Whereas nearly all adults in developing world still carry the organism, its prevalence is much lower in developed countries such as the U.S…. thanks to improved hygiene, which blocks the transmission of the bacteria, and to the widespread use of antibiotics.  As H. pylori has retreated, the rates of peptic ulcers and stomach cancer have dropped.  But at the same time, diseases of the esophagus—including acid reflux disease and a particularly deadly type of esophageal cancer—have increased dramatically, and a wide body of evidence indicates that the rise of these illnesses is also related to the disappearance of H. pylori.

[One species of H. Pylori produces a protein CagA, which is associated with] higher risk of acquiring peptic ulcer disease or stomach cancer than people with strains lacking the gene…. This [TFSS] structure injects the CagA protein into the epithelial cells that line the human stomach….. Strains of H. pylori bearing the cagA gene cause more severe inflammation and tissue damage than do strains without the gene…. The gene VacA  encodes a toxin which is stored in vacuoles.  This protein turns off the infecton-fighting white blood cells in the stomach, thus diminishing the immune response to H. pylori.  There are 4 major strains of vacA.   H pylori strains with both m 1 and s 1 variations produce the most damaging form of the VacA toxin.  Thus it is not surprising that strains bearing this genotype of vacA, combined with cagA gene, are associated with the highest risk of stomach cancer.  To make matters even more complicated, some people are more susceptible to these kinds of cancer because of variations in their own genes that enhance the inflammatory response to bacterial agents…. The collision of particularly aggressive H pylori strains with particularly susceptible hosts appears to account for most cases of stomach cancer.   

[I]n fact, the genetic variations of H. pylori can be used to trace human settlement and migration patterns over the past 60,000 years. [h]umans are the only hosts for H. pylori, and the spread of the bacterium involves mouth-to-mouth or feces-to-mouth transmission. The geographic differences in H. pylori infection rates—much lower in the developed world than else­where—may be partly the result of improvements in sanitation in the U.S., Europe and other developed countries over the past century. But I believe that the widespread use of antibiotics has also contributed to the gradual elimination of H. pylori. Even short courses of antibiotics, given for any purpose, will eradi­cate the bacteria in some recipients. In developing countries where antibiotics are less commonly used, 70 to 100 percent of children become infected with H. pylori by the age of 10, and most remain colonized for life; in contrast, fewer than 10 per­cent of U.S.-born children now carry the organism. This dif­ference represents a major change in human microecology.

Furthermore, the disappearance of H. pylori may be a sen­tinel event indicating the possibility of other microbial extinc­tions as well. H. pylori is the only bacterium that can persist in the acidic environment of the human stomach, and its pres­ence can be easily determined by tests of blood, stool, breath or stomach tissue. But other body sites, such as the mouth, colon, skin and vagina, have complex populations of indige­nous organisms. If another common bacterium were disap­pearing from these tissues, we would not have the diagnostic tools to detect its decline.

What are the consequences of H. pylori's retreat? As noted the incidents of both peptic ulcer disease and stomach cancer are clearly declining in developed countries.  [I]n 1900 stomach cancer was the leading cause of cancer death in the U.S.; by 2000 the incidence and mortality rates had fallen by more than 80 percent…. Substantial evidence indicates that the continuing extinction of H pylori has played an important role in this phenomenal change.  This is the good news. 

At the same time, however, there has been an unexpected rise in the incidence of a new class of diseases involving the esophagus. Since the early 1970s, epidemiologists in the U.S., the U.K., Sweden and Australia have noted an alarming jump in esophageal adenocarcinoma, an aggressive cancer that devel­ops in the inner lining of the esophagus just above the stomach. The incidence of this illness in the U.S. has been climbing by 7 to 9 percent each year, making it the fastest-increasing major cancer in the country. Once diagnosed, the five-year survival rate for esophageal adenocarcinoma is less than 10 percent.

Where are these terrible cancers coming from? We know that the primary risk factor is gastroesophageal reflux disease (GERD), a chronic inflammatory disorder involving the regurgitation of acidic stomach contents into the esophagus. More commonly known as acid reflux disease, GERD was not even described in the medical literature until the 1930s. Since then, however, its incidence has risen dramatically, and now the disorder is quite common in the U.S. and other western coun­tries. GERD can lead to Barrett's esophagus, a premalignant lesion first described in 1950 by English surgeon Norman Barrett. The incidence of Barrett's esophagus is rising in tandem with that of GERD, and patients suffering from the condition have an increased risk of developing esophageal adenocarcinoma. It is becoming clear that GERD may initiate a 20- to 50-year process: in some cases, the disorder slowly progresses to Barrett's esophagus and then to adenocarcinoma, parallel­ing the gradual changes that lead to cancers in other epithelial tissues.  But why are GERD and its follow-on disorders becoming more common?

