Helicobacter Pylori, Gastric Ulcers and Cancer

Stomach Pathogen or Immune Regulator?

Helicobacter pylori (Hp) has co-evolved with the human stomach.  Hp has always been passed from mother to child as the child started premasticated solid foods.  The advent of processed baby foods and antibiotics has eliminated Hp in 90% of the US population and coincides with a dramatic rise of allergies, asthma and autoimmune diseases (commonly explained by the hygiene hypothesis.)

Hp Is Stomach-Adapted

Hp is adapted for growth in an acidic environment.  It produces ammonia to neutralize stomach acid. It also provided me with great perplexity in searching for heparin-binding domains in Hp proteins suspected of binding to stomach epithelial cells.  I generalized that pathogens must have proteins on their surfaces that bind to the heparan sulfate proteoglycans of epithelial cells.  I checked candidate Hp proteins and found histidines where I expected to find basic amino acids, either lysine or arginine.  The “duh” moment came when I realized that the pH of the Hp milieu was acidic and hence histidine would have a positive charge and function like the other two basic amino acids.  Hp was adapted to its stomach world.

Is Hp Good or Bad?

I have been trying to incorporate Hp as a pathogen into my view of gut function.  After all, Hp causes stomach ulcers and gastric cancer.  Several studies over the last few years have shown an association between Hp and asthma, but it is a negative association.  Hp seems to provide protection from asthma and I think that it is likely that the protection extends to allergies and autoimmune diseases.  It is also noteworthy that analysis of genetic predisposition to gastric cancer only reveals polymorphism in genes associated with inflammation, e.g. IL-1 or TNF.

Hp Lives on Hydrogen from Gut Biofilms

Further evidence of the integral nature of Hp as part of the natural gut flora is its use of molecular hydrogen (H2) as an energy source, i.e. high energy electrons for its electron transport chain to produce ATP or to power membrane transport.  The source of the hydrogen is Klebsiella in biofilms in the intestines.  The hydrogen diffuses into the intestinal blood supply and is circulated to the stomach lining where it provides energy for Hp.  Attacking gut biofilms may starve Hp and feeding starch (indigestible branch oligosaccharides are unique food source only accessed by Hp pullulanase) enhances Hp hydrogen nutrients.  [Since regulation of the Hp genes is not thoroughly understood, it is also possible that ample starch could shut down nitrogenase and starve the Hp.]

Hp Increases Tregs

Allergies and autoimmune diseases point to problems in self/non-self recognition, i.e. immunological tolerance.  And tolerance is dependent on regulatory T cells.  In this context, it is interesting that Hp stimulates the accumulation of regulatory T cells.  The gut is the major repository of cells of the immune system.  It seems to follow that by elimination of the stomach Treg population by curing Hp infections, the body may be deprived of it major resource to suppress immunological responses to innocuous antigens in foods, pollens, etc. and to self antigens.  Coupling a shortage of Tregs with chronic inflammation may lead to allergies and autoimmune diseases.  Another source of Treg depletion that may further compromise the immune system is circulating LPS, endotoxemia, that is associated with obesity (and leaky gut?)

Erectile Dysfunction Diet

Inflammation Leads to Hypertension, Nitric Oxide Inadequacy and Impotence

Drugs for erectile dysfunction (ED), e.g. sidenafil (Viagra), compensate for inadequate nitric oxide (NO) production from arginine by inhibiting the enzyme, phosphodiesterase (PDE5), that hydrolyzes the cyclic GMP that mediates the NO-triggered process of vascular dilation.

Inflammation Is the Core of ED

Drug treatment to compensate for inadequate NO production is a multibillion dollar industry that avoids curing the underlying cause of the ED.  All of the physiological predispositions to ED result in or derive from chronic inflammation.  The major cause of ED, hypertension, frequently as a result of kidney disease, diabetes or metabolic syndrome, can be treated with diet and exercise.  Of course the typically recommended diet is essentially the Anti-Inflammatory Diet, compromised by the unenlightened persistence in the counterproductive use of grain starches, high fructose corn syrup, omega-6 polyunsaturated fatty acids and low saturated fat.

