Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (24 page)

I list these other conditions here, because there have been convincing studies showing the relationship of C-section with these other modern plagues. Now that we know how medical interventions affect development and could lead to these diseases, perhaps we can find ways to prevent and treat them. But first, let’s examine them more closely.

14.

MODERN PLAGUES REVISITED

In 1974, when Kathy was thirteen, she had to get a routine physical before going to summer camp. I knew her family well. She was so full of energy, no one expected what was about to happen. The doctor called her mother to report that Kathy’s urine had sugar in it. “She has diabetes,” he said. “It appears to be mild, but you will need to watch her very carefully.” Kathy’s grandfather had developed it in his forties and died in his early fifties. Still, this was a shock.

At first, Kathy was lucky. Many children diagnosed with diabetes fall desperately ill. They lose weight rapidly, wet their beds, are constantly thirsty, and feel painfully exhausted. But Kathy had no such symptoms. She was an athletic, healthy girl with thin brown hair, brown eyes, glasses—as normal as can be. For that first year, she was able to control her diabetes by watching her diet. But being a young teenager, Kathy resented the restrictions suddenly placed on her. She would rebel and have ice cream cones with friends after school and deliberately ignore instructions from her diabetes nurse.

A year later, Kathy’s blood sugar rose to dangerous levels and she had to take insulin shots every day. This is when she developed a lifelong anger toward her illness. It wasn’t fair that she couldn’t eat whatever she wanted. It wasn’t right that she had to live life differently. Admonitions to keep her disease under “tight control” went unheeded. Soon Kathy needed insulin twice a day. A few times when her blood sugar dipped too low, she had to be hospitalized.

Despite the ups and downs, Kathy lived her life fully, showing enormous courage, willful strength, and a generous spirit. She graduated from college, became a social worker, married, and had a daughter when she was twenty-five. The diabetes complicated her pregnancy. She tried an insulin pump, but it didn’t work well for her, and she never tried again. After she gave birth, her sugar levels settled back down for a while, but eventually the roller coaster of struggling to control her blood sugar resumed. Kathy continued to occasionally binge on forbidden foods. She did not exercise. She played around with her insulin levels.

Over the years, the diabetes took its toll. Kathy lost sensation in her feet and the tendons in her hands began to contract, contorting her fingers. When she was thirty-five, her daughter, then nine, also became diabetic and was started on insulin injections. Doctors blamed the condition on a genetic predisposition, which made Kathy feel horribly guilty.

Nevertheless, Kathy persevered. Well into her forties, she was very much her own woman. She divorced, remarried, adopted a son, and lived life on her terms, not the disease’s. But then her kidneys began to fail. She was put on the kidney transplant list. She had a heart attack when she was forty-six. Her diabetes became even more difficult to control, with lots of episodes of low blood sugar. She grew very thin. One day in 2011, Kathy felt confused. The next moment she was in a coma, and one week later she was dead. She just missed her fiftieth birthday.

Type 1 or juvenile diabetes is an autoimmune disease in which types of T-cells—immune cells that recognize foreign proteins called antigens—turn against the body’s own proteins. In this instance, T-cells attack the pancreas and destroy the islet cells that make insulin. The disease can occur at any age but is most commonly diagnosed from infancy to the late thirties. (In contrast, adult onset or Type 2 diabetes is a condition of insulin resistance in which the body’s cells fail to respond to insulin properly. It is linked to obesity and tends to occur later in life.)

Insulin is the key that allows the major form of sugar circulating in the blood, called glucose, to enter and nourish cells throughout the body. When Kathy’s islet cells were destroyed, her insulin production collapsed. Without insulin, her tissues were starving, even though her bloodstream was full of glucose. The sugar could not get into her cells. Because her kidneys could not filter the excess sugar, it spilled out of her body in her urine so often that she became dehydrated. Essentially she was peeing out the calories that her body could not absorb.

