Helicobacter Pylori

Gerhard Adam

Helicobacter is a good example in our changing understanding of the role of microbes and the human body environment. Some may recall that this particular bacteria was introduced to the public in a rather striking experiment where it was suspected of causing stomach ulcers and gastritis. Dr. Barry Marshall drank a petri dish containing cultured Helicobacter Pylori and within days developed gastritis. This demonstrated a firm connection between bacteria and gastritis/stomach ulcers as well as the role of using antibiotics to treat this condition.

Helicobacter is presumed to be present in about 50% of the world's population upper gastrointestinal tract, while fully 80% of individuals harboring this organism are asymptomatic.

Furthermore, Helicobacter has been associated with the development of stomach cancers.

Now we get to the difficult bit.

Helicobacter has been declining in many developed countries, which has been associated with an increase in esophageal adenocarcinomas. This isn't merely a speculative connection.
http://www.ncbi.nlm.nih.gov/pubmed/20399210
http://www.ncbi.nlm.nih.gov/pubmed/19138977
http://www.sciencedaily.com/releases/2008/10/081006092511.htm

As a result, one fundamental perception is changing, as it relates to the germ theory of disease. It appears that not all microbes that may be pathogenic in one sense are necessarily uniformly pathogenic. In other words, while a microbe may cause some problems in susceptible individuals, it may also confer benefit to others (1). In short, the notion that microbes are only associated with disease outcomes isn't necessarily correct.

As a result, their evolution is inextricably linked to human evolution, as well as to human disease. “Our microbes are a part of human physiology… as much a part… as our liver, or our kidneys, or our heart,” Blaser commented. “They are a metabolic compartment or a series of metabolic compartments in the human body and how they behave and… their characteristics are relevant to health and disease.”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1479565/pdf/7400699.pdf

This is causing a reevaluation of the differences between short-term infections and persistent colonization, even for the same microbe. What may appear to be a beneficial eradication of the problem microbe, may create other problems that are worse than the original.

In short, we may have to shift our disease paradigm to a more complex understanding that these microbial relationships may have a biological cost/benefit extending beyond simple "good" or "bad" assessments. Essentially the human body, in this example, is simply the environment in which these microbes live, exploiting and modifying their "world" to best suit their own needs. In the same way we see organisms modifying their environments in the macro-world, we are the environment being modified in the micro-world.

As a result, the viewpoint of good and bad must be replaced with what works and what doesn't. Simply viewing this intricate ecosystem as being an "us versus them" scenario is wrong.

From a purely speculative perspective, it appears that we may be experiencing microbes in various stages of adaptation with respect to our bodies. Some manage the environment well and help us survive. Some may be harmful or beneficial, depending on circumstances. Even our notion of disease may simply be the result of new "colonizers" entering a territory and engaging in chemical warfare with those already present.

Clearly there are some, including viruses, that have no fundamental connection to this human environment and simply exploit the available resources before they move on, or are eradicated. In any case, science is beginning to recognize that our relationship with microbes is significantly more complex than previously thought, and that life isn't merely a metaphorical web, but is inextricably linked; organism to organism, in a complex relationship of environments and ecosystems that are exploited for diverse purposes.

For more on the history of Helicobacter:
http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.0020120

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(1) Helicobacter as been inversely associated with childhood asthma, type II diabetes, and even obesity.

In addition, H. pylori affects gastric hormones that have a role in energy homeostasis, such as leptin and ghrelin; a link between its disappearance and the increasing prevalence of metabolic syndrome, type II diabetes and obesity has also been postulated (Blaser&Atherton, 2004).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618379/

Comments

This isn’t really a “new” idea, although your article would imply it hasn’t quite caught on yet with the general public…? In any case, there was a fairly comprehensive article on this in SciAm a few months ago.
People have been pushing probiotics for a long time, the reason being that “good” bacteria are important to metabolism and help outcompete “bad” bacteria, etc. We know that diet is important for promoting diversity (this is key) of gut bacteria, ultimately leading to better health, etc. Sometimes changes in the composition of intestinal bacteria is enough to promote disease- it’s not necessarily always about what is there, but also in what proportions certain types of bacteria are present. Also, the "germ theory" of immunity explains the increased incidence of asthma/allergies in 'first world countries' by pinning the blame on too little exposure to germs&pathogens (we're too 'clean'!). I could go on and on, but it all boils down to the fact that its been pretty well established bacteria are important to us. Genetics does seem to have some role in all of this, but ‘nurture’ easily outcompetes ‘nature’ in this instance.

Eve Hardy | 10/19/12 | 11:28 AM

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Sorry, I wasn't as clear as I probably should have been. I agree, that the notions of "good" or "bad" bacteria have been around for quite some time, and even though we only have a vague sense of what that even means, it is something that is generally recognized in the public [although if one listens to the germophobia that is prevalent, the view is that bacteria are more of a nuisance/problem than a valued commodity]. Given many people's almost phobic desire to be "germ-free", it suggests that they don't fully appreciate how devastating such behaviors can be on bacteria. It would be like trying to prune a tree with explosives.