Decreasing Testosterone Results from Declining Health -- not Age

Recent studies also indicate that testosterone levels do not normally decline with age, but rather with declining health.  Healthy men have higher testosterone levels.  I would suggest that reduction in serum testosterone could be used as a measure of chronic inflammation in men.  This also suggests that many of the symptoms associated with aging in men actually reflect increasing chronic inflammation and reduced testosterone.

ED Diets Are Just the Anti-Inflammatory Diet Plus Veggies

A chronic high starch/sugar/HFCS diet with omega-6 oils in place of saturated fats, leads to chronic inflammation, high triglycerides, risk of metabolic syndrome and obesity.  Of course, diabetics have an even lower tolerance for this type of diet.  This diet, which is rather typical in many modern cultures, also provides a high risk of damage to endothelial cells lining the circulatory system and to ED.  The opposite of the inflammatory diet is the low carb, high omega-3 fish oil, no vegetable oil, meat/fish/dairy, Anti-Inflammatory Diet.  This is supplemented with exercise and high vitamin D.  Foods labeled as beneficial to ED also include specific herbs, spices and leafy vegetables, because these contain organic chemicals that inhibit components of the inflammation system or are anti-oxidants.
 
ED and Biofilms

I would suspect that men with ED suffer from chronic dietary inflammation and one of the consequences of this type of diet is the accumulation of pathogenic biofilms.  Hypertension, which is a contributor to ED and a consequence of chronic inflammation, is also associated with periodontal biofilms and kidney disease (aggravated by renal biofilms.)  I suspect that endothelial cells of capillaries are compromised by biofilm-derived endotoxins that ultimately contribute to apoptosis, decrease in capillary beds and elevation of blood pressure.  All of these assaults on endothelial cells undermine penile vasculature and contribute to ED.

Viagra Can Lead to Rosacea

Men taking Viagra or other PDE5 inhibitors typically have compromised vascular systems that are the basis for ED.  Increasing the response to NO in men with ED produces an increased risk of rosacea.  Withdrawal from PDE5 inhibitors stops the rosacea, which returns if the PDE5 inhibitor use is reinitiated.  Thus, the flush that is the goal of Viagra therapy, leaves some redfaced.

ref:
Ioannides, D. et al. (2009) Phosphodiesterase-5 inhibitors and rosacea: report of 10 cases. Br. J. Dermatol. 160: 719-20.

Migraine Headache Diet

Simple Guidelines to Lower Chronic Inflammation and Avoid Pain

If I stick to this Anti-Inflammatory Diet and Lifestyle, I don’t get migraine headaches any more. I can still get a migraine, if I let myself get very dehydrated or drift into carbohydrate excess, but I am shocked when it happens. I can still enjoy chocolate and coffee. Avoiding the headaches is under my control and the diet is healthy and easy to follow.

Chronic Inflammation Is the Foundation for Migraine Headaches

The details and rationale for the Basic Anti-inflammatory Diet and Lifestyle are discussed in many articles on this blog. The guiding logic is that migraine headaches are based on chronic inflammation, although in each individual case there may be specific health problems that contribute and trigger migraines. If the chronic inflammation is removed, then migraines can’t happen or are reduced in frequency and/or severity.

Common Migraine Guidelines Point to Inflammation as the Problem

Feverfew is present on all of the lists of traditional treatments to avoid migraines. Extracts of feverfew contain parthenolide, a sesquiterpene lactone, that has been shown in mouse studies to inhibit activation of NFkB, the inflammation transcription factor. Stress reduction, acupuncture, etc. all point to vagal stimulation to reduce chronic inflammation. I would also recommend that migraine sufferers investigate vagal stimulation exercises to augment the basic diet and exercise to eliminate chronic inflammation.

