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?)
28 comments:
Art, I like this post. I really can't see H pylori as a pathogen if this chap's blog is correct.
I just don't see us carrying a cancer bug around with us for the last 60,000 years...
Peter
Dr. Ayers,
Yes this is fantastic!
If Hp is microaerophilic and living from methanogenesis off hindgut flora (Kleb) off of dietary oligosac's... then what sets Hp off to overgrow? Gluten? Legumes? Other plant toxins??? Add to that excessive starches and fructose?
G-cells. Are they responding to localized inflammation by producing more gastrin because of leaky gut-gastritis or really Hp gastritis? Or both?
The rate of esophageal adenocarcinoma (which is highly fatal and killed one of my best friend's dad 2 yrs ago) has exploded tracing the SAME exponential curve as fructose consumption in the U.S.
I think you will find it interesting that 'infection' with cagA(+) Hp strains is considered 'protective' for Barrett's esophagitis and perhaps adenocarcinoma.
Cancer Prev Res (Phila Pa). 2008 Oct;1(5):329-38.
Helicobacter pylori and esophageal cancer risk: a meta-analysis.
Islami F, Kamangar F.
I would highly bet whole grain consumption probably follows an identical death curve for adenocarcinoma. And GU and DU!!
Having had asthma, I suspect you are totally correct in regards to the role of our gut microbiome and autoimmune/ allergy conditions. I remember my parents premasticating food and feeding me... it's cultural! *haa* But obviously has benefits in transferring good probiotics.
-G
BTW I had asthma as an adult after taking oral contraceptives (never as a child/teen). I highly suspect the OC ruined something in the enterohepatic circulation of bile acids/chol/fat-soluble vitamins, etc.
Thoughts?
Peter,
I agree the data a persuasive that Hp is a mutualist and humans benefit from its presence. The exchanges include hydrogen and various nutrients, but what is the communication that keeps the Hp under control? Did migrating tribes have ulcers and stomach cancer? I doubt it. Maybe grains and starch are the culprits. I would like to know if nitrogenase and pullulanase are expressed together or alternatively in Klebsiella. That would help to explain dietary impact on Hp.
Thanks for the comments.
Dr. B G,
I think that you are right about all of the associations. Hp stabilizes the immune system and I think that the major impact is as providing a Treg reservoir.
In a mouse model, Hp infection provided an increase in Tregs that provided protection against castor oil-induced inflammatory bowel.
Hp infection should reduce the incidence of Crohn's disease and IBDs. It would be interesting to know if Hp infection was a cure for IBDs. It is also an interetsing comparison to Helminth therapy.
If you developed asthma, that would suggest that you were cleared of the Hp that was protecting you in your youth or you had childhood allergies that would suggest that your whole family was Hp-deficient.
I appreciate your continued input.
Dr. Ayers-
Having just "found" your blog, it will take some time before I have absorbed enough to contribute to any depth, but I would like to make some comments on H. pylori from my position as a person with Parkinson's disease. Numerous studies have shown linkages with such matters as malabsorption problems of both nutrients and medications as well as a positive impact upon function of successful eradication as well as disasterous consequences of failed attempts.
One facet that particularly interests me, however, is the historical context. PD was almost unknown prior to the Industrial Revolution and was not described until 1817, roughly one generation into that event, and in London which was the center of same.
Among the changes occurring at that time and which relate to both Hp and inflammation were-
1) the advent of chronic stress rather than simply acute into life; 2) the drop in price in processed sugar; and 3) the rise in exposure to ultrafine particulates as more and more coal was used. Combined with the work of a German researcher named Braak which shows the stomach wall as one of the first places to show the "footprint" of PD, Lewy bodies, one cannot help to suspect a connection.
Rick
Dr. Ayers,
I never heard of helminth therapy but that makes sense!! One article said that immunomodulation from helminths is related to shifting to Th2 and Treg immunity (much the same way I believe that vitamin D works and improves UC and Crohns).
Most immigrants have Hp and my parents are from a rural village in Taiwan (no running water). Being a first born and my father a physician, I received way more antibiotics and thus more opportunities for Hp eradication than my younger siblings. My lil bro (being a male offspring) however probably had the most antiobiotics and incidentally he developed an autoimmune disease very very young. I did have bronchitis 2 consequent yrs as young teen -- so that may count as reactive airwy dz or asthma. In my 20s (after publishing a paper on Hp eradication) I tested negative to Hp serology.
