Showing posts with label peptic ulcers. Show all posts
Showing posts with label peptic ulcers. Show all posts

Vitamin U may help combat the ulcergenic effects of NSAIDs




Summary - Taking NSAIDs increases the risk of you developing stomach ulcers by inhibiting your natural protective system. There are several measures you can take to help get rid of stomach ulcers due to NSAIDs -

    1) reduce the dose
    2) change the NSAID to one less irritating 
    3) counteract with other drugs
    4) switch from NSAIDs to other pain relievers
    4) take Vitamin U

Vitamin U in the form of fresh vegetable juice or supplements can be used in combination with other measures to combat ulcers. However, Vitamin U will not counteract all of these negative effects as NSAIDs are powerful drugs. If you have an ulcer and are taking NSAIDs, talk to your doctor as there may be a solution.

-----------------------------------------------------------------------------------------------------------------------------


Stomach ulcers result from an imbalance between protective and destructive factors. There are several destructive factors including infection with Helicobacter pylori, overproduction of stomach acid, overeating salt, alcohol and sugar, and taking NSAIDs. Ulcers often result from a combination of these factors. The focus of this post is the role NSAIDs play in causing your ulcer.

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are widely used to reduce pain and inflammation. The most commonly taken NSAIDs are aspirin (e.g. Bayer), ibuprofen (e.g. Advil, Motrin), naproxen (e.g. Aleve), mefenamic acid (e.g. Ponstal), diclofenac (e.g. Voltaren), piroxicam (e.g. Feldene). A more complete list is linked here.

NSAIDs reduce inflammation and pain by inhibiting the enzyme COX-2. COX-2 is part of your body's inflammatory response. A certain amount of inflammation is good and necessary for healing. However, too much inflammation causes pain and further damage, which is why we take NSAIDs.


How do NSAIDs cause stomach ulcers? 

In addition to inhibiting COX-2, NSAIDs also inhibit the related enzyme COX-1, albeit to a lesser extent. COX-1 catalyzes the same reaction as COX-2, that being the synthesis of prostaglandins from arachidonic acid. However, COX-1 and COX-2 have different functions due to their different expression patterns. COX-1 is expressed throughout the body continuously, in contrast to COX-2 which is only expressed during inflammation. In the gastrointestinal tract, the continuous production of prostaglandin E2 catalyzed by COX-1 stimulates mucin production. Mucin forms a mucus bilayer in the stomach that protects the lining against corrosive agents such as stomach acid. The inadvertent inhibition of COX-1 by NSAIDs reduces mucin production, leaving the stomach wall vulnerable. To compound the problem, NSAIDs also have a multitude of other negative effects including increasing the production of stomach acid and increasing oxidative stress (Matsui et al, 2011), which for people with an ulcer will cause more discomfort and make the ulcer worse.

Fortunately, not all NSAIDs inhibit COX-1 equally. Some NSAIDs are more ulcergenic than others. For example, some of the early NSAIDs like aspirin are notorious for upsetting the stomach. More recently, scientists have developed NSAIDs that don't inhibit COX-1 as much as their predecessors and while still inhibiting COX-2 strongly, so-called COX-2 inhibitors, e.g. celecoxib (Celebrex). Consequently, these newer NSAIDs may reduce ulcer formation while still providing pain relief elsewhere in your body. If you have an ulcer and are taking NSAIDs, talk to your doctor about alterative NSAIDs. Be warned that these new generation NSAIDs are not without other side effects.

 
Can Vitamin U help?

The short answer is probably. Vitamin U is a naturally-occurring nutrient found in all vegetables, fruit and grains. One of its functions is to stimulate the secretion of mucin onto the walls of the stomach. How it does this is not well understood, but it is doesn't seem to have anything to do with COX-1/2 and prostaglandins. As a result, Vitamin U can be used to counteract the mucus-depleting effects of NSAIDs.


Are there any studies supporting the use of Vitamin U to counteract the ulcergenic effects of  NSAIDs?