Once Kathy began taking insulin shots, she was able to keep her blood sugar in a more normal range. But danger lurked constantly. If she took too much insulin, her blood sugar could fall dangerously low. She might get shaky, sweaty, or even pass out. When her blood sugar remained too high over the long term, her heart, blood vessels, nerves, skin, and kidneys all were damaged.

I’m telling this story not to convince you that diabetes is a terrible disease (although it is) but rather to sound an alarm about its sudden rise to epidemic proportions. Today, the rate of Type 1 diabetes is doubling every twenty years all over the developed world; moreover, children are coming down with the disease at younger ages. When Kathy was diagnosed, the average age of onset was about nine. That means that at nine essentially all of the insulin-producing cells in a patient’s pancreas were already gone, which means that the process had actually begun years earlier. But now, the average age of onset is around six, and some children are developing the illness when they are only two or three. This means that for some children, their islet cells are disappearing before their second birthdays.

Of course, there are many hypotheses about why this increase is happening. While several genes are known to predispose children to the disease, and such genes may have been carried by Kathy’s grandfather and passed down (sometimes entire generations are skipped), recent research has focused on environmental factors that might be triggering it. These include our old friend the hygiene hypothesis, viruses, vitamin D deficiency, and antibodies resulting from drinking cow’s milk.

As I studied the literature, I found other markers for risk of the disease. Juvenile diabetes is more likely to develop in babies born by C-section, in boys who are tall, and in babies who gain weight more rapidly in the first year of life. Each of these observations suggested to me that perturbation of our resident microbes very early in life could be a contributing factor.

In March 2011, at a meeting of the Human Microbiome Project, I met Jessica Dunne, a very dedicated program officer from the Juvenile Diabetes Research Foundation, who invited me to give a talk at the organization’s headquarters in New York. She had heard me speak about our work on antibiotics and obesity and was curious about our thoughts on diabetes.

I was lucky, because at the time I had begun to work with Alexandra Livanos, an NYU medical student who was interested in how pancreatic inflammation affects the microbiome. I suggested to Ali that she change the focus of her project from the pancreas in general to Type 1 diabetes in particular. It wasn’t a huge shift in target—we still were studying damage to the pancreas—but it was a big change in terms of what we were looking for and how we would approach it.

By July, Ali had begun to study the effects of early-life antibiotics in a mouse strain (the NOD mouse) that spontaneously develops a disease strongly resembling Type 1 diabetes in humans. We had a hypothesis in mind. Studies show that various treatments can delay diabetes. But could anything accelerate it? Our idea was that antibiotics would speed up the onset and severity of the disease.

In the meantime, in applying for funding from the diabetes foundation, I proposed that we study diabetic mice exposed to either the subtherapeutic regime (STAT) or the pulsed therapeutic doses of antibiotics (PAT). Happily we were funded but got only half of the support we requested. Limited for funds, the foundation said that we should focus on STAT rather than PAT, because our preliminary data on obesity looked more promising. Fortunately, I had some research money in reserve that allowed us to include both in the experiments.

The work is in progress as I write this, but Ali has already presented some of her preliminary results at scientific meetings. Her studies show that the disease comes on faster after PAT, but so far the effect is seen only in males. Even before the diabetes developed, the pancreases in antibiotic-exposed mice looked terrible, with angry immune and inflammatory cells tearing up the insulin-producing islets. Ali also found that intestinal immune cells are altered by the drugs, again before the onset of diabetes. This is evidence that an abnormal interaction in the intestine precedes the destruction in the pancreas. Very recently, Ali showed that PAT significantly alters the composition of the resident microbes well before the mice develop early diabetes and certain organisms stand out as potentially being protective. Interestingly, all of the PAT effects were stronger than STAT, so we had made the right decision to pursue both research avenues.

