Mouth ulcers and Vitamin U

Summary - Mouth ulcers result from a breach of the mucous layer that protects the lining of the mouth and an underlying inability to repair the mucous layer quickly. Taking Vitamin U in the form of fresh vegetable juice and/or supplements is a great way to naturally heal mouth ulcers. Talk to your doctor or dentist.

Mouth ulcers (aphthous ulcers or stomatitis) are small, painful, circular sores that form in the lining of the mouth. They are very common. Right this minute, 1-2% of people have a mouth ulcer. Over a lifetime, about half of the US population will get at least one if not many. They mainly afflict teenagers. Ulcers normally heal spontaneously in one to two weeks, although they can reoccur many times. Recurrent ulcers indicate an underlying health problem. Sores in the corner of the mouth or outside the mouth are not ulcers and should be treated differently.  

Why do I have a mouth ulcer? 

The lining of your mouth is covered by a thin layer of mucus. The main purposes of this mucus is to protect the lining of the oral cavity from physical and chemical damage, infection, and to help digest food. Mouth ulcers develop when the protective mucus layer is breached and the body shows a delayed repair response with non-specific oral bacteria infecting. The integrity of the mucus layer is a function of constructive vs destructive factors. 

Destructive factors

Biting your mouth while eating or from a nervous habit is probably the most common way ulcers start. Physical or chemical damage from food is another very common cause - 

• Crusty food like bread or toast
• Crispy food like chips
• Salty food like pretzels
• Sweet food like candy
• Sticky food like cookies
• Sour food like vinegar
• Hot food like coffee

Abrasive, salty and hot foods/drinks physically damage the mouth. Sour foods/drinks chemically burn the mouth instantly. Sweet and sticky foods burn slowly by feeding oral bacteria, which metabolize sugars to produce corrosive acids. 

Drugs are another destructive factor. Alcohol is oxidized by oral bacteria to acetaldehyde, which is toxic and a carcinogen (Tagaino et al, 2019). Some acetaldehyde is even produced from sugar by oral bacteria. Acetaldehyde is also found in cigarette smoke (Sprince et al, 1975). As with peptic ulcers, NSAIDs like aspirin inhibit prostaglandin E2 synthesis which reduces mucin secretion. People swishing aspirin in their mouth to quell inflammation are actually slowing down ulcer healing (Slomiany and Slomiany, 2000).

Poor dental hygiene is yet another destructive factor. Harsh brushing makes tiny holes through which corrosive agents can meet the cell surface. Ineffectual or nonexistent brushing leaves food and bacteria in position to generate more organic acids and acetaldehyde.

Constructive factors

The major factor protecting the mouth is mucus. There are five kinds of mucin produced in the mouth - MUC5B and MUC7 being the most important (Frenkel and Ribbeck, 2015). MUC5B is a very long protein rich in serine and threonine amino acids to which glycans attach. These glycans attract water to form a gel and gives your mouth that slippery feeling. The protein overall looks likes a bottle brush with one end attached to the cell. MUC7 is similar, but is unattached and therefore flows freely aiding in formation of the soft bolus from food. MUC5B proteins form polymers via disulfide bonds. Cysteine is unusually common in MUC5B and is essential for disulfide bond formation.

A shortage of many dietary factors have been suggested to cause mouth ulcers. Examples include vitamin B9 (folate), vitamin B12, vitamin C, vitamin E, selenium. All play a role in antioxidation, and it makes sense that these nutrients are low in ulcers as the environment shows signs of oxidative stress (elevated malondialdehyde and depressed glutathione)(Arikan et al, 2009). 

Despite this speculation, however, the evidence has been inconclusive. There are certainly some patients who respond well to supplementation with one or another of these micronutrients. However, many times mouth ulcers occur in people with no apparent deficiency and/or supplementation has no effect. Considering that some of these micronutrients work in some cases, it's possible that they help in an indirect way, or that chronic mouth ulcers are indicative of a systemic redox imbalance. For example, chronic ulcers are more prevalent in those with other problems in their digestive tract (Brailo et al, 2007).

Can Vitamin U help heal and prevent mouth ulcers?