The rise of these diseases has occurred just as H. pylori has been disappearing, and it is tempting to associate the two phe­nomena. When I began proposing this connection in 1996, I was greeted first by indifference and then by hostility. In recent years, though, a growing number of studies support the hy­pothesis that H. pylori colonization of the stomach actually protects the esophagus against GERD and its consequences. What is more, the strains bearing the cagA gene—that is, the bacteria that are most virulent in causing ulcers and stomach cancer—appear to be the most protective of the esophagus! In 1998, working with researchers from the National Cancer Institute, we found that people carrying cagA strains of H. pylori had a significantly decreased risk of developing adenocarcinomas of the lower esophagus and the part of the stomach closest to the esophagus. Then, in collaboration with investi­gators from the Cleveland Clinic and the Erasmus Medical Center in the Netherlands, we showed a similar correlation for both GERD and Barrett's esophagus. Independent confirma­tions have come from the U.K., Brazil and Sweden. Not all investigators have found this effect, perhaps because of differ­ences in the methods of the studies. Nevertheless, the scien­tific evidence is now persuasive.

A Theory of Interactions

how can colonization by H. pylori increase the risk of stomach diseases but protect against esophageal disorders? A possible explanation lies in the interactions between the bacte­rium and its human host. H. pylori has evolved into a most unusual parasite: it can persist in a stomach for decades despite causing continual damage and despite the host's immune re­sponse against it. This persistence requires that virtually all the "up-regulatory" events that cause inflammation in the stomach tissue must be balanced by "down-regulatory" events that pre­vent the damage from worsening too rapidly.  There must be an equilibrium between microbe and host; otherwise, the host would die rather quickly, and the bacteria would lose their home before getting a chance to propagate to another person. But how can two competing forms of life achieve this equilib­rium? My hypothesis is that the microbe and host must be send­ing signals to each other in a negative feedback loop.

Negative feedback loops are common in biology for the regulation of cellular interactions. Consider, for example, the feedback loop involving glucose and the regulatory hormone insulin. After you eat a meal, glucose levels in the bloodstream rise and the pancreas secretes insulin. The insulin causes glu­cose levels to fall, which signals the pancreas to reduce insulin secretion by modulating the peaks and valleys in glucose levels.  First described in the 19th century by French physiologist Claude Bernard, this concept has become the basis for under­standing hormone regulation.

In essence, I took this idea one step further: the feedback relationship can involve microbial cells as well as host cells. Over the years, working with mathematicians Denise Kirschner of the University of Michigan at Ann Arbor and Glenn Webb of Vanderbilt University, our concepts of feedback have be­come more complex and encompassing. In our current formu­lation, the H. pylori population in a person's stomach is a group of extremely varied strains cooperating and competing with one another. They compete for nutrients, niches in the stom­ach and protection from stresses. Over the millennia, the long coevolution of H. pylori and H. sapiens has put intense selec­tive pressure on both species. To minimize the damage from infection, humans have developed ways to signal to the bacteria, through immune responses and changes in the pressure and acidity in the stomach. And H. pylori, in turn, can signal the host cells to alleviate the stresses on the bacteria.

A good example of an important stress on H. pylori is the level of acidity in the stomach. Too much acid will kill the bacteria, but an extremely low level is not good either, because it would allow less acid-tolerant organisms such as E. coli to invade H. pylori's niche. Therefore, H. pylori has evolved the ability to regulate the acidity of its environment. For example, strains bearing the cagA gene can use the CagA protein as a signaling molecule. When acidity is high, the cagA gene pro­duces a relatively large amount of the protein, which triggers an inflammatory response from the host that lowers acidity by affecting the hormonal regulation of the acid-producing cells in the stomach lining. Low acidity, in contrast, curtails the production of CagA and hence reduces the inflammation.

This negative feedback model helps us understand the health effects of H. pylori, which depend in large part on the intensity of the interactions between the bacteria and their hosts. The cagA strains substantially increase the risk of stom­ach cancer because they inject the CagA protein into the stom­ach's epithelial cells for decades, affecting the longevity of the host cells and their propensity to induce inflammation that promotes cancer. Strains lacking the cagA gene are much less interactive, so they do not damage the stomach tissues as se­verely. On the other hand, cagA strains effectively modulate acid production in the stomach, preventing acidity levels from rising too high. People who carry strains lacking the cagA gene have a weaker modulation of acidity levels, and people who are not colonized by H. pylori have no microbial controls at all. The resulting swings in stomach acidity may be central to the rise in esophageal diseases, which are apparently triggered by the exposure of the tissue to highly acidic stomach contents.

