Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (20 page)

NHANES III was a treasure chest (your tax dollars actually at work). Yu was able to link
H. pylori
status with results from allergy skin tests on more than twenty-four hundred people. For each of the six allergens studied, there was an inverse association of sensitivity with
H. pylori
, and for four of them (ragweed, rye, thistle, and alternaria) the differences were statistically significant. As with asthma and hay fever, people with
H. pylori
were less likely to have skin reactions to allergens. To be clear, I’m not suggesting that there is any direct relationship between
H. pylori
and, let’s say, thistle. But rather it appears that
H. pylori
is having some general effect on immunity, on people’s ability to turn off an allergic response.

These additional findings were very important, showing similar relationships between each of three different but related diseases—asthma, hay fever, and skin allergies—and
H. pylori
. They also confirmed our findings in larger samples. This happened again when Yu and I performed another large study that involved samples from people enrolled in NHANES in 1999 and conducted about a decade later, which showed highly consistent results. In scientific research, a single study is rarely enough to prove a point. It’s always better if multiple studies show consistent results.

I had begun to study asthma because of its relationship with GERD. I had gone along with the popular explanation that reflux could lead to asthma by exposing the lower esophagus to acid, bile, and other toxic substances, which then might move up the esophagus and then down the trachea into the airways. But that theory does not explain the incidence of hay fever and skin allergies, since their primary sites are far away from the esophagus. Considering that these maladies are all allergic disorders, the obvious question became whether
H. pylori
influences immunity. And then: How can a stomach microbe affect a person’s immune status?

The answer I eventually came to can be traced back to the original observations of Robin Warren, the Australian pathologist who linked
H. pylori
to gastritis. Gastritis is a large accumulation (more than what is considered normal) of inflammatory and immune cells in the stomach wall. But which stomach wall is normal, the modern wall with no
H. pylori
and small numbers of such cells (no gastritis) or the more ancient wall with
H. pylori
and large numbers of those cells (gastritis)?

Like your intestines, your stomach wall is home to numerous cell types involved in immunity. These include white blood cells that fight infections and others that regulate immunity. Your stomach also has so-called dendritic cells with long protruding processes that sense and respond to nearby bacteria. When these dendritic cells are activated by bacteria or their products, they sound the alarm to lymphocytes, white blood cells that are a central part of your body’s police force.

Lymphocytes ramp up defenses in many ways. They also have an intelligence function; they have memory. Each of us has an army of memory cells, most of which remember some chemical aspect of a particular event, such as a component of a bacterial wall from a prior infection. Memory allows your body to accelerate responses to danger, to bring out the reinforcements for something that is a remembered threat when it reappears. Every time children get a strep throat, their bodies gain more memory of the components of the bacteria, and eventually they stop having symptoms, even when reexposed. They have become immune. Vaccines and their booster doses take advantage of our memory functions to provide strong immunity.

It’s not surprising that the wall of your gastrointestinal tract, from your mouth to your anus, is populated by dendritic cells that sense bacteria and by lymphocytes that react to bacteria. These defenders respond to your regular microbial residents and to unwelcome invaders but not always in the same way. These lymphocytes remember the usual suspects that need rounding up when they are detected or the ones to be treated with kid gloves.

Your stomach wall has its own populations of lymphocytes: B-cells that produce antibodies and T-cells that orchestrate the complete defenses. But like your arm muscles, which are comprised of biceps that flex and triceps that extend, immune cells can have opposing functions. They can be activators or suppressors. Some T-cells predominantly turn up inflammation, whereas others, called regulatory T-cells or T-regs, modify and suppress the responses. We don’t want every minor incident to erupt into full-scale war; that would be too destructive. We need a police force to regulate the army, like military police, who keep order among the troops. That’s one role performed by T-reg cells, which along with the activator types of T-cells live in the stomach’s wall. Part of the “gastritis” that pathologists see in the stomach wall when people are colonized by
H. pylori
is the lymphocytes that are reacting to the organism. There are many more lymphocytes and far more T-reg cells in the
H. pylori–
positive stomach than in the modern
H. pylori
–free stomach. And they are there doing their job, calibrating inflammation.

As such, the gastritis observed by pathologists is not all bad. This is a paradigm shift. I believe that the T-reg cells that reside in your stomach help, through their suppressive functions, protect you from asthma and allergic disorders. Pathologists and physicians need to recognize that “inflammation” of the stomach is normal. It has a biological cost in terms of ulcers and stomach cancer, but it has biological benefits that we are just now recognizing.

A Swiss group led by Dr. Anne Mueller has conducted important experiments in mice to understand the significance of
H. pylori
–induced immune responses. Their work strongly supports a protective role of
H. pylori
in asthma. Mueller and her colleagues induced asthma in mice by spraying an aerosolized allergen into their lungs. They showed that when the mice were infected with
H. pylori,
their responses to the allergen were reduced. Having living
H. pylori
in their stomachs protected them against the asthma; giving the mice dead
H. pylori
cells conferred no benefit. Moreover, the mice infected with
H. pylori
at a very young age gained greater protection than did the mice infected as adults. These findings parallel the epidemiology in humans. We showed that most
H. pylori
–associated protection against asthma occurs early in life.

Further experiments in mice by Mueller’s group showed that
H. pylori
interact with the sensing dendritic cells of the stomach wall, causing them to program the immune system to turn out T-reg cells. What a smart strategy for
H. pylori
; the T-reg cells suppress immune responses that act to eliminate it. But it is a grand bargain because a collateral benefit to us is the suppression of allergic responses, as Mueller and her colleagues showed in mice.