The use of Vitamin U to treat or prevent mouth ulcers has undergone little investigation (Kato and Takayasu, 1961). Vitamin U has been shown to be a useful treatment for gum disease (Sulym, 2016), and sulfur compounds like cysteine are effective in quenching the damaging effects of acetaldehyde in the mouth, particularly when combined with vitamins B1 and C (Sprince et al, 1975; Syrjanen et al, 2016).

The fact that Vitamin U has been shown to heal and prevent peptic ulcers by stimulating the release of mucin suggests that it may also have this function in other parts of the digestive tract which also secrete mucin (Watanabe et al, 2000). One can't help but wonder whether mouth ulcers have a similar etiology to its more dangerous relatives. If this is indeed the case, one may speculate as to whether Vitamin U or a metabolic derivative could have this effect on the release of mucin from not only the mouth or other parts of the alimentary canal, but even other epithelial tissues, including the lungs, trachea, nose and eyes.  

Vitamin U may also support mucosal function in indirect ways. Firstly, Vitamin U yields cysteine, which is the rate-limiting component of glutathione, the master antioxidant that fights oxidative stress. Secondly, the relatively large amount of cysteine required to tether mucin to the epithelial tissue means that extra cysteine in the form of Vitamin U may prove useful. Thirdly, much of the glycans that attach to mucins are themselves sulfated, requiring more sulfur. 

Many people, especially those whose diet is low in the sulfur amino acids methionine and cysteine, have limited antioxidant capacity due to having low levels of glutathione. For those people, alternative sources of sulfur amino acids like Vitamin U are an important alternative source. Drinking freshly-made vegetable juice or taking Vitamin U supplements in combination with the cessation of destructive practices will probably help clear up your current mouth ulcer and help prevent future ulcers.

Vitamin U complements H2 blockers

Summary - H2 blockers are drugs used to reduce stomach acid in people who have pain due to stomach ulcers. Vitamin U in the form of fresh vegetable juice or supplements can be used alongside H2 blockers to speed up the restoration of the protective mucous bilayer.

The human stomach is a very acidic environment. The pH of a correctly-functioning stomach is 1.5 - 3. The acidity of gastric juice is due to hydrochloric acid (HCl), which is produced by parietal cells in the upper parts of the stomach (fundus and cardia). Parietal cells produce acid using enzymes called proton pumps (H+/K+ ATPase), which use the energy derived from the hydrolysis of ATP to pump H+ into the stomach. It is the protons (H+) that cause acidity. 

The parietal cells pump acid into the stomach in response to signal molecules binding receptors. There are numerous kinds of receptors that respond to different stimuli, either positively or negatively. The most important for acid production are the H2 histamine receptors. Protein in food is broken down in the stomach by acid and the enzyme pepsin to form peptides. These peptides stimulate the release of the hormone gastrin from G cells in the stomach and duodenum. Gastrin stimulates the release of histamine from ECL cells. Histamine binds receptors in the base of parietal cells where it stimulates the movement of proton pumps to the apical surface, where they pump acid into the stomach cavity (lumen). This acid accelerates this whole cycle, breaking down more proteins in food by hydrolysis as well as activating pepsin.

H2 blockers bind to the H2 receptors, which stops histamine from binding. If histamine can't bind, the levels of acid in the stomach remain fairly low and the corresponding pH relatively high. (H2 blockers are often referred to as H2 antagonists because they block the binding of histamine without itself stimulating the function of the receptor, an important distinction from agonists). 

H2 blockers were invented in the 1960s and have to a large extent been superseded by proton pump inhibitors due to the latter's more potent acid-suppressing abilities. Commonly used H2 blockers include omeprazole (e.g. Prilosec), famotidine (e.g. Pepcid) and cimetidine (e.g. Tagamet). Ranitidine (e.g. Zantac) was the most prescribed drug in the US during the 1980s, but the FDA has recently banned its sale due to carcinogenic impurities. 

