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
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
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.
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
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.