This theory, while not yet well known, makes evolutionary and physiologic sense, and the epidemiologic, histologic, and experimental studies provide parallel lines of evidence:
H. pylori
–induced immune-cell populations protect against asthma. Again, the idea is not that
H. pylori
have anything to do with cockroaches or with ragweed. Rather, their presence early in life helps ensure that when the host encounters them, it should be able to turn off its immune responses before the allergies get out of hand. And this dynamic may not be limited to just
H. pylori.
There might be other microbes that have disappeared and with them their dependent immune-cell populations.
H. pylori
may be the bellwether, the lead sheep in the flock, the main actor in a large company, or it is the star of the play, or a one-man show. We don’t yet know. But these old troupers are fast disappearing, which may be sufficient to explain the growth of asthma.

*   *   *

My ideas about
H. pylori
—that they appear to be beneficial early in life for health and well-being but dangerous to health in later life—have not been well received by many of my colleagues. Just the opposite. Some have even labeled me a heretic.

A big part of the problem is that
H. pylori
was discovered as a pathogen, and a significant edifice has been built about it being bad for you. In part, this resistance appropriately reflects adherence to a beloved scientific principle: showing an association is not the same as showing causation. People who rob banks may smoke more than those who live ordinary lives, but that does not mean that smoking causes them to rob banks. In fact, there may be “reverse causation.” Robbing banks is stressful, and people might smoke more to calm their nerves.

Despite the many studies from multiple investigators examining different populations, direct proof for
H. pylori
’s dual nature is limited. Still, the degree of skepticism is out of proportion to the nature of the evidence. For example, a causal role for
H. pylori
in ulcer disease has never been shown. Investigators have shown that eliminating
H. pylori
markedly reduces the risk of ulcers recurring, and that is extremely important clinically but doesn’t address what caused the ulcers originally.

Imagine that I spilled gasoline on my hands and that someone lit a match. My hands would wind up with burns. Let’s say that we conducted a study of treatment and applied an antibiotic salve to my right hand but not my left and that the right hand healed better. What could we conclude? Clearly, applying the antibiotic improved the outcome. If we did this trial with many people, and on average their treated hand responded better than the untreated one, it would become the new standard for care.

But such a trial would not prove that bacteria caused the burn. Only that their removal improved recovery. The burn was caused by the conjunction of the gasoline and the match. After-the-fact studies of treating
H. pylori
in people who already had ulcers are just like that. Actually, the only study I am aware of that examined whether
H. pylori
might precede ulcers was ours. Again working with Abraham Nomura and the population of Japanese-American men in Hawaii, we showed that having
H. pylori
in the 1960s was associated with an increased risk of developing an ulcer in the next twenty-one years. So I am not at all against the idea that carrying
H. pylori
has important costs to us. It’s just that like many complex problems in human biology, the specifics of causation are hard to pin down. And while
H. pylori
is generally necessary for ulcer disease, it is far from sufficient. In 1998, I proposed that ulcers are due to the changing microecology of the stomach, meaning changes in the numbers of
H. pylori
, in the types of strains, in the variety of strains, and in the other organisms present and their distribution. Sixteen years later, the idea still looks valid.

Following the initial work by Warren and Marshall, a group of “helicobacteriologists” emerged. Meetings were held all over the world, and a group of us acquired many stamps in our passports. Each year the European community holds an annual
H. pylori
workshop, with attendance by gastroenterologists, microbiologists, pathologists, and their students, who grew in number to the thousands by the mid-1990s. Ample support from pharmaceutical companies eager to identify with the new “movement” provided important fuel and rationale for these meetings.

In 1996 and 1997, when I presented the idea that there might be “good” helicobacters, reactions ranged from amused tolerance to disdain. Remember, the only good
H. pylori
are dead ones. Warren and Marshall’s Nobel Prize in 2005 didn’t help my cause either, although the Nobel Committee was very precise in its citation, which referred to both the discovery of
H. pylori
and to its role in peptic ulcer disease. The great revolution created by the discovery of
H. pylori
was to overturn the dogma that ulcers were due to stress and its consequent hyperacidity. Now a new dogma, that
H. pylori
should be
eradicated,
became as firmly entrenched.

Among doctors who felt they were doing an obvious good by eliminating
H. pylori
, patients who were worried about the “infection,” and the pharmaceutical industry, which was happy to sell its products, including acid-suppressive therapies (among the best-selling drugs in the world), a steamroller had formed to flatten the ancient microbe. Even though relatively few people actually had ulcers at any one time, the momentum continued to build.

Nonetheless, I believe that ultimately we will understand that an ecological shift of this magnitude—the disappearance of
H. pylori
—must have many consequences, good and bad. All along, my work with
H. pylori
has shaped my thoughts and has led me to where I am today, concerned about the disappearance of many microbes from our ancestral bacterial heritage. How many other organisms have disappeared or are disappearing?

My colleagues continue to have “consensus conferences,” largely underwritten by pharmaceutical companies, that keep extending the umbrella of who needs to have
H. pylori
eliminated. “Test and treat” is still the practice of the day. The military analogy would be “search and destroy.” People everywhere are scared of the
H. pylori
in their stomachs, and doctors feel they are duty bound to remove this pathogen. Despite publishing our results in many leading journals, I have not been able to budge the clinical dial.

However, my ideas have resonated in the broader community of microbiologists and ecologists. Because of the role my team has played in putting
H. pylori
on the map as a pathogen, I am invited to many meetings and universities and have been inducted into leading scholarly societies. In my articles, I stopped calling
H. pylori
an infection. I call it a colonization, just like the colonies of countless other organisms that live in your body, mostly happily, for years. About that, I am certain.