So... again you are RIGHT ON -- I might been colonized but Hp was probably cleared at some point. (btw also my bro was the last child and I don't recall my Westernized parents premasticating food for him, not that it mattered b/c Hp was probably cleared in them as well).
Thank you for your brilliant thoughts. I look forward to ALL your posts like a big freakgeek. All med students should be forced to read the ED post -- every inflamed male has ED.
-G
Is there a test to know if you have too much Hp or no Hp? How do you get 'infected' with it if you don't have enough? Is Vit D a substitute for Hp if you are deficient? How do starches help or hurt? I'm getting so confused...
Tanya,
The quick answer is that Hp and Kp are not easy to measure and their relationship to disease is speculative. We don't even know enough to suggest Hp infection under certain circumstances. It is also not known what triggers Hp to cause ulcers or cancer. All that is known is the anti-inflammatory diet leads to health in most people. Starch in general in not healthy and I am trying to understand why. The tight connection between Kp and starch seem to explain why starch leads to inflammation. Vitamin D and omega-3s are separate inputs that are anti-inflammatory for different reasons. VitD may also be produced by biofilms and act as a gut hormone.
I guess that I am writing for a very broad audience and try to make as many connections as possible between daily activities, such as eating, and physiology/cell biology. Since, in my not so humble opinion, medicine and the biomedical literature, has not attempted to make those connections or only makes the connections via pharmaceuticals, that leaves most connections between diet and disease unexplained and without clinical trials. So I am mixing logical extensions with a scattershot of clinical data in an attempt to make medicine rational. That also, unfortunately makes it confusing.
I can't define the healthy diet and expect that it will be healthy for everyone, because people already suffer from various diseases and developmental problems. Diets could be adjusted to support a path for each individual, but medicine has not chosen that path. I can only explain why I think components of my diet guidelines are important for health.
So, I speculate and try to connect the dots and hope that readers straighten me out with observations that they have made or provide other related problems.
Thanks for your comments.
My asthma has gotten much worse in the last couple of years, coinciding with me eating few starches (and moving across the country...)
Is there any way to know if I have Hp or not?
SM
SM,
It is hard to definitive about Hp colonization of the stomach. After several generations in a culture in which antibiotics are commonly used, many are free of Hp. Absence of Hp and presence of an inflammatory diet, is what I think leads to allergies and asthma. Reversing these immunological problems is difficult, but is helped by removing the major sources of inflammation, e.g. diet.
Starch is a major contributor to inflammation, but it also has some impact on biofilms, so reducing starch may indirectly trigger inflammation via the biofilm connection. Stick with low carbs and reduce the other inflammatory components in your diet.
I think that following the Anti-Inflammatory Diet outline should reduce asthma symptoms and start to heal your immune system. Check your vitamin D levels, eliminate vegetable oils (switch to olive oil and butter) and increase your omega-3s.
Thanks for your comments.
I'm on (a variant of) the anti-inflammatory diet already. My D levels should be high since I'm white and spend a good amount of time outside and use sunscreen sparingly.
Three weeks ago, I started fasting until 4:00 each day, which is reputed to be anti-inflammatory. My asthma had already worsened before I started fasting and I've seen no change since.
I suspect moving across the country made it worse. And then moving into an apartment with lots of ducks (and their feathers & feces) nearby might have something to do with it.
Still looking for ideas but I'm definitely planning to stick with an anti-inflammatory diet.
Thanks for your thoughts. Keep blogging, this is all great stuff.
SM
SM,
I would bet that you are vitD deficient. Most people who have symptoms of inflammation, e.g. asthma, are vitD deficient even though they get plenty of sun. I think that inflammation inhibits skin conversion of vitD.
Most variants of "anti-inflammatory diets" merely add plant antioxidants to an otherwise inflammatory diet. So make sure that you actually have a diet that doesn't continue to support inflammation. If your asthma symptoms don't abate, I would continue to search for sources of inflammation.
It is possible to eliminate the symptoms of asthma, because Helminth therapy works, and it presumably manipultes the regulatory T cells that are inadequate in allergies and asthma.
Thanks for your comments.
I'm doing a paleo diet but adding much much more fermented foods (kimchi, fermented tofu) some more nuts and dairy. No grains, few legumes. I'm lean and getting leaner from the new diet. It's much like your anti-inflammatory diet in practice but not in name.
I'll grab some D3 supplements. I was hoping that wholemilk (vitD fortified) yogurt and being active in Davis CA would do it!