The absence of H. pylori may have other physiological ef­fects as well. The stomach produces two hormones that affect eating behavior: leptin, which signals the brain to stop eating, and ghrelin, which stimulates appetite. Eradication of H. py­lori with antibiotics tends to lower leptin and increase ghrelin; in one study, patients who had undergone treatment to elimi­nate H. pylori gained more weight than the control subjects did. Could changes in human microecology be contributing to the current epidemic of obesity and diabetes mellitus (an obe­sity-related condition) in developed countries? If this research were confirmed, the implications would be sobering. Doctors might need to reevaluate antibiotic treatments that rid the stomach of H. pylori (and remove critical bacteria from other parts of the body as well). Although some of the consequences of eradication may be for the better (for example, a reduced risk of stomach cancer) other effects may be for the worse. The balance between good and bad may well depend on the pa­tient's age, medical history and genetic type.

Probiotics

if researchers conclude that H. pylori would actu­ally benefit some individuals, should physicians reintroduce the bacterium to these patients' stomachs? For more than 100 years, both medical scientists and laypersons have been search­ing for probiotics, microbes that can be ingested to aid human health. The earliest studies focused on the Lactobacillus spe­cies, the bacteria that make yogurt and many cheeses, but the effects of reintroduction were, at best, of marginal value. Re­searchers have largely failed to find any effective probiotics despite a century of trying.

One reason for this failure is the complexity and coevolution of the human microbiota, the organisms that share our bodies. Our microbiota are highly evolved for living within us and with each other. How likely is it that a newcomer, an un­related strain of bacteria from outside the body, can success­fully rechannel the pathways of interaction in a beneficial way? The existing organisms have survived strong and continuous selection, and this "home court advantage" usually enables them to reject and eliminate any strangers.

But a new day for probiotics may be coming. The key step will be gathering more knowledge of our indigenous micro-biota and how they interact with us. I believe that complex interactions take place wherever microbes colonize our bodies (for example, in the colon, mouth, skin and vagina), but be­cause of the array of competing organisms in those tissues, the relations are difficult to elucidate. H. pylori, though, largely excludes other microbes from the stomach. By the paradox of its great adaptation to humans and by the accident of its progressive disappearance during the 20th century, H. pylori may become a model organism for investigating human microecology.

Once scientists fully catalogue the myriad strains of H. py­lori and discover how each affects the host cells of the stomach, this research may give clinicians a whole new arsenal for fight­ing diseases of the digestive tract. In the future, a physician may be able to analyze a patient's DNA to determine his or her sus­ceptibility to inflammation and genetic risks of acquiring dif­ferent kinds of cancers. Then the doctor could determine the best mix of H. pylori strains for the patient and introduce the microbes to his or her stomach. What is more, researchers may be able to apply their knowledge of H. pylori to solve other medical problems. Just as the Botox nerve toxin produced by Clostridium botulinum, the bacterium that causes botulism, is now used for cosmetic surgery, the toxin VacA could become the basis for a novel class of drugs that suppress immune func­tion. The study of our longtime bacterial companions offers a new avenue for understanding our own bodies and promises to expand the horizons of medical microbiology.

MOR£ TO EXPLORE

Dynamics of Helicobacterpylori Colonization in Relation to the Host Response. Martin J. Blaser and Denise Kirschner in Proceedings of the National Academy of Sciences USA, Vol. 96, Issue 15, pages 8359-8364; July 20,1999.

Traces of Human Migrations in Helicobacter pylori Populations.D. Falush, T. Wirth, B. Linz, J. K. Pritchard, M. Stephens, M. Kidd, M. J. Blaser, D. Y. Graham, S. Vacher, G. I. Perez-Perez, Y. Yamaoka, F. Megraud, K. Otto, U. Reichard, E. Katzowitsch, X. Wang, M. Achtman and S. Suerbaum in Science, Vol. 299, pages 1582-1585; March 7, 2003.

Helicobacter pylori Persistence: Biology and Disease. Martin J. Blaser and John C. Atherton in Journal of Clinical Investigation, Vol. 113, No. 3, pages 321-333; February 2004.

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