According to the latest statistics from the Centers for Disease Control, more than a third of U.S. adults are obese — nearly 79 million people. On top of that, obesity also affects our kids, with nearly 18 percent of children and 21 percent of adolescents categorized as obese. The price tag for our girth as a nation is equally impressive. In 2008, the medical cost of obesity in the U.S. came to $147 billion, as obesity-related diseases — including heart disease, stroke, and diabetes — ranked among the leading causes of preventable death.
More than likely, when it comes to explaining all of those extra pounds, you think you’ve heard it all before. It’s a simple equation: We’re consuming too many calories and burning too few. But what if that familiar story about diet and exercise has left out a rather complex and mysterious plot twist? Could our burgeoning waistlines, along with other diseases of modern life, also be tied to medicines that otherwise healthy people are taking and giving to their kids for the purpose of getting well?
Growing evidence points to antibiotics and their overuse as an unexpected culprit behind our obesity woes. You see, antibiotics are generally indiscriminate when it comes to killing bacteria. That might sound okay if you think of microbes only as “germs.” But scientists are now coming to understand the intricate role that those microbes, known collectively as a microbiome, play in our health, metabolism, and basic physiology. (For more on this topic, see “Change Your Microbiome, Change Yourself” in our Spring 2014 issue.) As Martin Blaser, the director of the Human Microbiome Program at the New York University School of Medicine and author of the book Missing Microbes, explains it, the human body is “somewhere between 70 and 90 percent bacteria.”
Microbes literally are us, and perhaps we are also what those microbes eat. A series of studies by Jeffrey Gordon, the director of the Center for Genome Sciences and Systems Biology at the Washington University School of Medicine in St. Louis and his colleagues showed differences in the microbial constituencies of obese people and mice compared to lean people and mice. When germ-free mice were given an “obese microbiota,” their bodies began to pack on more fat than did mice given a “lean microbiota.” The findings imply that the composition of the gut microbiome alters the effective number of calories retained from the foods we (and those mice) eat. In the researchers’ words, an obese microbiome comes with “an increased capacity to harvest energy from the diet.”
Later studies of pairs of twins conducted by Gordon’s team added to evidence for an obesity-microbiome link, with obese individuals showing lower bacterial diversity. Those differences in human microbiomes and the weight gain or loss that went with them were readily transferable to mice and also transmissible between them. Mice with an obese microbiome were “rescued” simply by living with mice carrying a leaner set of microbes.
Now consider this: As our waistlines have been growing in recent decades, antibiotic drugs have also been playing a prominent role in modern life. In 2010, doctors prescribed 258 million courses of antibiotics to outpatients. On average, that’s 833 prescriptions for every 1,000 people, with considerable variation in prescription habits from one state to the next. Prescription rates are highest for kids under age 10 and adults age 65 and up. And it’s estimated that about half of the prescriptions written probably aren’t necessary in the first place.
There are some glimmers of hope when it comes to discouraging the obvious overuse of antibiotics. A recent study in the journal Pediatrics shows a marked decline in outpatient antibiotics prescribed for children in the last 20 years. That drop has been driven not by concerns about those drugs’ effects on obesity or other chronic conditions, but rather by concerns that antibiotics are making us sicker by inadvertently encouraging the rise of antibiotic-resistant superbugs.
The Pediatrics study noted that the decline in the use of antibiotics for children under 6 years old was driven more by a decline in the diagnosis of certain infections than by better management of medications. And the use of stronger antibiotics as the initial medication for common illnesses increased, despite clinical standards reserving these medications for penicillin allergies or when initial antibiotics failed. This trend, along with its effects on our microbiomes, is probably something that parents, doctors, and policymakers should be worrying more about. In fact, Blaser goes so far as to say in his book, “as terrible as resistant pathogens are, the loss of diversity within our microbiome is far more pernicious.”
