Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (26 page)

In 2010 more than 10 million courses of azithromycin were prescribed to children under eighteen and nearly 2 million just for those under the age of two.

For a drug that wasn’t even invented twenty-five years ago, it has gained a remarkable foothold in the medical community. Lots of our epidemics seem to have gotten worse in this time period. Could these newer highly effective macrolides be playing a role? For me, it is just a hunch, but the mouse data are consistent, and the Centers for Disease Control maps of antibiotic use in the United States also point a finger at macrolides. Interestingly, macrolide use is highest in the states with the highest obesity.

And then there is autism, a disease that strikes terror into the hearts of parents as its incidence continues to soar. When the disorder was first described by Dr. Leo Kanner in 1943, it was uncommon. Today, about one in eighty-eight children has autism or autism spectrum disorder (ASD). Although overdiagnosis is likely contributing to the rise in cases, it is not enough to explain the enormous increase. When differences in diagnostic criteria are taken into account, the disorder has still grown fourfold from the 1960s to the present.

Autism falls on a spectrum, from high-functioning children to those who are severely impaired. Basically, autistic brains are wired differently. Many complex interactions, especially those involved in communicating with other people, in understanding nuances and nonverbal cues, are impaired. Young children need these abilities to learn how to understand social contexts, and these skills get more and more important as they grow to adolescence and adulthood.

As with our other modern plagues, multiple theories abound to explain the increase in autism cases, including toxins in food, water, and air; exposures to chemicals and pesticides during pregnancy; and particular characteristics of the fathers. But no one knows. That there are so many theories indicates what a mystery it is.

My theory rests on the fact that gut microbes are involved in early brain development.

Your gut contains more than 100 million neurons—around the same order of magnitude as the number of brain cells—that operate more or less independently from the brain in your skull. They are found in two weblike layers between the muscles of your digestive tract, where they contract to propel and mix intestinal contents. They help keep things moving. The signals go right to your brain, but these nerve cells also can sense what’s going on in your gut, most simply whether it is bloated. A rich network of nerve endings in your intestinal wall sends signals directly to your brain via the vagus nerve. Another recent group of research papers, again using models in rodents, shows that this signaling from bottom (gut) up (to the brain) can affect cognitive development and mood.

These neurons, a part of the enteric nervous system, have regular contact with the microbes in your gut. There is an enormous amount of cross talk. One of the more interesting aspects of these brain-gut interactions is that your gut contains cells that make the neurotransmitter serotonin, which is involved, among other things, in the regulation of learning, mood, and sleep. We think of serotonin as being made and trafficked in the brain, but the neuroendocrine cells in your gut actually make 80 percent of it. And the bacteria in the gut are talking to these neuroendocrine cells, either directly or through inflammatory cells they recruit. In any event, it is an active conversation. Many of the microbes in the gut also make chemicals that the developing brain needs to function normally. These include gangliosides, small carbohydrate-like molecules that nerve cells use to build their coats.

Now think about what happens when a child takes antibiotics. If the composition of the microbes that lead to the production of gangliosides and serotonin is perturbed, the brain will be perturbed. There might still be a conversation among the microbes, gut wall, and brain, but it may be in the wrong language. In an adult, this might not make a big difference, but in a newborn baby or young child whose brain is developing rapidly? Although we do not know which is cause and which is effect, extensive studies point to abnormal serotonin levels in the blood of autistic children.

We know that antibiotics affect the development of metabolism (think of obesity) and immunity (as with asthma or Type 1 diabetes), so it’s not a stretch to think they affect the complex development of the brain as well. This is a critical area for study, and we have begun our own lab work on the problem.

The final connection I want to make between changes to the microbiome and modern plagues is at this point still mostly theoretical. Antibiotics affect hormones, estrogens in particular. This was first noted when oral contraceptive pills were developed in the late 1950s. Women on the pill who received an antibiotic to treat an infection sometimes developed breakthrough bleeding; their periods might start in the middle of the month. It was quickly found that their estrogen levels had dropped. How could antibiotics do that? You guessed it: microbes were involved.

