Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (21 page)

I am also convinced that time is on my side, that truth will out, and that we will learn to give more personalized treatments—to decide who should have
H. pylori
eliminated, who should keep it, and who should have it restored. We are moving in the right direction, but today’s medical practice has many counterproductive incentives and a lot of inertia, especially when sacred cows are involved.

12.

TALLER

We were on a back road, taking what on the map looked like a very direct route to Chichén Itzá, a large pre-Columbian city built by the Mayas. It was dry and dusty, but the dirt road was good. Now and again, we could see the roofs of houses through the bush. Other than the road, there wasn’t much evidence of progress amid the seared landscape. Yet the Yucatán had once been one of the centers of a civilization encompassing millions of people, stable over centuries. Now, not far from the ruins of a great ceremonial site, the land was mostly scrub forest, desolate and monotonous.

But down the road I could see two children. As we got closer and drove past them, their faces came into view. They were purely Mayan, with jet-black straight hair and broad, smooth features, the type we see in murals or sculptures on a classical Mayan stele. But something was immediately askew. These kids, maybe eight and eleven years old, were much too heavy. They were obese. I could expect to see obese children on the roads of Arkansas, Ohio, or Bavaria, but here in the Yucatán it was a shock.

“It’s even happening here,” I said to Gloria, who was traveling with me. She knew that I was studying obesity, so my implication was evident. I was surprised how far the epidemic had spread, reaching even to remote areas in developing countries. Later, when I related what I saw on the road to one of my colleagues at NYU, he told me that he had observed the same thing in Ghana: “When I started working there more than thirty years ago, the major problem in children was malnutrition. Now it’s obesity.”

Why are people all over the world getting fatter? For the first time in human history, overfed people outnumber the underfed. Globally, one in three adults is overweight. One in ten is obese. By 2015, the World Health Organization estimates that the number of chubby adults will grow to 2.3 billion, equal to the combined populations of China, Europe, and the United States. Children and adolescents are also heavier everywhere we look. Are people eating too much junk food and exercising too little?

As a doctor and scientist who studies human health, I am both disturbed and fascinated by this question of why people are getting fatter. And I have found what I believe are some promising leads for answering it. But before I get to them, I want to discuss a related question that led me, circuitously, to those answers: Why are people all over the world getting taller?

Average human height has been increasing in many countries for the last one hundred years. When I ask most people why they think this is happening, they say it is because of better nutrition, and it is hard to argue with that. In developed countries, we are certainly eating more than our ancestors did, although whether our diets are better is a whole other issue. Famine is mostly a thing of the past. In that sense, nutrition has clearly improved, and I am not diminishing its importance. But, as always, I have been most interested in the contribution of microbes to how humans develop.

Some years before, I remembered a study carried out between 1964 and 1973 by Leonardo Mata, a microbiologist and public-health expert at the University of Costa Rica, on the relationship between malnutrition and infection in the children of Santa Maria Cauque, a rural community in Guatemala. Back then childhood mortality was staggeringly high in Guatemala, about 96 deaths per 1,000 births compared with our 6 per 1,000 in the United States today. Sanitation was poor and the children suffered from a litany of diarrheal illnesses. Mata and his colleagues found that the more often the kids had diarrhea, the more slowly they grew. With more disease, they were shorter. Mata’s work was consistent with a wide body of data, but his study in particular caught my attention because his findings were so clear.

It’s widely believed that the period of maximal growth velocity (otherwise known as the growth spurt) occurs during adolescence, but that is not the case. The first two and half years of life, the period with the greatest velocity, is the main critical window for the development of adult height. Experienced pediatricians know that if you double a child’s height at age two, you can closely estimate how tall the child will be. Studies of children adopted from Asia showed that if they moved to America before their third birthday, they grew to the average height of their new playmates. But if they moved later, then they retained their height status from the old country. Thus, the place to look for factors that affect height is early childhood.

Another key observation on what influences height came from studies of
H. pylori
. Soon after the microbes were discovered, scientists began searching for associations between them and all aspects of human health. For example, people who carried
H. pylori
in their stomachs were more likely to have been impoverished in childhood. Moreover, adults who had
H. pylori
were, on average, shorter than those without. The studies focused on the idea that
H. pylori
stunted growth, which was consistent with the view in those days that
H. pylori
was always bad for you. This research suggested that pathogens made people short. If you got rid of the pathogens, they would grow taller. It made sense to me.

By the 1990s we knew that
H. pylori
was acquired in the first few years of life, when it could plausibly make a difference in height. And
H. pylori
was associated with poverty in childhood, which also fit, since poorer people tend to be shorter. But no one knew whether
H. pylori
alone was stunting height or if it was a marker for other microbes, perhaps acquired by the same fecal-oral route.

We subsequently learned that
H. pylori
affects the regulation of the hormones ghrelin and leptin, both produced in the stomach and both involved in the storage and use of energy. We can imagine that young children growing up with
H. pylori
in their stomachs might be metabolically different from those without and that this hormonal variation could slow down their growth trajectory, making them shorter. This is a hypothesis that requires experimental support, but some of our more recent experiments with mice, described below, provide additional evidence.

In 2000, when I returned to NYU, I looked for someone to help me research the question of why people are taller. Albertine Beard, a medical student, took up the challenge and soon uncovered lots of interesting data. It turns out that long-term changes in height are relatively easy to measure; anthropologists use skeletons to estimate height, and armies have been measuring the height of their soldiers for centuries and keeping records of it.