The few medicines I've tried don't seem to help much. I'll keep looking for sources of inflammation! Many thanks for your help on this.
Anon,
Just a word to the wise. VitD3 supplementation is frequently unsuccessful, because the starting serum levels are not measured and then checked after supplementation to see if it worked. If supplementation is needed, a high starter dose is needed to replenish reserves, before any change in serum levels occurs and subsequent maintenance supplements are too low. I would expect you to be taking 2000-5000 IU/d.
Studies in San Diego and Miami show most people who spend hours each day in the sun are vitD deficient. Davis CA is no vitD safe zone. Paleo is good, especially if it is grass fed. Otherwise it may be omega-3 deficient. What about the quality of your fat?
Thanks for your comments.
Thanks for the helpful warning about D3. I'm due for a physical soon so I'll see if they can do bloodwork.
I'm moving toward more grass-fed and wild sources but haven't completed the transition. I don't really know how good my omega 3 levels are but I'm working on it.
Dr. Ayers,
Here is the link for adenocarcinomoa related to fructose (HFCS) and carb intake.
upper GI adenocarcinoma (esophageal):
http://www3.interscience.wiley.com/cgi-bin/fulltext/119387359/PDFSTART
Fig 2 is interesting -- it appears cancer risk is lower at < 60 grams (I believe that is daily consumption).
high carbs and gastric cancer:
http://annonc.oxfordjournals.org/cgi/reprint/15/4/581
Thanks,
G
SM, I adopted a paleo type of diet and besides grains, had to drop dairy to get rid of my asthma (which also got worse when I moved to California from the east coast). Maybe they have more A1 dairy out here?
Dr. B G,
I think that it would be interesting to determine hydrogen production and Hp activity (ammonia) production following meals with different amounts of starch in people with and without Hp infections, in regions with high stomach cancer rates. It would appear that high starch produces high hydrogen production by intestinal Klebsiella and the high hydrogen stimulates/changes the Hp and produces stomach cancer. It may also be that cooking of pasta and rice is altered to make the starch more available for amylase and leaving the amylopectin (alpha 1,4-1,6 glucosyl residues) oligos for the Klebsiella.
I thought methanogenesis was restricted to archeae. Doesn't Hp just get the first shot at glucose released from starch by salivary amylase?
Thanks for your comments.
Anon,
I have spent a lot of time looking a protein sequences of allergens. The caseins from cow milk lack the expected basic triplet of amino acids, but they do have a strong heparin-binding domain. Since the critical function seems to be internalization, the unusual properties of caseins in solubilizing fats may be important. Caseins may not cause a problem unless the caseins are exposed in an unusual way by homogenization, for example.
Raw milk may not participate in starting allergies, but after they exist, antibodies probably persist in binding to them.
Thanks for the comment.
Art,
Wouldn't that be a most cool experiment? Tritium labelled? Or C13 or C14 like the HP breathing test?
I think our colons are like cockroaches... the way our sigmoid and transverse wrap back up around as you mentioned provides protons into the enteric mesentery and to to our gastric flora for energy provided from Kp and other gut methanogenesis.
I like how your ideas are about the gut housing our immne system and its own sort of nervous system. When my daughter was 8 yo she told me that the legendary herbivore Stegosaurus had 2 brains -- a larger 2nd brain in its hip! That sounds not unlike our vagal and GI nerves!
http://en.wikipedia.org/wiki/Stegosaurus#.22Second_brain.22
Perhaps fructose and high carbs causes a toxic 'bloom' of Kp, protons, Hp and inflammation? Korea and certain parts of China have high gastric cancer rates and pretty high dietary carbohydrate intakes (beer, rice, baos/buns, instant noodles).
Also achlorhydria is common in gastric cancer. Couple that with Hp overgrowth which further lowers gastric pH (right? that is how Hp exerts a protective role). The reason for achlorhydria maybe related to an autoimmune response, eg auto-antibodies against parietal cells. Parietal cells contain the potent acid-pumps. Can u say autoimmune wheat/gluten effects?? Low thyroid effects? Jacked GI immunity??
I had another thing I was curious about. Are all virulent microbes and pathogens (except Hp) exhibiting binding sites for heparin? Without protective Hp and corollary Tregs... could we produce autoantibodies even against nonspecific parts of the heparin binding sites which may lead to autoimmune diseases?
Also, are there any relationship between the various HLA types and 'types' of heparin binding sites? It appears to me that for each organ-specific autoimmune disease, a specific HLA type is highly correlated.
