Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (18 page)

For example, the amount of inflammatory traffic in the stomach determines immune responses. Maybe the interactions early in life, when a baby is developing, also help determine immune tone. A person’s immunity can be twitchy, causing wheezing in response to an insect crawling across his or her arm, or it can be sluggish, with little response to a pathogen. There is no one universal tone in which one size fits all. Yet we have evolved over the millennia to have particular tones; it is not random. With our changing gastric microbiome, twitchier interactions seem to be increasing.

The loss of
H. pylori
from a person’s stomach has created a new milieu. Instead of the ancient equilibrium, now the regulation of immunity, hormones, and gastric acidity is a dance without a partner. And like the ending of most long-term relationships, the effects are not just immediate or local; they are lifelong.

The changes that have happened in this past century have bearing beyond the stomach. At the very least, they affect the nearby esophagus, the next stop in the saga. New diseases related to the loss of
H. pylori
are rising.

10.

HEARTBURN

More than 60 million Americans experience heartburn at least once a month, and another 15 million have symptoms every day. If you’re among them, you’re in good company. Remember Bill Clinton’s hoarse voice when he was in the White House? He suffered from acid reflux, the medical term for heartburn. So did George W. Bush when he drank coffee or ate peppermints. Star quarterbacks Brett Favre and John Elway played football with heartburn as did baseball greats Jim Palmer and Nick Markakis. When singers choke up and have trouble performing, the problem often can be traced to discomfort in their esophagus. So what exactly is this part of human anatomy and what causes it to give so many people grief?

The esophagus is a tube about eight inches long that connects your throat to your stomach. Just like the stomach, its entire length is lined with slippery mucus that helps food slide down. Every time you finish chewing, a bundle of muscles near the top of your esophagus open and you swallow what was in your mouth. If you take a swallow now, you will feel them.

Another group of muscles sit at the bottom of your esophagus and provide an opening to your stomach. When food collects in your esophagus, this sphincter opens so that your meal can drop into your stomach. When your esophagus is empty, it closes. In this way, food progresses in an orderly fashion down into your stomach, essentially as a one-way street. While swallowing is under your conscious control, the opening and closing of this lower sphincter is not.

When your esophagus is in good working order and you are not in the act of eating, this lower sphincter stays shut; stomach acid and stomach contents can’t back up into your esophagus. But if it fails to close completely, you experience reflux. Acid creeps up the tube, leading to a burning sensation.

Reflux often comes and goes and is not, by itself, such a terrible problem. Wait for it to pass or take a couple of antacid tablets, and you’re good to go. But when reflux becomes chronic, you’re in danger of developing GERD, or gastroesophageal reflux disease, which can be extremely unpleasant and cause reflux every day. In addition to heartburn, patients may experience nausea, regurgitation, difficulty swallowing, and chest pain. The esophagus is irritated and ultimately may become scarred. GERD is now one of the fastest-growing health complaints in the developed world, affecting between 10 and 20 percent of adults in the United States.

One of my first hints that
H. pylori
might play a role in esophageal disease came out of left field. Recall that in 1987 Guillermo Pérez-Pérez and I developed a blood test for
H. pylori
and that I had tested positive, although I had no symptoms. And recall that a few years later we used my serum to identify a protein made by a particularly virulent group of
H. pylori
strains that are found most often in people afflicted with ulcers. By 1993 we found that this protein, CagA, is also involved in stomach cancer.

My father had an ulcer. My mother was from eastern Europe, where stomach cancer rates are high. Was I in danger of getting stomach cancer because of my family history? I felt fine, even though I had the
H. pylori
strain most closely associated with ulcers and stomach cancer. But obviously, if I had believed the results of my own studies, I should have taken antibiotics to eradicate
H. pylori
and see what happened. Why take a chance on getting a horrible disease if I could prevent it?

It was time for a team effort. I asked my colleague Richard Peek, who had just finished his fellowship in gastroenterology, to perform an endoscopy. He would run a tube through my nose, down through my throat, through my esophagus, into my stomach. He would look closely as he passed it down and as he withdrew it. Through the tube, he would pass a tiny scissorlike apparatus, so he could snip biopsies of my stomach.

Another colleague, John Atherton, who came from England to work with us on
H. pylori
, would process the biopsies and isolate my particular
H. pylori
strain on a culture plate. And Guillermo Pérez-Pérez would again examine my blood for its antibody levels. Then I would take a course of antibiotics directed against
H. pylori
, and we would see whether over time my antibody levels would decline.

I hadn’t reckoned on the discomfort the procedure would cause. On the day of the biopsy Rick gave me a drug to relax and reduce my ability to remember much of anything, and it worked, except for one thing: each of the seventeen times he passed the endoscope into my stomach to obtain a biopsy, I gagged. Why so many biopsies? We were researchers, and since I was willing, why not get a lot of material for all kinds of future studies.

Once it was over, they told me that they hadn’t seen an ulcer or anything abnormal. I expected as much, but it was still good news. John Atherton put three bacterial samples taken from my stomach onto plates and waited for them to grow. Then I took antibiotics for ten days.

We waited. And we waited some more.

To my surprise, nothing grew. No lush colonies of
H. pylori
appeared in the bacterial samples. Blood tests had indicated that I carried
H. pylori,
but where were they? We guessed that I had carried relatively low numbers of the organism despite my high antibody values on the blood test. Or maybe it was because the high levels were suppressing the organism but not eliminating it, a little like how an oyster coats a grain of sand to produce a pearl. The oyster can’t eliminate the sand, but it can make it less irritating. Over the next year we took a new blood specimen almost every month, and Guillermo found that my levels of antibodies reacting to
H. pylori
went down progressively and substantially, just as would be expected after successful antibiotic therapy. So now I could breathe easy. My risk of getting stomach cancer fell to almost zero.