Albertine found that the history and prehistory of humans has not been a long, inexorable path to greater height as we all might think. Skeletal remains indicate that people grew taller at various times in prehistory and history, and then got shorter. This pattern varied by locality and across time periods. We learned from U.S. Army records that the soldiers in George Washington’s army in the eighteenth century were taller than the soldiers who fought in the Civil War in the 1860s. Why would that earlier generation have been taller?

More recent is the remarkable trend of increased height in the late twentieth century. The Dutch, who were among the shortest people in Europe in the early twentieth century, are now among the tallest. The streets of Amsterdam are filled with young giants, male and female. In Asia, the trend has been even more dramatic. When I studied in Tokyo in 1975, I saw a sea of black-haired heads when, at six foot two inches, I rode in the overcrowded subway cars. As I returned over the years, a face would pop up from the crowd on occasion and then more faces. Now, nearly forty years later, there are many tall young Japanese people, and to make things even more strange, their hair, thanks to chemical dyes and fashion, is blond, red, purple, and blue. In China, which had an increase in growth later than Japan, the average six-year-old boy in 2005 was more than two inches (6.5 cm) taller than his counterpart in 1975; girls had a similar (6.2 cm) increase. These are monumentally rapid changes.

These trends have many possible explanations, including better nutrition, but we developed a theory about how microbes might affect height. It is not that we think nutrition is unimportant, but it’s not sufficient to explain the temporal and geographic patterns seen. As discussed in prior chapters, the nineteenth century was a time when sanitation first got much worse in industrializing countries, and then as a result of public-health measures it began to get much better. During the early nineteenth century, municipal water supplies usually contained a microbial soup of human pathogens as well as friendly or commensal bacteria, both of which are ingredients of fecal contamination. From the late nineteenth century onward, when water supplies were filtered and chlorinated in many parts of the world, pathogens began to be eliminated and people got healthier—and taller. There was less cholera and milder diarrheal illnesses. Vaccines controlled diphtheria, whooping cough, and other important infections of young children.

But it also is possible that observed changes in height may be due to the loss of friendly bacteria as well as these pathogens. Our understanding of the microbes inhabiting us is at an early stage, so we don’t yet know the identity of microbes that could help make us taller or even if they exist, but based on our recent work I’m willing to wager that we’ll find them.

This connection between microbial transmission and height does shed light on the question of why soldiers in the Revolutionary War were taller than those in the Civil War. If you were raised on a farm in the mid-eighteenth century, you would have grown up relatively isolated. Eighty years later, growing up in overcrowded urbanized America, you would have been subject to childhood epidemics, and your water was likely to have been more contaminated.

In 2002 we published these ideas and the supporting evidence in an article entitled “The ecology of height: the effect of microbial transmission on human height” in
Perspectives in Biology and Medicine,
a well-respected journal, but the article received very little attention—another big yawn.

Nevertheless, I was already thinking of the sequel, “The ecology of weight,” with many parallel ideas in mind. As it turned out, I never wrote that paper because an alternative pathway to understanding why we are fatter became much more exciting. To begin that story we need to go back to 1979, when I went to work in the Enteric Disease Branch at the Centers for Disease Control, where I was the salmonella surveillance officer of the United States. My assignment was to track and study
Salmonella
as well as other bacterial pathogens affecting the GI tract. That’s also the time I had my own serious
Salmonella
infection, as I described. Unlike my case from eating tainted watermelon, most of us get
Salmonella
infections from foods of animal origin, including meat, eggs, milk, and their products.

Recall that farm animals are given low (subtherapeutic) doses of antibiotics to promote their growth. At the time, no one was curious about why growth promotion was so effective. When writing the paper on height, I realized that a great experiment had been happening on our farms with results consistent with my ideas about the role of microbes in height and weight.

If farmers can purposefully enhance the growth of their livestock by giving antibiotics to young animals, what are we doing to our children when we give them many similar medications? Could our widespread use of antibiotics to treat infections in children be having analogous effects?

On the farm, the practice is deliberate, and animals are given low doses of antibiotics more or less continuously. Obviously it works; the animals gain weight. We give our kids much bigger therapeutic doses, but only episodically, to treat their infections. In one sense, this is a big difference, but in total, the idea is the same: exposure to antibiotics early in life causes microbial perturbations at a crucial time, just when organs and systems are developing. The idea that antibiotics might be causing weight gain in our children, that they could be a “missing link” in the obesity epidemic, seemed a reasonable possibility, but we would have to study it to see if it was true.

*   *   *

There is no question that antibiotic use fundamentally changes the development of the youngest animals. The earlier that farmers start to give antibiotics to chickens, cows, and pigs, the more they alter their development. Most significant is that farmers have found that virtually any antibiotic promotes the growth of their livestock. They all work, despite differences in chemical class and structure, mode of action, and the spectrum of activity for the microbes they target.

If despite their differences they all work, then it must be because of their effects on the microbiome in general, not because of their unique side effects or the specific bugs they target. The drugs must affect the very composition of the microbial community and the interactions they have with their hosts. They must be affecting many if not all aspects of growth and the development of metabolic systems during a critical window.

Also of great interest to me was that the earlier in life farmers started giving animals antibiotics, the stronger the effect. The simplest explanation is that antibiotics lead to a shift in the overall equilibrium of our gut microbes. Some bugs become more dominant; others are suppressed. As we know, microbes evolve along with each animal species they inhabit. Now farmers were deliberately changing the conditions under which microbes and their hosts coevolved to attain equilibria. As John Nash’s model predicts, when equilibria are perturbed, bad things can happen. The idea was simple, but the implications were huge.