a methyl group from folate. Embryos supplemented with dTTP do not develop neural tube defects despite very low folate levels, indicating that dTMP shortage is the causal factor (Leung 2013). At conception, nucleotides must be synthesized in utero, and therefore a shortage of folate results in low production of dTMP, which in turn results in NTDs.


Figure 1 - A simplified depiction of the folate cycle. The enzymes responsible for catalyzing each step are -

1. Serine hydroxymethyltransferase

2. Thymidylate synthase

3. Dihydrofolate reductase

4a. 5,10-methylenetetrahydrofolate dehydrogenase NADP+

4b. 5,10-methenyltetrahydrofolate cyclohydrolase

4c. Formate-tetrahydrofolate ligase

5. Phosphoribosylaminoimidazolecarboxamide formyltransferase

6. Methylenetetrahydrofolate reductase

7. Methionine synthase


N.B. 4a-c are three components of MTHFD1



Which folate should you take and where should you get it from? 

First a note on nomenclature. The term 'folate' is commonly used to refer to any of the components of this pathway plus other forms like folic acid and folinic acid. Naturally-occurring folate is a mixture of these forms, with the exception of folic acid, which is a non-natural, oxidized version that is relatively stable and therefore used to fortify food in which natural folate has been removed or degraded. Vitamin supplements usually contain either folic acid or 'methyl folate' or 'activated folate', which usually refers to 5-methyltetrahydrofolate.

The best source of natural folates are green leafy vegetables, although all vegetable sources (including fruit and grains) are reasonable sources. Folic acid is a form of folate that is often added to processed grains that have been polished, e.g. wheat flour, white rice. For most people, it makes little difference whether their folate is derived from natural or synthetic sources. The important factor is getting the right amount. However, some people do not metabolize synthetic folic acid effectively and as such can actually suffer from a deficiency in functional folate even when their serum levels of folic acid seem sufficient (Bailey and Ayling 2009). Sometimes too much folic acid can even cause fertility problems (Cornet 2019). 

There are other components in the folate cycle that also have an effect on neural tube formation, albeit to a lesser extent. For example, vitamin B12 is an essential cofactor for the enzymatic conversion of 5-MTHF to THF, and low B12 levels have been linked to NTDs (Li 2009). Another example is Vitamin B6, which is a coenzyme for serine hydroxymethylfolate transferase. Cobalt is a component of B12 and therefore is vital for methionine synthase function.

Where does genetics fit in? While folate supplementation reduces risk, unfortunately genetic polymorphisms in the mother are responsible for the majority of NTDs cases (Copp 2013). Mutations of genes in the folate cycle and other branches of one carbon metabolism (methylation) are particularly relevant. There are many enzymatic steps in the folate cycle, and each enzyme is encoded by a gene. Polymorphisms are nucleotide changes (mutations) in these genes that differ from that found in the majority of people. Most polymorphisms have no significant physiological effect by themselves, but may have an effect in combination. However, there are a few polymorphisms that do correlate with the occurrence of NTDs, such as MTHFR C677T and MTHFD1 R653Q (Copp 2013). 

Genetic testing is becoming an increasing-popular tool to identify polymorphisms. Though it is tempting to do so, it is important to not assume that polymorphisms necessarily result in reduced physiological function. Human physiology is not fully understood and often contains redundancies that can mask over minor metabolic blocks. The correct way to establish whether there are deficiencies within the folate cycle is through biochemical analysis of the various folate metabolites. Biochemical analysis in combination with genetic analysis is used by specialists to establish whether there is a functional deficit in the mother that results in heightened risk of NTDs in her baby. Consult with your doctor or dietitian to determine if you have polymorphisms, and if you do, whether these actually affect your metabolism (often they don't) and what measures can be taken to relieve any metabolic blocks.

Aside from the folate cycle, there is another cycle that is even more important in meeting our methylation needs. The methionine cycle is the way in which the methyl donor S-adenosylmethionine (SAM) is generated (methionine cycle). SAM is the methyl donor for just about all methylation reactions, with the notable exception of those in the folate cycle. It has been shown that a functioning methionine cycle is essential for correct neural tube formation (Leung 2017). When there is a shortage of methyl groups in the methionine cycle (low S-adenosylmethione:S-adenosylhomocysteine), methyl groups are directed from the folate cycle into the methionine cycle. Instead of being used to make nucleotides, 5,10-methylenetetrahydrofolate is reduced by MTHFR to make 5-methyltetrahydrofolate, which donates its methyl group to the methionine cycle in a reaction catalyzed by methionine synthase. The folate molecule is conserved within the folate cycle, but must be remethylated. When maternal folate levels are low and flux through the folate cycle is already slow, this shunt may reduce methylation capacity in the folate cycle to critical levels. 

The methionine cycle obtains a large amount of its methyl groups from the folate cycle. This shunt operates at moderate levels most of the time - this is actually a normal process. In addition, the methionine cycle obtains methyl groups from methionine, betaine and Vitamin U. Similar to the methionine synthase reaction, betaine and Vitamin U donate methyl groups to homocysteine via enzyme-catalyzed reactions. Importantly, methyl groups in the methionine cycle cannot enter the folate cycle. For example, SAM from the methionine cycle cannot substitute for 5,10-MeTHF required for dTMP synthesis. Low maternal methionine levels pre- and post-conception are associated with a heightened risk of neural tube defects (Shaw 2004). There is evidence that betaine entering the methionine cycle reduces the flow of methyl groups from the folate cycle, which in principle should support 5,10-MeTHF levels (Benevenga 2007).

Where does Vitamin U fit into all this? It should be emphasized that there has not been any scientific research testing whether Vitamin U supplementation can prevent NTDs. The studies have simply not been done. However, there is some genetic evidence that suggests that Vitamin U may play a role in correct neural tube formation. 

  • Vitamin U supplies methyl groups to mammals via its reaction with homocysteine to form methionine catalyzed by the enzyme BHMT2. This is very similar to that of betaine, though whether Vitamin U plays this role in embryonic tissue has not been investigated. 
  • Vitamin U is abundant in vegetables, the benefits of which have been long known in preventing neural tube defects. While the presence of folate is most likely the primary factor, it is possible that some of the benefits conferred by eating vegetables are due to the provision of methyl groups from Vitamin U.
  • A preconception diet rich in methionine reduces the prevalence of neural tube defects. Vitamin U is essentially methionine with an extra methyl group. One molecule of Vitamin U actually supplies two molecules of methionine, one being the newly-methylated homocysteine, the other being the demethylated Vitamin U.
  • Studies have shown that methylation in the embryo is supplied by methyl groups from both the folate cycle and betaine. If we assume that methionine synthase and BHMT1 contribute to embryonic methylation, then Vitamin U is also likely to make a contribution. It is logical that the benefits of green vegetables in preventing neurological abnormalities is due to the combined effects of folate, betaine and Vitamin U, with the emphasis on folate.

Summary

  • Folate is absolutely necessary at some level to provide the embryo nucleotides during the first weeks following conception. It cannot be replaced by other molecules.
  • Folate requirements may be lowered as long as adequate levels of methyl groups are provided by methionine and betaine from the methionine cycle. 
  • Though its role in fetal development has not been investigated, it is likely that Vitamin U has a similar role to that of methionine and betaine, and would be of greater importance for people whose diet is low in protein and fat such as vegans.


Further Reading