Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (17 page)

It soon became clear that
H. pylori
was not just along for the ride. Carrying
H. pylori
preceded the development of stomach cancer. In 1994, based on our work and that of others, the World Health Organization declared
H. pylori
a Class 1 carcinogen for its relationship with stomach cancer. It was like smoking and lung cancer: no arguing about cause and effect.

No wonder doctors around the world began to believe that “the only good
Helicobacter pylori
is a dead one.” From ulcers to cancer, everything indicated that carrying
H. pylori
is costly to humans. Doctors everywhere started to look for it in patients who had any kind of gastrointestinal symptoms; and if they found it, they would eliminate it using antibiotic-based treatment regimens. Part of the rationale was the fear of the cancer, and part of it was to treat the symptoms that patients had. But except for ulcers, clinical trials did not show that symptoms improved any more than by chance alone. Still, everyone was happy to eliminate
H. pylori
whenever they found it.

*   *   *

Yet for years I kept returning to a question: Why did Warren discover the association of
H. pylori
with gastritis when it had been missed for so long? Eventually I remembered learning that nineteenth-century pathologists had found those curved and spiral organisms in the stomach of virtually everyone. By the 1970s, in the slice of Australia where Warren worked, only about half of the adults were positive. Pathologists in other developed countries saw the same thing:
H. pylori
and associated gastritis in a fraction of the people, not everyone.

However, in contemporary studies from Africa, Asia, and Latin America, nearly all adults carried
H. pylori.
It was as if they had nineteenth-century stomachs, while we “developed peoples” had twentieth-century stomachs.

I made a leap: Warren was able to find the association with gastritis because
H. pylori
was no longer universal; it was disappearing. This ancient organism was becoming extinct. Other researchers noticed that
H. pylori
was less common in younger people, but they all thought it was a sign of progress, and of course in a way it was.

Our more recent work shows that most people born in the United States in the early twentieth century carried the organism. But fewer than 6 percent of children born after 1995 have it in their stomachs. Similar trends have been documented in Germany and Scandinavia. In fact, wherever we look
H. pylori
is disappearing from humans, most rapidly in developed countries but also in developing areas. This variation is not based on geography but rather on socioeconomic status. Poor people tend to have
H. pylori
; wealthier people tend not to. We see this everywhere we look all over the world. The presumption has been that it’s better to be without
H. pylori
just as it is to be wealthier.

But why is
H. pylori
disappearing? Why is an organism that has survived so long in nearly all of our ancestors as the dominant bacteria in our stomachs been receding everywhere we look? The answer can be summarized in two words: modern life. A persistent colonizer like
H. pylori
must deal with two major biological problems: how it is transmitted to new hosts and how it is maintained until passed forward.

Transmission is the biggest bottleneck.
H. pylori
lives only in humans. As noted earlier, we do not get it from our pets, farm animals, or foods of animal origin, as we get other transient organisms such as
Salmonella
; nor do we get it from dirt. The major reservoir in the world for
H. pylori
is the human stomach. The microbe must pass from one stomach to another, and the only way to do that is to go either up or down the gastrointestinal tract.

H. pylori
can easily travel up from the stomach to the mouth via burping or reflux. It can set up shop in dental plaque. In many parts of the world, mothers prechew food and pass it on to their babies’ mouths, thereby transmitting the microbe. When people vomit,
H. pylori
is present and can be carried by the air for several feet, contaminating the nearby environment—comforting thought.

Down is easier. Everything in the gastrointestinal tract has the potential to come out at the bottom in the feces, and both
H. pylori
DNA and live organisms have been detected there. Usually live
H. pylori
are excreted at very low levels, but more come out after a microbial bloom. When hygiene is bad, as has been the case most of the time we humans have been on the planet, feces contaminate food and water. Fecal
H. pylori
is thus transmitted to the next person.

Young children are the most susceptible to
H. pylori.
They seem to resist it in their first year of life, but after that, in countries where sanitation and hygiene are poor, about 20–30 percent acquire it every year. Between the ages of five and ten, most kids get colonized, often with several different strains. After that, the transmission frequency drops.

Why the decline over the past one hundred years? One obvious reason is sanitation. In the late nineteenth century, cities began to provide clean water for their citizens from watersheds that were not grossly contaminated with feces and with the important advance of chlorination. Such measures helped prevent the transmission of cholera, typhoid fever, hepatitis, and childhood diarrheal illnesses. Resounding public-health successes, they account for a major part of our improved health and longevity in the first half of the twentieth century. Yet in preventing the spread of pathogens, these practices also reduced transmission of our ancient colonizing microbes, like
H. pylori
. The benefit of clean water is so huge that we must not denigrate its importance, but we should also recognize the potential for hidden consequences that diminish our ancestral microbiome.

Drinking contaminated water is how a child could acquire
H. pylori
from a stranger, but most transmission occurs closer to home. As indicated above, a baby can get
H. pylori
from her mother chewing his or her food. We don’t know all the ways that children get
H. pylori
from their mothers, but studies have shown that the number-one predictor of whether a child has
H. pylori
is whether his mother has it.

Children also get
H. pylori
and other microbes from their older siblings. In a sense, the siblings amplify the transmission from mom, providing new opportunities for the organism to spread. Big families are an important reservoir for the organism, yet in developed countries families have been getting smaller. In a family with five children, 80 percent of kids have an older sibling. With two children, it is 50 percent. With an only child, it is zero. Before people became more prosperous, kids used to sleep in the same bed, sometimes with parents as well. Such close contact facilitated transmission of microbes, especially during critical windows, like early childhood.

