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?)

Autoimmunity, Allergies and Basic Triplets

Basic Triplets Only in Primate Forms and Allergens

I have examined the proteins, autoantigens, that are the focus of a dozen autoimmune diseases and a similar number of allergens. All of these proteins have basic triplets that I previously associated with heparin-binding. I have had two recent revelations. First, these triplets appear to not be involved with heparan sulfate proteoglycans for internalization. In fact, HSPGs don’t appear to be involved, even though the process is inhibited by heparin. So this suggests a transport system, perhaps using the LDL receptor or the mannose-6-phosphate receptor, (or a protein with an acidic triplet or quartet.)

The second interesting observation is that the mouse, cat, dog, etc. versions of the human autoantigens lack the basic triplets. This suggests that these diseases cannot occur in non-primates by the same mechanisms. So what is the role of these basic triplets in humans? They didn’t evolve to cause problems under unusual conditions of chronic inflammation, so what is their adaptive advantage?

I think that the answers to these questions could yield the identification of a fundamental cellular transport process and associated cellular phenomena that could be worth a Nobel prize in medicine and it could be unravelled by a group of high school kids doing some straightforward bioinformatics.

Oh. I just remembered that IL-1 beta, the inflammatory cytokine, has a basic triplet. I just checked NCBI, and that basic triplet is found in all of the mammalian IL-1 betas. Oddly, the soluble receptor for IL-1 beta has an acidic quartet. I looked up the protein structure of the IL-1 beta bound to the IL-1 receptor and did a quick illustration using Chimera:

I put the surface on the IL-1 beta and left the IL-1R wrapping around it in as a ribbon. The basic triplet of IL-1 beta is in blue and the acidic quartet of the receptor is in red. One of the basic amino acids is stabilized by hydrophobic bonding over the face of a tyrosine, in yellow. Clearly, there is a simple ionic, plus-minus charge, bonding between the basic and acid amino acids. I don’t normally see this interaction between basic heparin-binding domains and other proteins. Other proteins that bind to heparin-binding domains use aromatic amino acids to make hydrophobic bonds with the hydrophobic arms of the basic amino acids, e.g. importin and nuclear localization signals or tryptophan/arginine ladders. The use of simple acid-base connections (with the projection of each stiffened by adjacent prolines) shows that this interaction is selected to be irreversible.

I don’t know all of the ramifications of basic triplets, but they are very important and are the basis for most modern allergic and autoimmune diseases.