Stomach ulcers and gastroesophageal reflux (GERD) are conditions characterized by pain caused by stomach acid coming into direct contact with the lining of the stomach and esophagus, respectively. Contrary to popular opinion, these conditions are rarely caused by excessive production of stomach acid. In fact, the acidity in the stomach of those with stomach ulcers is typically low (i.e. relatively high pH). GERD is caused by normal stomach acid coming into contact with the esophagus, an organ that is not designed to withstand such exposure. Unlike the stomach, the esophagus is not coated with a protective alkaline mucous bilayer and is very sensitive to contact from even small amounts of gastric juice.

One unfortunate problem with taking H2 blockers for stomach ulcers is that they reduce the secretion of mucin (Ichikawa et al., Diebel et al). So while they reduce pain by reducing the amount of acid produced, they also increase the risk of pain by weakening the mucous bilayer. 

Vitamin U is a nutrient abundant in vegetables and fruit that stimulates the secretion of mucin in the stomach. As fresh vegetables and fruit have been a major component of our diet for a very long time, it is reasonable to conclude that dietary Vitamin U plays an important role in the maintenance of optimal stomach function. 

Can Vitamin U be combined with H2 blockers? 

Considering Vitamin U stimulates mucin secretion and H2 blocker reduce it, one may wonder whether Vitamin U can be taken with H2 blockers to negate the negative effects. The evidence suggests yes. In 2009, Ichikawa et al. showed that co-administration of Vitamin U with famotidine reversed the mucin-blocking effects of famotidine without affecting the acid-suppression effects. These results suggest that Vitamin U can add another level of protection to the gut in those taking H2 blockers.

Considering these findings, drinking fresh vegetable juice daily or taking Vitamin U supplements may help restore your mucous bilayer, ease discomfort and heal your ulcers.

Vitamin U is a mucin secretagogue

Summary - Vitamin U is a nutrient abundant in vegetables and fruit whose main function is to stimulate the secretion of mucin and enable the formation of the mucous bilayer that protects the stomach from acid and Helicobacter pylori.

In the human body, Vitamin U heals and protects against peptic ulcers. It does so by stimulating the secretion of mucins onto the walls of the digestive tract, acting as a precursor to the biosynthesis of the master antioxidant glutathione, and supplies methyl groups for gene regulation, polyamine biosynthesis and a range of other molecules. Of these three functions, stimulating mucin secretion is the most direct way in which Vitamin U works.

In the stomach, there is an alkaline mucous bilayer gel that protects the stomach from gastric acid, pepsin digestion and bacterial infection. Mucus consists of two layers - a deep gel-like layer attached to cells and a superficial loosely-attached layer on top. The proteins that make up mucus are called mucins (MUC1, MUC5AC, MUC6), which are heavily-glycosylated proteins that attract water, thereby forming a gel. Mucins are made in foveolar cells lining the stomach and are stored in vesicles awaiting summons to the lumen. At the surface, some mucins stay attached to the cells and act as an anchor for the loosely-bound mucins to attach by disulfide bonds. When this mucous bilayer is disrupted, gastric juice can reach the lining of the stomach causing irritation and inflammation. Left long enough, a peptic ulcer may form.

Your body has a number of different ways to stimulate the secretion of mucin. The molecules that trigger secretion are called mucin secretagogues. The prime mucin secretagogue is prostaglandin E2, a hormone-like molecule that has many functions in the human body. It has a protective role in stomach function, suppressing production of gastric acid and pepsin, while at the same time promoting secretion of mucin and the alkaline molecule bicarbonate (Park et al). NSAIDs reduce prostaglandin E2 synthesis by inhibiting COX-1, leading to less mucin, less protection and a greater risk of ulcers.

Vitamin U (S-methylmethionine) is a nutrient found in all vegetables and fruit, and especially members of the cabbage family. Vitamin U protects the digestive tract by stimulating the secretion of mucin from the foveolar cells. In 1996, Watanabe et al. showed that exposing gastric mucous cells to L-cysteine or methylmethionine sulfonium chloride (MMSC or Vitamin U) prevented the formation of stomach ulcers caused by exposure to 50% ethanol. They demonstrated that Vitamin U and cysteine work in a similar manner via a sulfhydryl group. Interestingly, Vitamin U does not have a sulfhydryl group, but rather a sulfonium group. Consequently, Vitamin U is usually described as a latent sulfhydryl. The fact that Vitamin U and L-cysteine activities were inhibited by the pre-administration of the sulfhydryl inhibitor N-ethylmaleimide suggests that Vitamin U is active as a sulfhydryl. Vitamin U is stable at acid pH, so activation probably takes place in foveolar cells. 