Interestingly, when adults live together, as we showed in two studies, the risk of transmission of
H. pylori
to one another seems pretty low. We studied couples who were going to an infertility clinic, a group that might be having more physical contact than others; positivity in one member was no more likely to be associated with the same status in the other than by chance. We also looked at adults who came to a clinic for sexually transmitted diseases. With many organisms, such as the ones causing gonorrhea and syphilis, the more sexual partners you have, the more likely you are to acquire them. Not so with
H. pylori
; the organism hardly ever spreads from adult to adult.

If it is actually acquired in childhood,
H. pylori
must be maintained, so it can be transmitted to the next human generation. We know from both human and monkey experiments that the organism needs a period of time to adjust to its host. Some don’t make it, as in the case of Barry Marshall’s self-inoculation. If conditions are difficult for the organism, the success rate of transmission goes down.

Given the number of doses of antibiotics given to our children today, it’s easy to imagine that a major impact on
H. pylori
colonization comes from treating all those sore throats and earaches. A single course of an antibiotic will eliminate the microbe in 20–50 percent of patients. When children are given those same antibiotics, they stand a similar chance of losing their
H. pylori
.

It is my belief that each time they take a course of antibiotics, and with each course given in a population of children, a few more kids lose the organism. Across the whole population, the trend is cumulative. This practice is a paradigm for the disappearance of other of our ancient organisms. Fitness is not guaranteed. In its protected gastric niche for eons,
H. pylori
was not at all prepared for the onslaught of antibiotics in the last seventy years.

The loss is multigenerational. Studies show that if the mother has lost her
H. pylori
, chances are small that her child will acquire it. And so it will go, generation after generation. Starting with sulfa drugs in the 1930s and then penicillin and others in the 1940s, in the U.S. and western Europe we already are in the fourth or fifth generation of antibiotic users. Remember the recent data implying that young people have had about seventeen courses of antibiotics by the age of twenty, essentially when the women are starting their child-bearing years. And loss of
H. pylori
in an older sibling removes another opportunity for transmission. Clean water, smaller families, and lots of antibiotics create a triple whammy against
H. pylori
.

A final cause of its disappearance is that
H. pylori
like to have sex with other
H. pylori
. This is an essential part of their biology. Some bacteria are more reclusive, like the ones that cause anthrax or tuberculosis. For
H. pylori
, free love is a way of life. In the old days, the average person probably had several different
H. pylori
strains in his or her stomach, just as we see today in people in developing countries. Contaminated water is again part of the reason. These mixtures of
H. pylori
strains represent a robust community. With their constant exchange of genes with one another, their populations shift, reflecting the changing tides in the stomach. Such gene exchange makes the community very adaptable, so it can take advantage of all of the resources that a stomach can provide. The overall community can be sustained for years, even decades. This is the strategy that
H. pylori
have evolved over the millennia: organisms competing with one another as always but also cooperating to ensure transmission to a new host. But in recent years, as transmission and maintenance have become more and more difficult, the number of individual strains able to colonize the average stomach has declined from three to two to one to zero.

*   *   *

As I came to realize that in just a few generations the microbial ecology of the human stomach has changed markedly, I wavered from the conviction that
H. pylori
are only bad. I could see that while
H. pylori
caused inflammation, it had been with us for a very long time and that most people who became ill, especially with stomach cancer, were much older. The average patients were in their seventies, and the cancer rates were higher still among people in their eighties. Across our entire population, the cost of
H. pylori
was not as high as that for malaria or diphtheria, for example, which kill children.

I began to think that maybe under some circumstances the inflammation caused by
H. pylori
could be good for us. My original ideas were fuzzy; I didn’t know what good there could be. I only knew that when ancient dominant organisms disappear, there are bound to be consequences. This was heresy to most of my colleagues; having discovered
H. pylori
as a pathogen, they focused on the costs and considered it imperative to speed up its departure from this planet. They were not thinking about amphibiosis, just elimination.

Later we did find those benefits. In retrospect they seem obvious, but uncovering the answers took me years, and all the while most of my colleagues in the field did not agree with me. I failed to convince them, and in fact most physicians still see gastritis as a pathological condition. To them, a normal stomach should never show inflammation. The crux of the dilemma is simple: What is normal?

When pathologists see a stomach mucosa loaded with lymphocytes and macrophages, they call it chronic gastritis. But this condition can also be defined as the physiological response to our indigenous organisms. Just as there are inflammatory cells in your colon and in your mouth interacting with your friendly bacteria, your stomach has inflammatory cells interacting with its local bacteria. Thus the same question arises: Is the gastritis caused by
H. pylori
good for you or not? Pathologists, who characterize gastritis as a disease, classify
H. pylori
as a pathogen, whereas ecologists look at ancient organisms in an entirely different light.

The interaction between
H. pylori
and our ancestors evolved in ways that maintained persistence of the organism. Since there is little or no cost during childhood or young adulthood for carrying
H. pylori,
there is no selection against it. In contrast, malaria is so lethal to children that over the eons a whole set of human genes evolved to enable us to resist it.

We and our ancient, more quiet microbes like
H. pylori
are always adapting to each other, maintaining an equilibrium like artists on a tightrope, holding arms out as they cross to the other side; no missteps and they’re safely across. Our microbes take up residence in particular niches and send signals to our human cells, which signal the microbes back in the form of pressure, temperature, and chemical messages, including defense molecules. The microbes signal us, we signal them back—communication develops, a language. Within this equilibrium, there is a dynamic of up and down regulation of inflammation in specific locales. It’s like a marriage: we decide who does the dishes, who walks the dog. The conduct of one partner determines that of the other.