People have been pushing probiotics for a long time

Yes, but in truth, they typically don't know what they're pushing. Since most of the microbiota has never even been cultured, it is exceedly presumptuous to conclude that we know what "good" or "bad" even is [except in the case of obvious pathogens].

The difference here is that the problem isn't so clear cut. On the one hand, Helicobacter is associated with gastritis, so treating it with antibiotics seemed like a good idea to control that situation. However, it also appears that by eliminating Helicobacter we may be increasing the incidences of esophageal adenocarcinomas. So the notions of "good" and "bad" aren't nearly as well-defined as most suppose.

In addition, there is the concern that somehow the population of Helicobacter is being reduced without any clear understanding of what may be causing such a change. Regardless, it indicates that any such changes in our microbiota will likely produce more unpredictable results than those anticipated.

...but also in what proportions certain types of bacteria are present.

Absolutely, but also something like whether the bacteria are present in their "proper" locations. Bacteria that are harmless in one location can behave like pathogens in other areas. Again, the point is to avoid over-simplifying the notions of "good" and "bad" bacteria. While there are some clear pathogens that cause disease, there are equally many more conditions for which declaring bacteria pathogenic is simply an incorrect view. The context must be appropriately considered.

Gerhard Adam | 10/19/12 | 12:13 PM

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"On the one hand, Helicobacter is associated with gastritis, so treating it with antibiotics seemed like a good idea to control that situation. However, it also appears that by eliminating Helicobacter we may be increasing the incidences of esophageal adenocarcinomas."

I think we would agree that it's unfortunate that all of this information hasn't yet been reflected in standard medical practices...it seems like a lot of doctors could benefit from using a little more discretion in how they handle our 'bugs'. Antibiotics in general are overprescribed, which seems to be contributing to the rapid rise in antibiotic resistance species (I recently had a doctor who handed me a prescription for an antibiotic for a virus...seriously?), many dermatologists still recommend long-term oral antibiotics for treating acne without explaining the negative side effects, etc. You would think that because we know at this point that our 'inner ecosystems' are extremely sensitive medical practitioners would exercise a little more caution and take this into account, but that's just not the case.

Eve Hardy | 10/19/12 | 12:36 PM

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Agreed. Several months back I went through an aggressive antibiotic treatment because of an infection in my leg and all I could envision was Armageddon in my gut. I had images from the Terminator movies of what was taking place.

It is important to consider that the over-use of antibiotics also tends to promote antibiotic-resistance which can then be conveyed to pathogens that may be present. Many pathogens have reportedly gained resistance from our own "good" bacteria through HGT.

Gerhard Adam | 10/19/12 | 13:16 PM

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As Eve says, Helicobacter isn't really that 'new' to scientists. It would be new to lay folks if: (1) it was deemed to be newsworthy (if it fit within the frame a particular editor wished to exploit), and/or (2) if a popular celebrity hopped on the bandwagon and declared that it was the cause of . . . and must be banned.

Let's face it; the vast majority of the population of the U.S. is undereducated in the majority of the sciences. If you were to ask the 'man on the street' what he thought about bacteria, he would likely answer that we need to kill them all.

>>Even our notion of disease may simply be the result of new "colonizers" entering a territory and engaging in chemical warfare with those already present.

That is an interesting idea. Even though our scientists are learning more every day, there is still a metric boatload to be investigated. You could start a long list of 'what ifs' along that line.

One of the links you listed, Gerhard, mentioned something that seems important to me. The gist of it is that while Helicobacter causes problems in some people, when the population of Helicobacter is reduced, or eliminated, other serious problems are manifested. As far as I can determine, we don't know why this happens.

I think that in a few generations medical students will be amazed that their ancestors (us) allowed themselves to be literally bathed in antibiotics. Those students will wonder how those primitives (us) could be so ignorant of the negative effects of killing those helpful and necessary bacteria that live in and on us.

I know that medical professionals are cautioning against the over use of broad-spectrum antibiotics. The key word here is cautioning. For some reason, the doctors and nurses don't seem inclined to tell the patient why they shouldn't be taking the antibiotics.

So, I suppose, the question becomes - - how to get the word out to the masses? How do you make it newsworthy enough to cause an editor to push the importance of our biota in her media?

Hmm. Now how would you tie the misuse of antibiotics in with the anti-vac crowd?

Frank (not verified) | 10/19/12 | 13:32 PM

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Sorry. I was late to the comment party trying to compost the comment in a halfway intelligent manner. Most everything I said above was covered.

Frank (not verified) | 10/19/12 | 13:37 PM

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It was a good comment though. :)

Gerhard Adam | 10/19/12 | 13:42 PM

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Did you like the 'compost' part?

Frank (not verified) | 10/19/12 | 13:45 PM

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I chose to give that a very liberal interpretation :)

Gerhard Adam | 10/19/12 | 13:55 PM

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It appears that not all microbes that may be pathogenic in one sense are necessarily uniformly pathogenic.