When estrogen is produced in the body—in both women and men but much more in women—it enters the bloodstream and is carried to the liver. There the estrogen is conjugated, meaning that liver cells add another compound, often a sugar, to the estrogen molecule. Then the conjugated estrogen is excreted by the liver into the bile, and from the bile it goes out into the intestine. If nothing interferes with its passage through the intestine, this so-called excess estrogen is excreted from the body as a component of feces.

On the other hand, the conjugated estrogen passing through the intestine might meet bacteria that see it as food. Such bacteria could easily cleave off the conjugate to nourish themselves, spitting out naked estrogen. This form of estrogen is readily reabsorbed by intestinal cells and ends up circulating back to the liver. So the fate of that estrogen molecule in the intestine depends on whether it meets a microbe that uses it for a meal or not. The presence of the microbe is the “switch” that determines whether the estrogen goes out of the body or is reabsorbed.

Thus, the composition of our gut microbes and their metabolic capacity have important bearing on our estrogen status. Dr. Claudia Plottel and I have called the microbes that affect estrogen “the estrobolome.” An important question is whether the estrobolome of today is the same as it has always been or whether it has changed in recent years as a result of antibiotics and the like. While the answer is not yet in, we do know that girls are reaching the age of their first period, or menarche, much earlier than they used to. Moreover, the breasts of young women are noticeably bigger than they were in the past, more women are having problems with fertility, and the rate of breast cancer is increasing. For each of these issues, multiple factors could be playing a causative role but a change in overall estrogen metabolism or in the proportions of the subsets of estrogens (we have at least fifteen of these) that are excreted and absorbed could be an important factor.

As for breast cancer, two decades ago researchers identified mutations in two human genes, BRCA1 and BRCA2, that markedly increase breast cancer risk. Women who possess one or the other of these genes have an extremely high (greater than 50 percent) likelihood of eventually developing the disease. But BRCA-positive women born after 1940 tend to develop breast cancer at a much earlier age than BRCA-positive women born before 1940. Something in the environment has shifted, and it’s not their genes. At this point, the role of an altered estrobolome is just speculative, but we are paying attention to it in the lab.

To reiterate my central idea, as our resident microbes succeed each other, we develop with them as an integrated circuit that includes our metabolism, immunity, and cognition. But we face unprecedented insults to our resident microbes. Although it may seem that I am blaming antibiotics and other modern medical practices for everything, including the kitchen sink, in fact I am only pointing to the diseases that have risen quite dramatically in the late twentieth century, the period in which these practices have been deployed. And indeed they all might have separate causes—and likely do—but there may be a single factor providing the fuel for each, tipping many people from a clinically silent stage into overt illness. It is like the loss of a reserve when the bank account of defenses is so depleted that with any new expense the account now is overdrawn. I believe that factor is the change in the composition of our microbiome, our resident organisms, just at the time when children are developing. And as we speculated five years ago, the changes in one generation may be compounding into the next.

To make matters even worse, I believe we may be heading toward a situation that I call antibiotic winter. This is an analogy to Rachel Carson’s brilliant
Silent Spring
, where she predicts that birds could go extinct due to pesticides. But we could be traveling down a similar path.

15.

ANTIBIOTIC WINTER

Peggy Lillis, a fifty-six-year-old Brooklyn native, worked many jobs, sometimes two at a time, while raising two sons. For her last few years, she was a kindergarten teacher, the kind you always remember with deep affection. In late March 2010, Peggy had a minor dental procedure; by mid-April she was dead.

Peggy’s dentist had prescribed a weeklong course of the antibiotic clindamycin, which is often given to ward off dental infections. Toward the end of the week, she developed diarrhea. Working with little kids, Peggy thought that she had the “stomach flu” and stayed home from work. But the diarrhea continued for four more days. Her family encouraged her to keep up with her liquids, and she contacted her doctor over the weekend. He arranged for her to see a gastroenterologist on Tuesday. But when Tuesday arrived, Peggy was too weak to climb out of bed, and her family called an ambulance. When the paramedics arrived at her home, they found her nearly in shock.