Then something strange happened. About six months after my
H. pylori
were eradicated, I started getting heartburn after meals or in the evening, something that I had never suffered from before. I began to wonder if the heartburn was connected to my taking antibiotics. At medical conferences, I had heard anecdotes from doctors about heartburn being an occasional side effect of an antibiotic regimen, but it had never been properly studied.

GERD, unfortunately, can cause much more serious problems if left untreated. It can lead to a form of tissue injury known as Barrett’s esophagus, which can then progress to the form of cancer called adenocarcinoma. In the past, nearly all esophageal cancers involved malignant changes in the upper and middle esophagus, closer to the mouth, and of a type different from adenocarcinoma. But ever since it was first identified in 1950, Barrett’s disease has been found to sometimes progress to adenocarcinomas, involving the lower esophagus or the upper part of the stomach. Once a rare disease representing only 5 percent of all esophageal cancers in the United States, esophageal adenocarcinoma now has the fastest-rising incidence of all major cancers, a sixfold increase in the past three decades. It currently comprises more than 80 percent of all new esophageal cancer cases in this country and is also increasing throughout the developed world.

We didn’t know these statistics at the time.

Despite many theories, no one had the answer to why all of these related disorders were rising dramatically: GERD, the mildest and most common, starting in the 1930s; Barrett’s, more advanced but less common, in the 1950s; and the much-feared adenocarcinoma in the 1970s, but they were clearly connected.

At that point, we were mostly studying how
H. pylori
were injuring the stomach. Rick Peek, the doctor who endoscoped my stomach, was investigating how CagA-positive (the most virulent) and CagA-negative (less virulent) strains differed in their effects on the stomach. Since associations had been made between
H. pylori
and so many different diseases, I asked Rick to look at their relationship with GERD. We could use our blood test to address whether GERD patients had
H. pylori
more often than people with a normal esophagus. Working with colleagues at the Cleveland Clinic who specialized in GERD, Rick rounded up a collection of serum specimens, and Guillermo ran the blood tests, blindly as usual, not knowing which specimens were from normal persons and which were from those with GERD.

Surprisingly, instead of finding a positive association between
H. pylori
and reflux, Rick saw an inverse relationship. The patients
without H. pylori
were about twice as likely to have GERD. Later studies found a ratio of eight times more likely. What could explain this?

I asked Rick about the association with CagA in the patients we were sampling, since we knew then that CagA-positive strains were more virulent. He told me that the association with Cag was even stronger and also in the inverse direction: less Cag, more GERD. This was the exact opposite of what we expected.

I actually knew very little about GERD at the time, and so I asked Rick whether GERD was increasing. When he confirmed that it was indeed, our
H. pylori
work moved in a new direction.

That first study formed an early basis for the hypothesis that
H. pylori
may be protective against GERD. The inverse association was there, of that we were sure. But what did it mean? What caused it to happen? How could a microbe living in the stomach that was involved in ulcers and cancer protect the esophagus? Or was it the disease in the esophagus that eliminated the organism?

For many years, a group in Germany had been treating patients who had duodenal ulcers with antibiotics to eradicate
H. pylori
. They began to study the consequences. Three years after the therapy, they examined each person’s stomach and esophagus. In about half of the patients, the treatment worked—they no longer carried
H. pylori
. But in the other half, the treatment failed, and
H. pylori
persisted. This was a common outcome in the early days after antibiotic therapy was developed to eradicate
H. pylori
. Today, doctors prescribe different regimens that generally have higher success rates—above 80 percent.

But in comparing the two groups, the German scientists found that of those in whom
H. pylori
remained 12.9 percent had reflux, but almost 26 percent of those with successful treatment, who now were without
H. pylori
, also had the problem. The elimination of
H. pylori
led to double the rate of esophageal disease. This was pretty remarkable and provided evidence of the direction of the causal relationship: therapy that eliminated
H. pylori
worsened the esophagus by promoting reflux.

Many other researchers in the area attacked this paper on a number of technical grounds, and over the next year or so it was fashionable at conferences to denounce it. But it caught my attention. I knew that the lead investigator, Joachim LaBenz, was a serious scientist of great integrity.

Over the next few years, my group carried out additional studies with colleagues from around the world and found the same dynamic: inverse associations between
H. pylori
and GERD, Barrett’s esophagus, and adenocarcinoma. People who had the more virulent
cagA
-positive
H. pylori
strains, the ones associated with ulcers and stomach cancer, had the highest degree of protection against diseases of the esophagus.

This presented quite a puzzle. How could
H. pylori
, the bad guy, protect the esophagus, and how could the
cagA
-positive strains, the most virulent ones, be especially protective?

We can look to stomach acid for clues. Acidity kills most bacteria. But over the eons of evolution,
H. pylori
has found ways to avoid annihilation in an acid environment. In a sense,
H. pylori
actually likes acidity, because even though there are costs associated with living in such a hostile environment, acid keeps away competitors. The enemy of my enemy is my friend.

In fact, a body of research from many labs, including mine, was showing that
H. pylori
help regulate stomach acidity by causing inflammation that affects stomach hormones that in turn switch acid production on and off. Over the first decades of life, this acid-balancing system works pretty well. Under the microscope, the glands that make acid resemble fronds waving in the breeze. But as a person gets older, chronic inflammation starts to wear down the stomach walls, and in those who have
H. pylori
they wear down faster. The glands that make acid begin to shorten and flatten out. When this occurs the stomach develops what we call atrophic gastritis—it makes less and less acid. As a consequence, ulcers tend to go away. Schwarz’s dictum—no acid, no ulcer—remains correct.