Missing Microbes: How the Overuse of Antibiotics Is Fueling Our Modern Plagues (30 page)

Meanwhile, health providers are slowly starting to wake up to the need for change. I predict that doctors will be more cautious about advocating for C-sections as they learn more about the consequences. With increasing data, hospitals and insurance companies will be more reluctant to accept the high C-section rates. One day, parents of a child who has developed a problem attributed to an elective C-section—maybe obesity or juvenile diabetes or autism—will sue the doctor and hospital for malpractice. That will really get people’s attention. Currently the fear of being sued is for
not
doing something: not getting an X-ray, not prescribing an antibiotic, not doing a C-section. Soon there will be the fear of getting sued because of unnecessary and unjustified actions. Fear is one of the great equalizers.

*   *   *

As I travel the country talking about missing microbes, many people ask me what I think about probiotics. Are they what they’re cracked up to be? When should people take them and for which conditions?

A few years ago, a colleague of mine—a healthy woman in her midsixties—woke up doubled over with pain in her lower abdomen. She had a fever and worried that she might need an operation. But after blood tests and X-rays, she was diagnosed with diverticulitis, an inflammation of the lower part of her bowel. This is a relatively common condition, especially in older people, but no one really knows what causes it. Often requiring hospitalization, it usually goes away by withholding food, resting the bowel, and taking a course of antibiotics.

Why the antibiotics? Because they work. As such, the conventional explanation is that by suppressing the overall gut “flora” or particular but unspecified bad actors, the inflammation subsides. That probably is correct, but the details are still missing.

In the case of my colleague, the terrible pain came back five times in separate episodes. She feared that something awful was happening inside her. After the fifth episode, she consulted a gastroenterologist who suggested she take a probiotic. She takes it every day and has had no episodes in the past two years.

Coincidence? Maybe, maybe not. When she told me her story much later, I was glad to hear that a probiotic worked in her case. Presumably, the cultures changed some sort of microbial equilibrium in her intestines. But the fact is we can’t explain their mechanisms of action, if any, because we cannot directly see the interior dynamics of the human gut.

Despite my colleague’s success story, I’m generally skeptical about the many claims surrounding all the probiotics crowded on our grocery store shelves, pharmacies, and health-food stores. They are almost completely untested. In our free country, it turns out that marketing probiotics is a kind of freedom of speech. The packages make all sorts of vague claims about health promotion, yet in most cases no rigorous trials were done to show that the ingredients were actually effective.

The definition of
probiotics
is broad, but so are the different types of bacterial cultures sold in stores. Sometimes they consist of single strains of bacteria; other times they are mixtures. They may be sold as liquids, powders, or salves. Sometimes what are apparently the same strains are sold under different labels with different text extolling their benefits. Some of the cultures were originally isolated from milk and milk products. Others, like
Bifidobacter,
originate from human babies, and still others from human adults. Combinations abound. It’s the Wild West; the field is almost completely unregulated.

The best that I can say is that they are generally safe: you can take them just as you would food, and if you are a normal, generally healthy person, the risk of a problem is small. But do they work? Many people swear by them, so on some level some of them must, but I cannot tell you which ones.

And then there are prebiotics. Unlike living probiotics, prebiotics are chemical compounds that stimulate the growth of organisms we consider favorable. For example, as discussed earlier, human milk is naturally full of prebiotics, including small sugar molecules that can only be used by particular bacteria present in the GI tract in babies. By their very presence in human breast milk, they select for the growth of the initial founding bacteria that colonize the early gut. Chemists have used these and related formulations as prebiotics to stimulate bacteria that people already have in their gut.

Synbiotics are mixtures of probiotics and prebiotics. The prebiotic increases the chances that the probiotic will colonize the intestines in greater numbers and for a longer time.