Yes. In 1993, Salim reported the findings of a clinical trial in which Vitamin U was found to accelerate healing of patients hospitalized for erosive gastritis (bleeding from the stomach) caused by NSAID intake. Erosive gastritis is a common precursor to stomach ulcers. The majority of the patients had been taking NSAIDs for either osteo- or rheumatoid arthritis for less than 3 months. The NSAIDs used included diclofenac, piroxicam, mefenamic acid, naproxen and ibuprofen. The double-blind study found that the patients who received 4 x 500 mg of Vitamin U (DL-methylmethionine sulfonium chloride) per day had significantly less bleeding than the negative controls. Similarly to Vitamin U, patients given the sulfhydryl amino acid L-cysteine were also found to have significantly reduced bleeding, demonstrating the action of Vitamin U is likely via its conversion to a sulfhydryl. Endoscopies performed two days after treatment revealed significantly greater healing in those who were given either Vitamin U or cysteine. Of the 57 patients who were not treated with either Vitamin U or cysteine, 4 died from their condition. In contrast, there were no fatalities in those who were treated with either of these compounds. 

Currently, it is standard medical practice in cases of erosive gastritis to get the patient to stop taking NSAIDs, or at least take less irritating types, and/or to suppress stomach acid production. For a person who is taking NSAIDs for arthritic pain, reducing the amount of NSAIDs taken is clearly not desirable. Switching to less irritating NSAIDs is an option. Talk to your doctor.

Suppressing acid production will reduce irritation of the stomach, but at what cost? Unless you are producing too much stomach acid (a rare condition), reducing stomach acid will have side effects. The major role of stomach acid is to digest protein in our food. Dietary protein must be unraveled then enzymatically chopped up by pepsin to produce peptides. Without an acidic environment, protein passes through to the duodenum half digested. Enzymes in the duodenum that further digest protein into tiny peptides or amino acids can only do so much, leaving a significant portion of protein to pass into the colon. Consequently, low stomach acid can result in inadequate protein absorption as well as colonic fermentation (smelly gas). Furthermore, long-term suppression of stomach acid production promotes the growth of Helicobacter pylori, a known carcinogen (more).

While the results of this clinical trial are promising, Vitamin U is not infinitely powerful. There is only a certain amount Vitamin U can do to reverse or prevent damaged induced by NSAIDs. Large doses of NSAIDs will probably damage the stomach faster than Vitamin U can reverse this damage. However, these findings suggest that Vitamin U may be of some use in counteracting some of the negative effects caused by NSAIDs. Drinking freshly-made vegetable juice on a daily basis provides Vitamin U as well as other beneficial nutrients such as folate. 

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.

Food sources of Vitamin U



Vitamin U is produced by all flowering plants (angiosperms). Pretty much any vegetable and fruit we eat comes from a flowering plant, so pretty much anything we eat that comes from a plant has some Vitamin U, at least before it is processed. In fact, the only plants or plant-like organisms that don't make Vitamin U are conifers, ferns, mosses, algae and fungi.

In general, vegetables belonging to the Brassicacea family are the best source of Vitamin U. This family includes cabbages, kale, broccoli, kohlrabi, collards and turnips. Other vegetables such as spinach, asparagus and celery also produce abundant amounts of Vitamin U. Fruit are also good sources, but not as good as vegetables. In general, there is more Vitamin U in the leaves and stalks than in the fruit, roots and seeds. Grains seem to have little when fresh, but Vitamin U is made during sprouting. Animal products have little to no Vitamin U as it is not synthesized nor stored in significant amounts in animals.

Several studies have measured the concentration of Vitamin U in various foods. Tables listing some of these results are included below. Many factors affect the amount of Vitamin U in a given vegetable. These factors include storage conditions, storage duration, harvest time, regional variations and species variations. For example, cabbages have more Vitamin U during spring and summer when freshly harvested, with the nutrient slowly degrading with storage. After six months in the fridge, the concentration drops by one third, with faster losses at room temperature. In contrast, when barley is germinated for making beer, the amount of Vitamin U rises over time, affecting the flavor of the end product. In some cases, there are varieties of fruit that produce less Vitamin U. Oranges that have been selected to produce less Vitamin U are used to make juice because Vitamin U breaks down with extended storage and pasteurisation to form dimethyl sulfide, a compound that negatively affects the taste of the product (Sakamoto et al 
https://pubmed.ncbi.nlm.nih.gov/8987599/.) 