In a follow up study, Watanabe et al. (2000) found that Vitamin U and cysteine induced the transport of vesicles containing mucin from deep within the cytosol to the cell surface for release into the stomach lumen, thereby forming a protective barrier. Interestingly, the movement they observed was independent of Ca2+ and cAMP. When signal transduction occurs via an endogenous molecule like prostaglandin-E2, there is a rise in the concentration of cAMP. When the P2 purinergic receptor is activated by ATP, there is an accompanying rise in Ca2+. Yet sulfhydryl-instigated movement did not induce a change in Ca2+ or cAMP levels. The authors suggested sulfhydryls promote mucus movement by a non-receptor mediated process.

Irrespective of how Vitamin U works, there's good evidence that drinking fresh vegetable juice or taking Vitamin U supplements may help restore your mucous bilayer, ease discomfort and heal your ulcers.

Cabbage Juice Heals Peptic Ulcers

In the 1940s and 1950s, Dr Garnett Cheney from Stanford discovered that having his peptic ulcer patients drink one liter of fresh cabbage juice every day healed their stomach and duodenal ulcers 3-6 times faster than a bland diet alone. Chronic ulcers disappeared in 1-2 weeks depending on their severity. Dr Cheney was of the opinion that peptic ulcers resulted from a deficiency of a nutritional factor he termed Vitamin U, later identified as the amino acid S-methylmethionine. While cabbages are a particularly rich source of Vitamin U, Cheney found that all raw vegetables, and to a lesser extent, fruit, contain Vitamin U. In addition to healing existing ulcers, Dr Cheney found that Vitamin U also prevented the formation of new ulcers.

Why do we get ulcers? Ulcers result from an imbalance in the digestive system between protective and destructive factors. An alkaline bilayer of mucus containing mucin protects the wall of the digestive tract from harsh elements such as stomach acid, infection by bacteria living in the digestive system, NSAIDs, and dietary factors like high salt and alcohol. In modern times, NSAIDs increasingly contribute to ulcer formation by inhibiting the mucus-stimulating function of our body's prostaglandins. When the mucus layer is depleted, these harsh elements irritate the epithelial cells lining the digestive tract causing inflammation and enabling deep infection. 

Ulcers are usually treated with proton pump inhibitors or H2 blockers to reduce acid production, antibiotics to treat bacterial infections (particularly Helicobacter pylori in the stomach), antacids to neutralize acid, and mucosal protectants such as prostaglandin mimics. Unfortunately, these only provide a temporary solution to the problem. Ulcers return soon after cessation of treatment. Excessive stomach acid is usually not the root problem, nor is H. pylori infection. Most people with ulcers produce a normal amount of stomach acid, and half the world's population has H. pylori yet remain ulcer-free. These facts indicate that while acid and infection contribute to the formation of ulcers, other factors are at play.

Given the findings of Dr Cheney, it's easy to see that eating a balanced diet rich in sources of Vitamin U is beneficial. But how does Vitamin U work? In later studies, it was shown that Vitamin U has three properties that help maintain a healthy gut.

1. Stimulating the release of mucin into the mucus layer, thereby protecting the walls from acid and bacterial infection (most important).
2. Reducing inflammation by acting as a precursor to glutathione, the master antioxidant of the human body via its conversion to cysteine.
3. Coordinating with other nutrients such as methionine, folate, B12, betaine, choline, SAMe and B6 to supply vital methyl groups required for optimal health.

Increasing the Vitamin U content of one's diet in combination with reducing the intake of foods that deplete the protective mucus layer has been shown to improve ulcerative conditions in the digestive system. A diet rich in fresh vegetables, vegetable juice and fruit, and low in salt, alcohol and sugars is a good approach for restoring the mucus bilayer in most patients.

References

https://www.ncbi.nlm.nih.gov/pubmed/18104715

https://www.ncbi.nlm.nih.gov/pubmed/10719747

https://pubs.acs.org/doi/pdf/10.1021/ja01630a032