-G
PS Marshall tested and proved Koch's theorem (and was duly awared a Nobel) by ingesting Hp and achieved a dose-related infection of Hp. (that is almost as bad as fecal-oral transfer, NO THANKS) I think that I would much prefer benign inoculation via household contact (hugging kissing plate- sharing) *haaa!!*
Dr. B G,
Another hallmark of autoimmunity is the anti-phospholipid antibody. Of course heparin-binding domains also bind to DNA as well as inositol phosphates or phospholipids. Thus, by inversion an anti-phopholipid antibody also is an anti-heparin antibody, and heparin is used to neutralize these antibodies and as a general anti-inflammatory to help women get pregnant and gestate.
The HLA that potentiates celiac has a strong heparin-binding domain along the lip that displays antigenic peptides.
I haven't found any antigens that have heparin-binding domains, so I think that something like a heparin-binding domain, e.g. the basic triplet, is involved in internalization prior to chopping and presentation.
It is not necessary to produce antibodies against the bacteria, when self antigens would also work directly under inflammatory conditions in the absence of adequate Tregs.
Thanks for the contributory speculation.
btw I don't know much about methanogenesis, achae, or bacteria... (tho I read Nick Lane but need to read again) but I believe that Kp fixes nitrogen; they have nitrogenases...and they use sulfur as the final electron donor (instead of O2 CO2 or acetic acid). Maybe that does not result in protons and methane? Protons and sulfites??
http://jb.asm.org/cgi/content/full/183/3/882
Termites. Cockroaches. You might find their biofilms are very curious!! Methanogens + Kp live together...
http://www.idosi.org/ajps/2(3)09/12.pdf
http://aem.asm.org/cgi/reprint/67/10/4657
Anonymous,
Interesting, I hadn't even heard of A1 or A2 dairy. I'll switch brands, switch animals or cut dairy out and see if that helps.
The asthma, by the way, is just induced by sprinting. I have no problems until I try to do a second 400m sprint.
SM
As a kid I remember having really bad allergies. In my teens my allergies were so bad I would sneeze so much my nose would bleed. When I was in a sneezing attack, I would smell an odor like feces. The sneezing was back to back for hours if not medicated. Everything would trigger sneezing. If it had a smell, I would sneeze, whether sweet or foul smelling. I had tons of sinus infections. I would also get these red marks on my tongue that would swell when I would eat spicy foods. I took years of taking over the counter medicine... I am now 37 and was diagnosed with GERDS, HPylori, I have a small ulcer forming and gastritis. NONE of the medication worked for the HP! I have extremely bad fecal breath and a white tongue. The only thing that helped was exercise daily... I do about 3-5 miles per day. Lot and Lots of water and a fruit and vegetable diet ONLY! Even with that change I still had the problems but it subsided by at least 60% I have perfect dental health so that can be ruled out. I stopped working out and went back to my bad diet and it returned with a vengeance. If I fast for a few days it gets 10x worse and by the third day of fasting all symptoms are gone. Day 4 if I eat, its back immediately. All doctors I go to are confused and have never seen it this bad. I thought the feces smell was from my tonsils so they were taken out. I still have my adenoids, but when I would go through the sneezing bouts the roof of my mouth would itch really bad. I had an ENT tell me I have lots of adenoid tissue but never said to remove it. She also said my GERDS it what causes the allergy and sinuses to trigger. Also as a teen I would get extreme abdominal pain in the mornings, and it would go away eventually. I was a not sexually active as a teen, but the doctor was someone I never saw as a teen either.
.
Just a little info on my childhood. I grew up in rural south Carolina. Grew up off your typical fried, sugary, fatty foods. The water lines were not with the city and we pumped it from the ground in the 80's. By the 90's it was city water. I never had a weight problem and was active in sports like softball and basketball.
What do you guys think of this case?
email:boodahboot@aol.com
I just had a 'light bulb' moment. So a friend was tested positive for Hp but negative for SIBO, however, she chose SIBO diet for Hp because she had lost faith in conventional treatment (i.e. antibiotics and PPIs) so as I understand the major change in her diet was eliminating the starches in form of grains, potatoes and etc.
Here is what you made me realise Dr. Ayers: Klebsiella feeds off the oligosaccharides (in starches,potatoes, table sugar and all over SAD) and produces hydrogen which is fuel for Hp, so after eliminating that her symptoms improved.
Any sense in it?
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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. cheap king comforter sets , handloom cotton bed sheets online 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.
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