“The microbiome is a part of human biology. It has been around for a very long time in every animal, and there is increasing evidence that it is very beneficial to us,” Blaser explains. “My hypothesis is that it’s particularly beneficial in that it helps us when we are babies in setting the tone for our development immunologically, metabolically, and cognitively. But because of modern practices, including antibiotics and cesarean sections, we are messing up this relationship. The consequence is that we are altering human development, which is increasing the propensity for metabolic diseases, like obesity and diabetes, and immunological diseases, like asthma, allergies, and juvenile diabetes.”
Blaser refers to These increasingly common chronic health conditions as our “modern plagues.” The antibiotics exposure and other disruptions to our microbiomes — naturally transferred to each of us initially by our mothers at birth — often occur right from the beginning. About 25 percent of mothers in the U.S. are treated with antibiotics before giving birth to prevent infection of their newborn infants with a pathogen known as Group B streptococcus. That hit to mothers’ microbiomes may alter the diversity of bacteria delivered to their newborns.
On top of that, almost one third of new babies are born in the United States today by C-section, which means their first experience in the world takes place in an artificially sterile, surgical environment. Studies are ongoing, but some have shown that babies delivered by C-section have differences in their microbiomes immediately after birth. Instead of inheriting a complex assemblage of microbes from their mothers’ birth canals, those babies are left to collect what they can from the environment, nursing staff, and everyday contacts with their mothers and other people. The shifts in their microbial makeups can in some cases persist for weeks, months, or even years.
And then in those important early years, the microbiomes of many children are hit on a semiregular basis with antibiotics, most often prescribed for fairly minor if persistent illnesses such as ear infections, sore throats, coughs, and sniffles.
The International Journal of Obesity published a study in 2013 by Blaser and his colleagues based on 11,532 children born in the United Kingdom. It found that those kids who were treated with antibiotics before six months of age were more likely to be overweight at 3 years old. (Another study released a few months later in the same journal pointed to similar risks to kids delivered by C-section.)
In November 2014, L. Charles Bailey of the University of Pennsylvania Perelman School of Medicine, and his colleagues added to that evidence with a report in JAMA Pediatrics. Among almost 65,000 children in a large pediatric primary care network in the eastern United States, cumulative antibiotic exposure — four or more courses of the drugs before 2 years old — increased the likelihood for childhood obesity. The effect on childhood weight was strongest for those kids prescribed so-called broad-spectrum antibiotics, those that act against the widest range of bacteria.
To help connect these dots from obesity to antibiotics and back to the microbiome, an earlier study in the Proceedings of the National Academy of Sciences by Stanford University’s David Relman and Les Dethlefsen also showed that repeated exposure to antibiotics — in this case Cipro — could lead to lasting changes in the gut microbiome. In fact, an initial study by Relman’s team suggested that the human microbiome can be rather resilient to a single hit. The microbes in the guts of healthy adults bounced back rather well after about a five-day course of Cipro, but after two rounds of Cipro a few months apart, the long-term effects become clear. Repeated use of antibiotics can change the composition of our resident microbial communities, as some closely related species swap places and others simply disappear.
In the release issued by Stanford University Medical Center at the time, Dethlefsen compared what they saw happen in those guts to the effects of forest fire, volcanic eruption, or pests on a wildlife refuge. “In the same way, recurring antibiotic use may produce a cumulative effect on our internal microbial ecosystems with potentially debilitating, if as yet unpredictable, consequences,” he said.
“It’s as if your beneficial bacteria ‘remember’ the bad things done to them in the past,” Relman added. “Clinical signs and symptoms may be the last thing to show up.”
Or, as new evidence seems to suggest, perhaps it’s more likely that those signs and symptoms have been there for quite some time. We just didn’t know we’d been looking right at them.
If you rarely take antibiotics or have kids who are lucky enough not to have needed them much, you might find yourself breathing a little sigh of relief. But most of us probably are taking antibiotics, even if we haven’t filled a prescription. That’s because the idea that antibiotics work as growth promoters isn’t news at all to farmers. Factory farms in particular have been giving animals low doses of antibiotics for decades, and for exactly this reason.