--------------------------------------------------------------------------------------------------------------------------

Song, Ji-Hoon, Hae-Rim Lee, and Soon-Mi Shim. 2016. “Determination of S-Methyl-L-Methionine (SMM) from Brassicaceae Family Vegetables and Characterization of the Intestinal Transport of SMM by Caco-2 Cells.” Journal of Food Science 82 (1): 36–43.

https://www.ncbi.nlm.nih.gov/pubmed/27883364


Food (Vitamin U concentration (mg/kg dry weight))

Radish (129-139)
Cabbage (535)
Kimchi cabbage (89-116)
Broccoli (150-350)

--------------------------------------------------------------------------------------------------------------------------
Scherb, J., Kreissl, J., Haupt, S. & Schieberle, P. Quantitation of S-methylmethionine in raw vegetables and green malt by a stable isotope dilution assay using LC-MS/MS: comparison with dimethyl sulfide formation after heat treatment. J. Agric. Food Chem. 57, 9091–9096 (2009).

https://www.ncbi.nlm.nih.gov/pubmed/19754146

Food (Vitamin U concentration (
mg/kg wet weight))

Celery (176)
Kohlrabi (124)
Leek (94)
Beetroot (89)
Cabbage (81)
White asparagus - Peru spears (161)
White asparagus - Peru stalks (86)
White asparagus - Germany spears (252)
White asparagus - Germany stalks (68)
White asparagus - Greece spears (113)
White asparagus - Greece stalks (101)
Green asparagus - Peru spears (234)
Green asparagus - Peru stalks (109)
Green asparagus - Germany spears (94)
Green asparagus - Germany stalks (53)
Green asparagus - Mexico spears (134)
Green asparagus - Mexico stalks (64)
Tomato (2.8)
Commercial orange juice (0.9)
Commercial strawberry juice (1.8)

Freshly-squeezed orange juice (1.2)
Barley - unprocessed (0.9)
Barley - after 4 days of germination (24)

--------------------------------------------------------------------------------------------------------------------------

Kim, G.-H. Determination of Vitamin U in Food Plants. Food Sci. Technol. Res. 9, 316–319 (2003).

https://www.jstage.jst.go.jp/article/fstr/9/4/9_4_316/_pdf

Food (Vitamin U concentration (mg/100g dry weight))

Spinach (45.2)
Pak-choy (34.3)
Kale (23.4)

Sumssukbujaengi - a wild korean leafy vegetable (19.8)
Leaf mustard (19.6)
Bud of aralia (19.3)
Broccoli (18.9)
Asparagus (18.7)
Sanmanul - a wild garlic (14.4)
Crown daisy (11.1)
Burdock (11.0)
Celery (8.3)
Komchi (4.7)
Wasabi (4.7)
Chamchi - a wild korean plant (4.0)
Shepherd’s purse (3.4)
Garlic (2.8)
Onion (2.7)
Green onion (2.6)
Laver (2.2)
Nurukchi (0.8)
Green tea (0.1)
Ginger (not detected)
Seaweed (not detected)
Red chilli (not detected)
Miscellaneous wild korean vegetables (not detected)
--------------------------------------------------------------------------------------------------------------------------

Kovatscheva, E. G. & Popova, J. G. [S-Methylmethionine content in plant and animal tissues and stability during storage]. Nahrung 21, 465–472 (1977).



Food (Vitamin U concentration (mg/kg wet weight))


Cabbage (50-104)
Kohlrabi (81-110)

Turnip (51-72)
Tomato (45-83)

Celery (38-78)
Leeks (66-75)
Garlic leaves (44-64)

Beet (22-37)
Raspberries (27)
Strawberries (14-25)

-----------------------------------------------------------------------------------------------------------------------------

Other references

1. 100-600 mg/kg dry weight (Bourgis et al and references within.)
  

How much Vitamin U do you need to heal ulcers?




Summary - Hospitalized peptic ulcer patients were cured by drinking cabbage juice containing 42-162 mg of Vitamin U per day for 7-10 days when eating a bland diet and getting bed rest.

A recommended dietary allowance (RDA) for Vitamin U has not been established by the US National Academy of Medicine. However, an estimate of how much Vitamin U you could try can be made by calculating the amount of Vitamin U used in Dr Cheney's studies. Cheney healed ulcer patients with 1 liter of cabbage juice per day over 7-10 days. At the time, Cheney didn't know exactly how much Vitamin U was in the juice. He just knew this much juice in combination with a bland diet and rest was enough. In more recent years, Vitamin U was identified as S-methylmethionine, and there have been several studies in which the amount of this amino acid has been quantified in cabbages. From these studies we can approximate how much supplemental Vitamin U is required to heal ulcers.

In 2003, Kim reported 26-46 mg/100 g of dry weight, which given that a cabbage is ~92% water, works out as 21-37 mg/kg of fresh cabbage. In 2009, Scherb and others found that cabbages have 81 mg of Vitamin U per kg of fresh cabbage. In 2017, Song et al determined that cabbages contain 50 mg/kg of Vitamin U. So we can estimate that there is roughly 21-81 mg Vitamin U per kg of cabbage.