Oh Gerhard, the smartest rancher in the wild west. I wrote a blog post sometime back about "pathogen genocide" and its implications for us. In that post I posed the question: so where do we begin and the environment begin? The boundary is rather fuzzy.

A couple of months ago a friend of mine sent me an interesting abstract. It stated that low levels of gram negative bacteria induced an anti-inflammatory response. But this group of bacteria can be potent killers via a massive inflammatory response. Weird! One way to approach this is to consider that the onset of a "danger signal" heralds both inflammatory and anti-inflammatory mediators to the site of danger; with T reg cells being particularly significant here. T reg cells exist in relatively low numbers but have profound implications for managing inflammation and autoimmunity. However low levels of these bacteria may not be doing so much damage but rather are generating an immune repsonse via PAMPs: pathogen associated molecular patterns, a function of the innate immune system. That is, before the gram negative bacteria can populate too much, the innate response(the adaptive response can take days) initiates a chain of responses to keep their numbers under strict control but also generate good numbers of T reg cells.

Autoimmunity is too often understood as pathological when it should be perceived as a basal function, hence the presence of many self reactive antibodies that are constitutively expressed. Again, the same pattern is at play. These self-reactive antibodies facilitate a very early immune response to identify potential damage before it gets too out of hand and drives a strong inflammatory response.

On a TV program I heard the strangest idea regarding why some animals like to role in the dirt. The bod suggested that they do this to pick up bacteria which release nitric oxide thereby enhancing circulation to the skin. Nitric oxide is critical to blood pressure regulation, so make sure you have your arginine-lysine intake at the right balance. I'm still not sure the idea is true but it wouldn't surprise me if it was. It's getting too weird so surprises are hard to come by these days.

Sometime back I suggested that while the current perspective is very much about how microbes impact on us, it is also true that our changing physiology can change the fate of various species that enjoy being part of us. So we should think carefully about maintaining our nutrition through more natural sources, avoiding processed foods, and perhaps not being so fussy about the pathogens around us, with some studies even suggesting that playing in the dirt is a good idea. So perhaps those animals are onto something after all.

Thanks for the post Gerhard. Giddyup!

John Hasenkam | 10/20/12 | 10:57 AM

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On a TV program I heard the strangest idea regarding why some animals like to role in the dirt. The bod suggested that they do this to pick up bacteria which release nitric oxide thereby enhancing circulation to the skin.

That may not be as far-fetched as it sounds. Perhaps that explains the experience [I'm sure, well known to anyone that has ever kept horses] that as soon as you take the time and trouble to bathe a horse, if you let them go afterwards, it will be about 5-10 minutes, before they're rolling in the dirt.

Gerhard Adam | 10/20/12 | 16:57 PM

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John

Any chance you'd let me repost your blog article as a guest article here? We would only need to include the part about pathogenic genocide and the hygiene hypothesis.

Gerhard Adam | 10/20/12 | 19:05 PM

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With increased hygiene, H. pylori has been becoming rarer in the past hundred years. It's not just associated with a lower rate of ulcers but also with a lower rate of stomach cancer. (When you look at age-adjusted stats, the incidence and mortality rates have continued to decrease in the last 34 years).

It's only one type of esophageal adenocarcinoma which has increased as H. pylori has come down in numbers. If you look at all esophageal cancers (age-adjusted again), the rates(incidence and mortality) have actually been stable since 1992.

Enrico Uva | 10/20/12 | 11:20 AM

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Part of the reason for the appearance of stability is the huge disparity that existed between African Americans and White Americans. As the incidence among white males has increased, the offset to improvements for African Americans creates the impression that nothing has changed.

However, there was substantial heterogeneity among studies (I(2) = 73%), with statistically significant associations in both directions. Our results suggest an inverse association between CagA-positive H. pylori colonization and risk of EAC. The prominent decline of H. pylori colonization in the past few decades may be partly responsible for the recent increase in EAC incidence in Western countries.
http://www.ncbi.nlm.nih.gov/pubmed/19138977

H pylori infection was associated with significantly reduced risks of EAC (OR, 0.45; 95% CI: 0.30-0.67) and EGJAC (OR, 0.41; 95% CI: 0.27-0.60) but not ESCC (OR, 1.04; 95% CI: 0.71-1.50).
http://www.ncbi.nlm.nih.gov/pubmed/20399210

http://onlinelibrary.wiley.com/doi/10.1002/%28SICI%291097-0142%2819981115%2983:10%3C2049::AID-CNCR1%3E3.0.CO;2-2/full

Also, it has not been suggested that Helicobacter is the only causal link to esophageal cancers, so clearly the statistics also need to be interpreted in light of other potential factors. The primary point here was that Helicobacter was implicated as being statistically significant enough of an influence to establish it's linkage as causitive for gastristis, and yet preventative for esophageal cancer. Obviously complete details are, as yet, unknown.

http://www.cancer.gov/aboutnci/servingpeople/snapshots/esophageal.pdf

Gerhard Adam | 10/20/12 | 16:47 PM