The theory behind probiotics, prebiotics, and synbiotics is appealing, but the current ways they are used smacks of placebo effects. Doctors used to give sugar pills or injections of salt water or shots of vitamin B
12
(to people who had normal B
12
levels), and, believing they were getting real medicines, the patients would feel better. Placebos are notoriously effective. They work for many people, particularly in conditions where attitudes play a role, such as lower-back pain. Pain, which can be devastating also, sometimes may be no more than opinion on the state of the body.

Some products claim they will make you feel better, perkier, more energetic. But this goal is vague, hard to define, and even harder to test. How do you know that you are feeling better and, most important, compared to what?

When you go to a health-food store looking for probiotics, the very act of walking in suggests you are seeking something to make you feel better. By buying the product, you are ready to be helped, and the placebo effect kicks in.

We won’t know if these products are doing any more good than placebos until we conduct blinded clinical trials. Subjects would be given a probiotic or a placebo that looks, smells, and tastes identical without knowing which was which. The study would look at the health effects, if any, of each treatment. Unfortunately few rigorous trials of this nature have been carried out. Manufacturers who make good money selling probiotics are disinclined to pay for such studies.

Another assertion is that a probiotic will help with a specific disease, say ulcerative colitis or cancer, or speed recovery from influenza. These claims, by their very nature, are easier to test. But few of the well-conducted trials that have been performed show efficacy.

It’s not hard to see why. Certain diseases like ulcerative colitis, for example, have a variable course in individuals and among patients. A study would require a large number of patients, maybe one hundred or more, to tease out the variation and to see any substantial effect. And that would be expensive.

I’m not dismissing probiotics. In fact, I think they will be very important in future disease prevention and treatment, but we need to have a much stronger scientific base for their efficacy. Which organisms exactly should we put back into our bodies? Maybe your lost bacteria are different from mine. How do we know what is suppressed in you or in danger of extinction? Since antibiotics suppress or eliminate some microbes, I predict that in coming years we’ll give people probiotics as a form of standard care to accompany the course of needed antibiotics. But first we must understand which microbes we’re dealing with.

*   *   *

Remember the tragic case of Peggy Lillis, the healthy woman who died from a
C. diff
infection? This awful problem continues unabated, but recently a new technique has shown remarkable success in treating people with multiple relapses of the disease.

Called fecal microbiota transplantation (FMT), it is the deliberate transfer of feces from one person to another. Of course, the very thought of this procedure is revolting, but it has saved lives, especially for people with recurrent
C. diff
infections.

To administer this treatment, the doctor obtains a fecal specimen—a fresh bowel movement from a healthy person who might be a relative of the patient or someone who is just a “good” donor whose poop has already helped many people. The doctor makes a slurry of it in a salt solution and then gives the resulting opaque brown liquid to the patient with the
C. diff
infection. It is delivered via a plastic tube or by endoscope through the nose down into the stomach or duodenum or in the other direction via colonoscopy or as an enema in the rectum.

Although the practice conjures up disgusting images, it works. A number of doctors have been doing this for some years, and in 2013 a pivotal and attention-getting study from the Netherlands was published in the widely read
New England Journal of Medicine.
The investigators conducted a randomized clinical trial in patients with recurrent
C. diff
infection; the participants were offered the chance to be treated either conventionally with antibiotics or with a fecal transfer. The cure rate for those getting the drugs was 31 percent, whereas for those who chose the fecal transfer it was 94 percent. The difference was so substantial that the trial was stopped because it would have been unethical to give the remaining subjects the standard treatment.

This well-conducted, rigorous trial established a “proof of principle” that restoring microbes to people with a damaged intestinal ecosystem—as occurs with
C. diff
—could be good medicine. With this evidence, investigators now can conduct trials to find the active “ingredient,” that is, which microbe or group of microbes are necessary to reverse the illness. The near universality of success using many different “donors” indicates that the key ingredients are common to all of us. It might be a single group of organisms or a variable group in which substitutions are permitted, like the Chinese restaurant where you can pick one from column A and one from column B.

