Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (15 page)

The baby also is affected in similar unintended ways. Any antibiotic that gets into the bloodstream of the fetus or into the mother’s milk will inevitably influence the composition of the baby’s resident microbes. A baby who starts life with penicillin in its blood or its gut is different from one without because of how the antibiotic affects each child’s developing microbiome, but we are only beginning to understand what this means. One likely scenario is that the antibiotics reduce some taxa of bacteria and enhance others. Whether the effect is transient and trivial or the first step in a cumulative process is unknown. I believe this is an important area for further study.

All in all, each year in the United States well over a million pregnant women are Group B strep–positive, and all will get intravenous penicillin during labor to prevent their babies from acquiring Group B strep. But only 1 in 200 babies actually gets ill from the Group B strep acquired from his or her mother. To protect 1 child, we are exposing 199 others to antibiotics. There must be a better way.

When penicillin had no perceived cost other than occasional allergies, massive overtreatment did not seem like a problem. But what if changing microbial compositions affect the baby’s metabolic, immunologic, and/or cognitive development? As we will see from experiments that my lab and others have conducted, such fears have a real basis.

Another important consideration is that while fewer babies today are born with serious Group B strep infections, the rate of other infections may be rising. By killing or inhibiting some bacteria, penicillin selects for other, resistant bacteria, such as certain virulent strains of
E. coli
, which themselves can infect susceptible newborns. It is possible that, in terms of avoiding serious neonatal infections, the net positive effect of exposing a million mothers each year to this penicillin is lower than anticipated. Also frightening is a conversation I recently had with a colleague who told me that his wife tested negative for Group B strep, but the doctor still wanted to treat her with high-dose penicillin (in case they had “missed” it). Fortunately, she refused.

Many women get yet another dose of antibiotics when they have an episiotomy, a surgical cut of the vaginal wall to prevent tearing and excessive bleeding as the baby’s head crowns. A generation ago, half of American women giving birth received episiotomies. Now, due to changing custom, it is a third. But in Latin America, nine of ten women giving birth vaginally for the first time get the procedure. The rates vary according to local custom and physician advice. But most mothers never realize that they received antibiotics when their babies were born; either they were never told or the news didn’t register.

Finally, the babies are directly exposed. Most parents are not aware that all American-born neonates today are given an antibiotic immediately after birth. The reason is that many years ago, before there were antibiotics, women who had gonorrhea, a sexually transmitted infection, were unable to clear the causative bacteria, even though they had no symptoms of the disease. Their infection would be discovered only when their baby developed a terrible eye infection. As the babies passed through the birth canal, they became inoculated on their face. Sometimes, the eye infection that ensued, called gonococcal ophthalmitis, was so severe that it blinded the baby.

For more than a hundred years, babies have been given eye drops to prevent this infection, first silver nitrate and then, more recently, antibiotics. Although much of the antibacterial effect remains local, the broad-spectrum antibiotics are absorbed into the bloodstream and circulate throughout the newborn’s body. The dose is low but likely is affecting the composition of the infant’s resident microbes just when the founding populations are developing. My lab hopes to soon start a study to measure the magnitude of the perturbation.

So 4 million babies born in the United States every year are being treated to prevent an illness that although catastrophic occurs very rarely. We should be able to develop a better way to screen, so we can target those babies at the highest risk, perhaps a few hundred among the millions of births a year. In Sweden, babies do not receive silver nitrate or antibiotic eye drops, with no effect on rates of infection, so there is precedent for a much more careful assessment of risk and benefit. But the public-health formulas to treat babies by the million to protect hundreds at risk were all based on the notion of essentially no biologic cost for the antibiotics given. What if it is not free?

9.

A FORGOTTEN WORLD

The continuing overuse of antibiotics in children and adults, changing birth practices, and the dosing of our farm animals with mountains of drugs inevitably have an effect on our bacteria, friend and foe alike. More than fifteen years ago, I began to think about what those effects might look like and to formulate the idea that the loss of our ancient, functionally conserved microbial inhabitants has led to the modern plagues I have mentioned: obesity, juvenile diabetes, asthma, and the rest.

The next five chapters explain the results of experiments I performed in my laboratory, first at Vanderbilt University and since 2000 at New York University, in an effort to confirm this hypothesis. The work has had many unexpected twists and turns, failures and successes, lots of hard work, and disappointments of every type. Still and all, the work is ongoing; the exciting days more than equal the busts, and we have been getting somewhere. Some days the results are so clear and so beautiful (thanks to great students who have learned to present their findings with artistry) that I can’t believe they are quite true. But the good ones keep happening again and again, and that’s how we know they are real. And I am running as fast as I can.

The ancient stomach bacteria
Helicobacter pylori
have been my guide for nearly thirty years. When they were discovered, or as you’ll soon see rediscovered, in 1979, their impact on human health was not obvious. Only later did it became clear that they led to specific diseases. But for the past eighteen years, my research has focused on how
H. pylori
keeps us healthy.

Making us sick/keeping us healthy—this may seem contradictory, but this dual nature has plenty of company in the natural world. More than fifty years ago the microbial ecologist Theodore Rosebury coined the term
amphibiosis
, the condition in which two life-forms create relationships that are either symbiotic or parasitic, depending on context. One day the organism is good for you—let’s say it fights off invaders. The next day it turns against you. Or, on any day, both happen simultaneously. Our colonization by the viridans streptococci discussed earlier is an example. Amphibiosis is all around us, including in our work relationships and marriages. It is at the heart of biology, in which the constancy of natural selection forces myriad nuanced interactions.

