The Microbe Blog (at http://www.smallthingsconsidered.us)

by Elio

Recently, a colleague called my attention to a paper with the puzzling title "Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells." Helicobacter and asthma? A bacterium that lives in the stomach has an effect on the respiratory tract? Makes you wonder.

To put this story in context, it is part of a broader concern discussed in a most insightful review by Martin Blaser and Stanley Falkow entitled: "What are the consequences of the disappearing human microbiota?" In the case of H. pylori, it has been known that people free of the bug have a greater incidence of gastroesophageal reflux disease (popularly known as "reflux"), and that's also true for certain cancers of the esophagus and stomach. On the other hand, those who carry H. pylori have a greater incidence of gastric ulcers and, in some cases, other kinds of stomach cancer, which is how the bug was discovered in the first place. So is H. pylori good or bad for you? The answer requires a great deal of clinical and epidemiological (and even psychological) information. Keep in mind that in about two generations, the incidence of H. pylori has decreased in the technological world from around 80% to a few percent, although overall about half of the people on Earth are still colonized by this bug. This is all a bit peculiar.

Many other things about H. pylori are peculiar. The most obvious is its distinction of being the major microbial species in the stomach. It survives the harsh acidic environment by chemotaxing towards the less acidic surface of the gastric epithelium and making a large amount of urease, which, by producing ammonia, raises the pH locally. Patients infected with H. pylori tend to have a higher pH in their stomach, but this is not due to the action of the bug's urease. Colonization by this bug affects the regulation of gastric hormones involved in acid secretion, such as gastrin that stimulates acid secretion and somatostatin that suppresses the release of gastrin. It gets even thornier. Gastrin is an H. pylori growth factor!

In people infected for many years, the level of stomach acidity decreases, and this leads to an increase in the risk of stomach cancer, but lack of H. pylori increases the chance for reflux and certain esophageal and stomach cancers. Moreover, some epidemiological studies say that H. pylori-positive individuals have a lower risk of childhood asthma, allergic rhinitis, and skin allergies. Is that all? In their review, Blaser and Falkow speculate: "It is possible that the disappearance of H. pylori might be contributing to the current epidemics of early-life obesity, type 2 diabetes and related metabolic syndromes."

Asthma has achieved epidemic proportions in the industrialized countries, making Blaser and Falkow's "disappearing microbiome" hypothesis tenable for this disease. The Swiss and German authors of this particular paper used a mouse model for asthma, complete with all sorts of immunological and histological manifestations. Infecting them with H. pylori alleviated these symptoms considerably, more so in neonates than adults.

What causes this effect? Because H. pylori causes inflammation, the stomachs of infected animals have a rich population of immune cells. Primary among these are the regulatory T-cells (known in my days as suppressor T-cells). Here's the clincher: The effect of the H. pylori residents was lost when the mice were depleted of their regulatory T-cells using a specific monoclonal antibody. And administering such T-cells to uninfected mice protected them from asthma. Of course, mice may react differently than people, and H. pylori is not a species found in mice, but the conclusions are highly suggestive.

The general point here is that we need to shift our outlook from one that simply labels our microbes as being good or bad to a much more nuanced view that all of them can be either helpful, harmful, neither, or both. H. pylori may turn out to be a relatively tractable bug, being that it establishes a near monoculture in infected people. Sorting out the interactions between the hundreds or thousands of species elsewhere in our body may well turn out to be a formidable task, but one well worth pursuing.

Arnold, I. C., N. Dehzad, S. Reuter, et al. 2011. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. J. Clin. Invest. 121:3088- 3093.

Blaser, M. J., and S. Falkow. 2009. What are the consequences of the disappearing human microbiota? Nature Rev. Microbiol. 7:887-894. (doi:10.1038/nrmicro2245)

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The amazing capacity of Helicobacter pylori to interact with immune cells
written by Hiroshi Nikaido , May 07, 2012

Elio,I apologize for this very late response, but I am very far behind in reading literature. Your blog on Helicobacter and allergy was most interesting, and reminded me of one experience of mine. Several years ago, a person close to me was diagnosed with lymphoma in the rectum, after a routine colonoscopy. This tumor was unusual because it did not occur in lymph nodes, but occurred right in the midst of mucosa. The patient was initially scheduled to undergo the usual terrible chemotherapy routine combined with radiation therapy, but luckily she had a radiologist with an inquiring mind, who found that most of the reported cases occurred in Japanese women and that the tumor was reported to have disappeared after antibiotic therapy for Helocobacter pylori. Some British workers actually tried to culture the lymphoma cells in vitro, and found that the tumor cells needed fragments of H. pylori for growth! Apparently the capacity of H. pylori components to stimulate the proliferation of T-cells was at the bottom of the issue. She was treated with antibiotics, and has been free of remission for the past five years or so. There are now apparently many papers on similar cases. I thought you might be interested. Hiroshi

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