Thus juvenile diabetes is another disease in which early exposure to antibiotics could be playing a causative role, at least in accelerating the disease. Once again, mice are not humans, but these early findings are consistent with our notion of the risk of perturbing the early-life microbiota, in this case, while the immune system is developing. We are in the middle of follow-up experiments to better understand the disease mechanisms involved, and we have teamed up with investigators in Massachusetts, Florida, North Carolina, and Sweden to extend our inquiries. But so far, in mice—at least in the males—we have evidence that early-life antibiotic exposures are increasing and worsening the risk of developing Type 1 diabetes, in terms of both the number of individuals affected and the age of onset, just as we had hypothesized.

*   *   *

My daughter Genia was born in 1983, and like many kids she had a lot of ear infections. In those days, pediatricians often advised putting tubes into a child’s ears to treat the infections, but as a doctor I didn’t like that idea because it could permanently scar her eardrums. Her doctor agreed with me, so until she was six or seven Genia received many courses of antibiotics for days or weeks on end. It was mostly amoxicillin, the pink liquid with the ultrasweet odor and taste. Her story is not unique.

As Genia was growing up, she developed a little asthma and some food allergies, including a severe reaction to the skin of mangoes. But overall, she seemed to outgrow her asthma, which was mild and, by avoiding mangoes, she had no further problems.

Genia has since become what my late mother would have called a great humanitarian. Since her teenage years, she has been going to Latin America, working, studying, helping disadvantaged people, and traveling and exploring along the way. Not surprisingly, based on how she traveled, where she stayed, and what she ate and drank, she had multiple episodes of diarrhea, which travelers and doctors call
turista
or
Montezuma’s revenge
. Sometimes these bouts lasted a few weeks. A few times she had a particularly uncomfortable intestinal infection caused by a protozoan called Giardia. Such infections are commonly treated with the antibiotic metronidazole (also sold as Flagyl). Metronidazole, which is often used to treat intestinal infections, not only targets Giardia but also has major, broad effects on the resident bacteria of the gut. Genia took four courses of metronidazole in 2008 and 2009, but her abdominal pain only became more frequent.

After working in Ecuador in 2009 and taking another course of metronidazole, Genia developed severe abdominal pain and continuing diarrhea. Her symptoms persisted for months. Blood tests indicated that she was anemic and that her body wasn’t absorbing certain vitamins very well. By then, she had returned to Boston to study law. One night, Genia’s symptoms were so bad that she went to the emergency room at Massachusetts General Hospital. The doctors there thought that she might have acute appendicitis, but fortunately her symptoms improved before they had time to operate.

I was distraught about her condition. I have colleagues all over the world who are specialists in abdominal problems, the diseases of travelers. I enlisted several truly outstanding doctors to evaluate her, but neither they nor I could find the cause of her troubles. She took blood tests for celiac disease, an intestinal malady that produces similar symptoms, but the assays were normal.

With celiac disease (the name derives from the Greek word for
hollow
as in
bowel
) people are allergic to the main protein in wheat (which also is present in barley and rye), called
gluten
. Even eating a tiny amount of gluten can trigger an immune reaction that attacks healthy cells lining the small intestine. In other words, the immune system treats gluten as a deadly invader, not as food. Symptoms include abdominal pain, diarrhea, bloating, and fatigue. Even if a person manages to avoid gluten for months, the symptoms can come back immediately on reexposure.

The incidence of celiac disease has skyrocketed in recent decades, more than quadrupling since 1950.

In 2009, Genia underwent endoscopy of her upper intestine, including a couple of biopsies to look for celiac disease, but again the tests came back normal. Meanwhile, her symptoms continued, lasting for more than a year. She was miserable.

A friend suggested that she might have a food allergy, and in May 2010 she went to see Dr. Bernard “Rardi” Feigenbaum, a colleague of mine who is a terrific allergist. He thought she might have celiac disease, despite negative test results. Sometimes people with otherwise classic symptoms test normal. This made sense to me because I have found that people often don’t have the textbook version of any particular disease. I know from my own experience that the chapters in the textbooks that I both write and edit contain general rules that try to cover the most important situations. But forms of illness are legion, and understanding variation is central to what good doctors must do. (That is one of the biggest dangers of cookbook medicine: we stop thinking, searching, analyzing, because we follow the guidelines.)