Anti-inflammatory Diet in a Nutshell

1. Vitamin D -- deficiency is common... even with adequate sun exposure
2. Low carbs -- starch is hyperglycemic, grain gluten intolerance is very common
3. Vegetable oils -- only olive oil is safe (trans fats are dangerous), butter is better
4. Fish oil -- omega-3 oils can reduce chronic inflammation
5. High fructose corn syrup -- eliminate all sources
6. Saturated Fats -- safer than polyunsaturated fats, major source of calories

Typical Meals for a Healthy Head

• Breakfast -- eggs, bacon, sausage, stewed tomatoes, cottage cheese, coffee, yogurt (low sugar, no HFCS) (avoid cereal, pancakes, waffles, toast, etc.)

example: scrambled eggs with sausage, yogurt (unsweetened, blended with fresh raspberries, strawberries or blueberries, sweetened with honey) coffee mocha

• Lunch -- soup, salad, chicken, ham, tuna, vegetables, modest amounts of fruit, etc. (avoid bread, buns, potatoes, pasta, rice), keep the carbs to less than 50 grams

example: homemade chili with extra ham; thin sliver of toast loaded with feta cheese, broiled and drizzled with extra virgin olive oil; salad with peppers, tomatoes and cubes of jalapeno cheese, olive oil/vinegar, herbs/spices

• Dinner -- fish, meat, vegetables, 50 grams of carbs (avoid grains)

example: broiled salmon with crushed pinenuts, garlic, butter and lemon; sauteed sliced zucchini/miniature squashes; wedges of small potatoes, microwaved ‘till soft and fried in light olive oil and butter; strawberries painted with melted dark chocolate

Why Conventional Diet Wisdom Gives You a Headache

The government food pyramid was designed by the food industry and was never supported by evidence from the biomedical literature. Research shows that saturated fats actually lower heart disease. Polyunsaturated fats in common vegetable oils are a major source of chronic diet-based inflammation. Starch/sugar raises triglycerides, not dietary fats. Grains are a major source of inflammation, because of the high incidence of gluten intolerance, the high content of hyperglycemic starch (even in whole grain breads, etc.) and in the support of gut biofilms based on Klebsiella, a contributor to Crohn’s and other autoimmune diseases. Blood lipid levels were not associated with heart disease and lowering these levels with statins does not improve health. Lowering inflammation uniformly improves health, as well as eliminating migraines.

Biofilm Transformation, Helicobacter, Klebsiella

Helicobacter pylori causes stomach cancer, but it feeds on hydrogen gas produced by Klebsiella pneumoniae in gut biofilms. DNA released by biofilm bacteria not only transfers antibiotic resistance, but it also provides protection against host antibacterial peptides, such a cathelicidins and defensins.

Exploding Labs

When I was working on host/pathogen interactions and plant disease resistance, I also became familiar with research on the formation of the plant equivalent of cancer, crown galls, and symbiotic bacterial nitrogen fixation. I mention this, because this also exposed me to the free-living bacterial nitrogen fixing system in Klebsiella and to the memorable urban legion of exploding labs. As the story goes, as bacteria convert atmospheric nitrogen gas into ammonia, nitrogen fixation, they use high energy electrons, e.g. from ferrodoxin, and lots of ATP, but they also produce hydrogen gas. In labs where they are researching nitrogen fixation, the excess hydrogen gas would accumulate on the ceiling until... boom! Now those labs are properly vented.

Helicobacter Uses Hydrogen as an Energy Source

Helicobacter pylori is considered the most common bacterial pathogen of humans and is the primary cause of ulcers and stomach cancer. H. pylori lives in the stomach by neutralizing stomach acid with ammonia. Another interesting ability of this bacterium is its ability to use hydrogen dissolved in circulating blood as an energy source. The high energy electrons from molecular hydrogen are transported to its electron transport chain, and the energy is used in membrane transport and ATP production. The circulating hydrogen is produced by gut bacteria.

Klebsiella Is not just a Soil Bacterium, Gut Gases

Klebsiella pneumonia is a lung pathogen and it also forms gut biofilms. Presence in the gut and the ability to produce hydrogen gas has some implications for hydrogen utilizing bacteria like H. pylori. Clearly, the stomach of someone with an abundant source of hydrogen fuel in their blood is a better target for H. pylori colonization. This explains why even at age 50, individuals who were exclusively breastfed have a lower incidence of H. pylori and stomach cancer, since even a single bottle of formula can shift an infant to adult, i.e. Klebsiella gut flora.