At the hospital, a colonoscopy revealed that Peggy had a severe infection involving the anaerobic bacterium
Clostridium difficile. C. diff,
as it is called, can be found in very low concentrations in the colons of healthy people. It usually minds its own business. But
C. diff
can wreak terrible damage when competing bacteria in the gut are wiped out by antibiotics. In a compromised colon,
C. diff
spreads like wildfire. It can double itself every twelve minutes and dominate the intestine in a matter of hours.
C. diff
produces two or three toxins that it uses to coax the epithelial cells lining the colon to do its bidding. This helps it live but injures human cells. When the toxins spew forth, the colon becomes as porous as toast.

No one knows where Peggy picked up her
C. diff
infection. It could have been her own
C. diff,
or she could have gotten it from someone close to her. Many patients in the hospital acquire it from another patient or from the hands of a health-care worker, but Peggy was not in the hospital. If your colon is healthy,
C. diff
should be blocked by the normal bacteria in your gut.

The antibiotic that Peggy took wiped out many of her normal bacteria.
C. diff
flourished and weakened her bowel wall. Fecal contents seeped through the wall of her bowel into areas that usually are bacteria-free. She became septic and spiked a high fever. Ironically, her treatment involved more antibiotics to clear her sepsis. When that wasn’t sufficient, her doctors, in desperation, took her to the operating room to remove most of her injured colon. Despite heroic attempts, Peggy died in the hospital, less than a week after falling ill and less than two weeks after her dental procedure. How could this active, healthy, vibrant woman be gone so quickly?

We have known about antibiotic-associated diarrhea for more than fifty years, though
C. diff
was discovered to be the major cause only in the late 1970s. Most cases occur in people who are hospitalized. This makes sense since they are often intensely exposed to antibiotics. Moreover,
C. diff
spreads by forming spores that can land on any surface or loft through the air. Thus hospitals, full of sick people, can be highly contaminated with
C. diff
. Tests show that hospitals often have a single strain circulating; other times, many different strains are present. Regardless, a single course of the correct antibiotic is sufficient to quell the infection in many patients.

But a single antibiotic course is not enough for up to a third of the afflicted; they relapse. And after retreatment, they may relapse again. This can happen thirty times and is sometimes so debilitating that patients waste away and die. Thankfully there is a new solution to the problem of relapse, which I will describe shortly.

It’s not difficult to understand why relapses occur so often. As long as a person’s intestinal ecosystem remains disrupted by antibiotics, chances are that these fast-multiplying organisms will bloom again. That the best treatment is more antibiotics only increases the disturbance. It’s almost surprising that there is no relapse in two-thirds of
C. diff
patients.

Through the 1990s, with better infection-control practices in hospitals, such as more hand washing by health-care workers, better mopping of the floors, and isolating patients with severe diarrhea, rates of
C. diff
infections declined. But the problem could not be eradicated.

Over the past decade, patients admitted to our hospitals are on average sicker than they have been in the past. Chemotherapies are more successful, but there are more side effects. Patients are surviving more complicated surgeries, but recovery takes longer. Transplantation saves lives but requires immunosuppressive drugs, making people vulnerable to infection. The result is that more hospitalized patients receive more drugs of all kinds, including agents that suppress gastric acid and gut motility, and, of course, more antibiotics, often multiple kinds, simultaneously and sequentially.

A recent study of nearly 2 million hospitalized adult patients examined the use of the fifty most common antibacterial drugs prescribed. Across all of the patients studied, the investigators found that there were 776 days of therapy for every 1,000 patient-days in the hospital. These numbers include people coming in for normal procedures, like scheduled medication courses and blood transfusions, for which antibiotics are usually not used. This enormous load of antibiotics had to have had some kind of effect on our collective microbiome, and indeed it has.