Why this variation? There are several probable explanations. One possibility is that different parts of the cabbage were analyzed by the various researchers. Kim found that the concentration of Vitamin U in the core, middle and outside leaves varied by 2-fold, with the middle leaves having the most. Scherb found that vegetables grown in different countries had different amounts of Vitamin U, suggesting that some of the variation may be due to geography. Another possibility is that the cabbages were not all of equal freshness or picked at the same time of the year. In an older study, Kovatscheva and Popova noted that cabbages lose 62% of their Vitamin U during six months of storage without refrigeration and 34% with refrigeration. Cabbages harvested in spring /summer have the highest Vitamin U content. Finally, it is possible that the various extraction procedures used in the studies resulted in slightly different yields of Vitamin U. 

1 liter of juice is typically extracted from about 2 kg of cabbage. Cheney arrived at 1 liter from prior studies in which various volumes of cabbage juice were given to guinea pigs subjected to chemically-induced ulceration. 100% of the guinea pigs responded to the guinea-pig equivalent of 720 ml of juice. The volume used in the clinical study was rounded up to 1 liter to take into consideration variations in body weight and unexpected factors. 

Taking all this data together, it can be estimated that 1 litre of juice contains 42-162 mg of Vitamin U, which probably represents a maximum daily requirement.

Issues with drinking 1 liter of cabbage juice





In the 1940s and 1950s, Stanford doctor Garnett Cheney healed his peptic ulcer patients by having them drink 1 liter of cabbage juice daily for a couple of weeks. Cabbage juice is not only rich in Vitamin U, but is also rich in folate, vitamin C, vitamin K and potassium among other nutrients. It's well worth trying this treatment for peptic ulcers rather than taking supplements. However, there may be some drawbacks. 


Taste

Many people find cabbage juice to be
 distasteful. The chemicals responsible for this bitterness are called isothiocyanates. These compounds are produced in the cabbage when the leaves are physically damaged during chewing or juicing. Glucosinolates are enzymatically converted by myrosinases to form the bitter isothiocyanates. Some people are lucky in that can't taste isothiocyanates all that well so they can readily drink cabbage juice. One way to prevent the formation of isothiocyanates is by boiling unbroken cabbage leaves before juicing to kill the enzymes. That's why boiled cabbage has a mild taste compared to raw cabbage. However, the problem with this approach is that Vitamin U is also unstable to boiling, negating any beneficial effects. 

One solution is to drink the one liter of juice as 4 cups throughout the day instead of all at once. Another solution is to mix in better tasting vegetables that contain Vitamin U such as celery. Cheney used mixes containing a 3:1 cabbage-to-celery to good effect.


Gas

A second issue is gas. Cabbage has a significant amount of raffinose, a sugar that is notorious for producing gas when eaten. The human small intestine lacks the enzyme required for the digestion of raffinose. Unfortunately, some types of bacteria in our large intestine do have such an enzyme and will ferment raffinose quite readily to form gases. These gases produced in the colon have only one way out and will cause bloating and discomfort until discharged. Ingesting one liter of cabbage juice will cause problems for most people. In principle, a possible solution is to treat the cabbage juice with Beano before drinking it. Beano is basically alpha-galactosidase, an enzyme that will break down raffinose into sucrose and galactose, both of which we can easily break down and absorb. I'm not sure whether anyone has tested this idea, though taking Beano along with the juice as recommended should help. Drinking several cups spread throughout the day should also reduce bloating.


Smell

A third issue is smell. Fresh cabbage juice smells fine - old juice does not. Vitamin U is degraded to homoserine and dimethylsulfide by enzymes found in cabbage. Dimethylsulfide has a disagreeable sulfur odor a little like that found in rotten eggs, though without the toxicity. These enzymes don't work as quickly as myrosinases, but leaving cabbage juice sitting around for a few hours will allow plenty of time for dimethylsulfide to form. Putting the juice in the fridge will slow the reaction somewhat, but after 24 h the juice still tastes terrible. Even if a person could stomach the old juice, there would not be much point as by this stage most of the Vitamin U would have been degraded. Cabbages also have other compounds that contain sulfur that when broken down produce disagreeable odors. The solution is to drink cabbage juice fresh before it has had a chance to go off.

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