Klebsiella Needs Carbs to Produce Hydrogen

K. pneumoniae has been associated with Crohn’s Disease and Ankylosing Spondylitis. It grows in gut biofilms and produces pullulanase, an enzyme that can utilize the branched glucosides left over from the action of amylase on plant starch. So K.p. has an untapped food source and it needs lots of ATP to produce hydrogen gas. The nitrogenase needed for nitrogen fixation and hydrogen production is very sensitive to oxygen, so this means that K.p. needs a partially anaerobic environment and must get its energy from fermentation. Fermentation yields much less ATP than respiration using oxygen, which means that K.p. can only produce hydrogen with lots of glucose from starch.

Low Carb Diet Cures Crohn’s Disease

It turns out that the antigen causing Crohn’s disease is the pullulanse (with collagen mimetics.) As you should expect, it has a basic triplet. Eating a low carb diet reduces the flareups of Crohn’s disease, presumably by starving out the K.p.. It is interesting that nitrogenase is the antigen involved in Ankylosing Spondylitis.

Biofilms Promote Transformation and Antibiotic Resistance

Just as a footnote to the benefit of K.p. as a citizen of a biofilm community, H.p. should also live in those biofilms, since that is the source of the hydrogen it uses. Biofilms also stimulate the exchange of DNA, because the quorum sensing chemical signals trigger the release of DNA. The DNA is a component in the matrix that binds bacteria in the biofilm and can work in conjunction with bacterial acidic polysaccharides and host heparan sulfate. These acidic polymers tend to bind the basic antimicrobial peptides, e.g. defensins and cathecidins produced as a major non-adaptive defense against bacteria. Thus, the release of DNA triggered by quorum sensing, builds matrix, facilitates DNA transformation that is the foundation for the spread of antibiotic resistance in gut biofilms and provides resistance against antimicrobial peptides.

Cytstic Fibrosis Overproduces Tissue Transglutaminase and Contributes to Celiac

Tissue transglutaminase (tTG or TG2) is produced in excess in some diseases, such as cystic fibrosis, and contributes to inflammation and disease symptoms. tTG also readily moves in and out of cells by virtue of its basic triplet and when in the cytoplasm, tTG is ubiquinated and degraded by proteosomes. I have previously pointed out that internalization and proteosome degradation are also the initial steps in processing of proteins for presentation by the immune system and antibody production, i.e. turning a cellular protein into an autoantigen involved in autoimmune disease.

Here is an image of a computational protein model of tTG I drew with Chimera. I have highlighted the basic triplet to show its exposure to facilitate transport.

Oxidative Stress Alters tTG and Triggers Inflammation

A recent article also links tTG intracellular chemical modifications (SUMOylation), which are linked to oxidative stress, to activation of NFkB and inflammation. Thus, tTG is a major player in controlling cell surface interactions with potentially toxic materials such as polyglutamine-rich gliadin, as well as triggering inflammation in response to oxidation stress.

Cystic Fibrosis Causes Overproduction of tTG

When I read that cystic fibrosis results in an increase in the production of tTG in lungs, I immediately thought of the role of tTG as an autoantigen in celiac disease and the progression of celiac into Hashimoto’s thyroiditis, which has the same autoantigen, tTG. I suspected that the overproduction of tTG and inflammation in cystic fibrosis should increase tTG autoantibody production and tTG-mediated autoimmune diseases of celiac and Hashimoto’s thyroiditis.

Extra tTG Leads to Autoimmune Celiac

A quick PubMed search of CF and celiac, revealed a study of comorbidity between CF and celiac in Norway. Just as expected, the two diseases occur together with a frequency three times higher than predicted by coincidence. CF stimulated tTG overproduction was driving the development of celiac.

references:
Luciani A, Villella VR, Vasaturo A, Giardino I, Raia V, Pettoello-Mantovani M, D'Apolito M, Guido S, Leal T, Quaratino S, Maiuri L. SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation. J Immunol. 2009 Aug 15;183(4):2775-84.

Fluge G, Olesen HV, Gilljam M, Meyer P, Pressler T, Storrösten OT, Karpati F, Hjelte L. Co-morbidity of cystic fibrosis and celiac disease in Scandinavian cystic fibrosis patients. J Cyst Fibros. 2009 May;8(3):198-202.