The other great benefit of the Dutch study and the work that went before it by pioneers like Drs. Alexander Khoruts and Lawrence Brandt is that it establishes fecal transfer and its future variations as potential therapies for other illnesses in which a deranged intestinal ecosystem, such as inflammatory bowel disease, celiac disease, and irritable bowel syndrome, may play a role. And it’s not far-fetched to think that it also could be used to treat obesity and a variety of immunologic disorders, possibly including autism. If a disordered intestinal microbial community is at the root of these problems, then restoration via fecal transfer could be a solution.

After the Dutch study, many desperate people began “do-it-yourself” fecal transfers at home, by enema. We don’t know if anyone has been harmed or how many people have been helped. In 2013 doctors providing the procedure were cautioned by the FDA to adhere to a series of regulatory hurdles designed to ensure safety. I believe that ruling was quite reasonable. The history of medicine is scarred by many episodes of the overly enthusiastic embrace of something that seemed so good, like DES or thalidomide, only to lead to real harm. This is especially important when considering the transfer of biologic materials from one person to another. The transfer of AIDS and hepatitis via blood and blood products reminds us of the peril. However, if we could give pure cultures of probiotic bacteria, the problems of human-to-human transmission would be obviated.

*   *   *

Now consider that most of our children may be growing up without the full complement of their necessary microbes. Where can we find the right ones to put back? Perhaps models of the assembly of the microbiota in developing mice can teach us the key principles. Are there places in the world where people have not been exposed to antibiotics? If so, perhaps their gut bacteria would be fully intact. Maybe we could turn them into medicine. Maybe the excrement of our fellow world citizens, people who have had the fewest exposures to antibiotics, antiseptics, and the accoutrements of modern life, the ones who live deep in the Amazon or in the highlands of New Guinea, are the ones we need for the microbe transfers. Are their microbes different from ours?

Gloria found answers in Venezuela. In 2008 an army helicopter pilot spotted a tiny village in the endless High Orinoco jungle. It didn’t appear on any map. The helicopter descended with an interpreter on board who spoke their native language. He told them that they were friends and that the government wanted to bring medicines. They said that they had seen helicopters in the sky before, and from other members of their tribe in other villages they had heard the word
medicina
. But they had never before seen people who were not of their tribe.

When the team surveyed the little village, they found two metal objects: a machete and a can. The people had traded for these objects with other Indians and had learned about the power of the
medicinas
. They wanted medicine because they had their share of misfortunes.

The villagers’ contact with the outside world was inevitable, and the Venezuelan government made the good decision, in my opinion, to vaccinate them. Measles and flu would eventually come to the village and be lethal. So under the auspices of multiple permits and with ethical committee approvals, a medical team made arrangements to return later. Gloria requested that they ask the villagers for specimens that she could study. When they returned to the village, with doctors and health workers ready to vaccinate and treat infections, they also obtained mouth and forearm skin swabs from thirty-five villagers across all ages as well as fecal specimens from twelve of them. Through close cooperation with the Venezuelan authorities and with investigators and institutions in Amazonas State with whom Gloria has worked for more than twenty years, those swabs were sent to her lab for careful investigation.

What a treasure those specimens were. Gloria now had resident microbes from people who were essentially from the Stone Age, with no written language, no mathematics, no contact with the modern world. They had never taken antibiotics. In a sense, their microbes were living fossils. The fecal samples were absolutely unique—and priceless.

A few years later, DNA from the specimens had been extracted and sequenced. One morning in our dining room in New York, Gloria and her fellow researchers Rob Knight and José Clemente pored over the latest analysis of the fecal samples. In their three accents—Spanish, Kiwi (New Zealand), and Venezuelan—they boisterously discussed the colorful plots of microbial populations in the intestines of the 12 Amerindians in comparison with those of 157 representative young adults and their families from Colorado. The graphs appeared one after another on José’s computer.