Amphibiosis
is a more precise term than
commensalism
. Commensalism has been used to describe guests who come to the dinner table to eat; it’s not so hard to serve them an extra meal, but they don’t contribute much if anything to the upkeep of the kitchen. Until recently, that is more or less how we considered the microbes living in the human body, what we called the normal flora. Now we know that Rosebury’s amphibiosis better describes the more complex relationship between our bodies and our indigenous organisms.
Helicobacter pylori
is the best model I know for these interactions, and exploring its biological interface with humans can help us understand the wider world of our normal resident microbes.

H. pylori
are curved bacteria found in essentially only one place: the human stomach. Billions of them live in a thick layer of protective mucus just inside the stomach wall. Mucus lines the gastrointestinal tract from your nose to your anus. It is a gel that helps food slide down and protects the walls of the GI tract from the digestive processes. In each part of the GI tract the locally produced mucus differs in its chemical composition, and, importantly, each zone has its own bacterial species. Your stomach mucus is particularly thick, forming a barrier against the highly acidic environment needed to break down food and repel pathogens. It’s here that we find
H. pylori
.

Helicobacter pylori
have deep roots in evolution. The first primitive mammalian ancestor had a single stomach that laid the blueprint for all the stomachs that followed. As mice, monkeys, zebras, and dolphins radiated in separate directions, so did their stomachs, each with its own acid secretions, mucous layer, and the microbes evolved for that niche. Today we can recognize many
Helicobacter
species in mammals:
H. suis
in swine,
H. acinonyx
in cheetahs,
H. cetorum
in dolphins, and
H. pylori
in humans.

We know from genetic studies that humans have carried
H. pylori
for at least 100,000 years, which is as far back as we can determine using available methods. It’s reasonable to assume that we have had the microbe with us since the origin of
Homo sapiens
about 200,000 years ago in Africa. It’s been a long-term relationship, not a one-night stand.

Genetic analyses also tell us that all modern
H. pylori
populations derive from five ancestral populations: two from Africa, two strongly associated with Eurasia, and one with East Asia. We can trace the movement of
H. pylori
as people migrated around the world, carrying the organism as hidden passengers in their stomachs. Studies from my lab provide evidence that when humans crossed the Bering Strait from the Old World into the New World approximately eleven thousand years ago, they had East Asian strains of
H. pylori
in their stomachs. Nowadays, European strains predominate in South America’s coastal cities as a result of the racial mixing that occurred after the Spanish arrived. But pure East Asian strains can still be found among Amerindians living deep in the continent’s jungles and highlands.

Until recently
H. pylori
colonized virtually all children early in life, shaping the stomach’s immune responses in ways favorable to the microbes as well as to the child. Once
H. pylori
take hold, they are remarkably persistent. Many other microbes that we come into contact with, including bacteria in your dog’s mouth, bacteria in yogurt, and viruses that cause the common cold, are not. They pass through us transiently. But
H. pylori
have evolved a strategy for hanging on even as some of them are swept out of the body by peristalsis, the motion that pushes mucus, food, and wastes along your gastrointestinal tract and out your bottom.
H. pylori
can swim and multiply sufficiently rapidly to maintain their numbers for most of a person’s life. For millennia, these bacteria have fought successfully against the tide and until recently absolutely dominated the stomach. But nothing prepared
H. pylori
for the twentieth century, which is the setting of my main story. But first we must go back a little further in time.

*   *   *

In the nineteenth century, early pathologists used microscopes to compare normal and abnormal tissues in people who were ill. This was the beginning of the medical discipline of pathology, and they immediately saw differences. Normal tissues have regular shapes and great symmetry, lines and lines of cells in perfect rows. But infected tissues, such as a wound, an inflamed joint, or a swollen appendix, are infiltrated with white blood cells that sometimes form sheets, like an endless army of soldiers. Other times, the white blood cells form a rim around a space filled with pus, which contains remnants of tissue destroyed in the battle between the white blood cells and a pathogen.

Such infiltrations, called inflammation, correlate with the swelling, redness, heat, and tenderness that we experience with an infection or arthritis. Sometimes the inflammation is extensive, as in a raging abscess. Or it can be subtle, as in a muscle that has been overexercised and is sore the next day.

Those early pathologists and clinicians also looked in the stomach, where they observed, in essentially everyone, large numbers of bacteria that were curved like commas or were S-shaped like spirals. But these organisms were very particular in their growth requirements and could not be isolated in the kinds of cultures established by microbiologists on petri dishes. Because these organisms could never be grown in the lab, as could many other organisms in the gastrointestinal tract, their identity remained unknown and as a result they were ignored. They were deemed to be just some ordinary commensals that everyone shared, not long after which they were forgotten.

Within a few decades, physicians were being taught that the stomach is sterile and completely free of bacteria. Of course there had to be a reason why the stomach, which is next door to the bacteria-rich intestine, had no bacteria in it. And, having forgotten all about the curved bacteria, the professors invented a reason: obviously nothing could survive in the highly acidic stomach. Since stomach acid is similar in strength to the acid found in a car battery, it made sense to deduce that bacteria could not live in that environment. Our view of the bacterial world was then pretty limited; we had no idea that bacteria can thrive in volcanoes, hot springs, granite, deep-sea vents, and salt flats.

Doctors also knew that a highly acidic stomach can cause trouble. It can become injured and inflamed, and when that becomes particularly intense, the surface of the stomach wall can break, forming an ulcer. Ulcers, which also form in the duodenum, the first part of the small intestine just downstream from the stomach, can cause severe pain. They can erode into a blood vessel, causing substantial bleeding that sometimes is fatal. Or they may burrow through the stomach wall, creating a perforation connecting the stomach interior to the usually sterile space called the peritoneum. In the old days, that almost always was fatal as well. Between meals or in the middle of the night, people with ulcers can experience a gnawing or burning pain in their abdomen or have bloating or nausea. These ulcers can persist, or they can come and go.