Some link the more prevalent use of antibiotics in livestock over the last 20 years with our growing waistlines.
Every year in the United States, estimates suggest almost 25 million pounds of antibiotics are given to otherwise healthy farm animals to make them grow fatter faster. The vast majority of the antibiotics consumed by those animals comes right out the other end, in tons and tons of manure. From that waste, those antibiotics land in surface and ground water along with the fertilizers used to grow the produce we eat.
Lee Riley, an epidemiologist and the head of the Division of Infectious Diseases and Vaccinology at the School of Public Health at the University of California, Berkeley, says he thinks this use of low-dose antibiotics in food production and its consequences for our live-in microbes may be the best explanation yet for our obesity problem. In a paper published in 2013 in Frontiers in Public Health, he noted that the rise in the use of antimicrobial agents for livestock happened just at the time the obesity epidemic really took hold. People aren’t actually exercising any less today than they did before, he says, and with all those yoga studios and gyms, we might even be exercising more. We may be consuming more calories, but not enough to add up, he says, and when antibiotics first came into widespread use for treating infections in the 1950s, they were “given like candy.”
The question about the obesity epidemic for him as an epidemiologist then was this: “Why the last 20 years? It’s really curious.”
After poring over the data, something struck him: The southeastern counties with the highest obesity prevalence in the country are also the places with the largest increase in concentrated animal feeding operations (or CAFOs) for raising broiler chickens.
“This intensified animal husbandry practice is associated with increased use of antibiotics as growth promoters,” Riley says. “Antibiotics released via chicken waste contaminate our environment, and the human intestine is then chronically exposed to low-residue antibiotics from ingestion of these contaminated products, which after some time will change the intestinal microbiome.”
The idea that farming practices may play an important role in our metabolic and microbial imbalances isn’t lost on Blaser either. A study he co-authored in Nature in 2012 showed that low doses of antibiotics given to young mice made them grow fatter as changes in their microbiomes shifted the way their bodies processed carbohydrates and fats. In a later study in Cell, Blaser and his colleagues found something even more disturbing: low doses of penicillin delivered to mice from birth led to changes in the microbiota and metabolism, amplifying diet-induced obesity. After the antibiotics were stopped, the animals’ microbes eventually recovered. Unfortunately for the animals, and likely for us too, their metabolisms never did.
Blaser hopes the news will encourage more doctors and parents to hold off on antibiotics when the children are not so ill, especially for their youngest children, who may be the most vulnerable to those long-term effects. Getting the persistent traces of antibiotics we consume in our food and water supply completely out of our lives will be a tougher fight to win.
Can Probiotics Help?
If you appreciate the value of microbes, then you may be in the habit of taking your antibiotics with a side of probiotics, perhaps yogurt or an over-the-counter probiotic powder, such as Culturelle or Florastor — and that’s not a bad idea. Probiotics are generally safe, and there is some evidence that they can help with the immediate side effects of antibiotics, including diarrhea. According to experts at the Mayo Clinic, probiotics may also help us to avoid yeast infections or reduce the severity of a cold. Emerging evidence suggests that probiotics may influence the immune system in complicated ways that may help people with inflammatory conditions like eczema or inflammatory bowel disorder.
Some of the most common probiotic bacteria are from the Lactobacillus and Bifidobacteria groups and have many different strains. Based on studies in mice and humans, scientists are discovering other types of bacteria, such as Akkermansia muciniphila, that show special promise for improving metabolism. A report in the Proceedings of the National Academy of Sciences showed an inverse relationship between that mucus-degrading bacteria and body weight in both rodents and humans, with possibilities for treatment or prevention of obesity and associated metabolic disorders, such as type 2 diabetes.
So far, however, conclusive clinical evidence in favor of probiotics is lacking in most cases. Experts haven’t settled on which probiotics really work for which people and, if they do, for how long. Probiotics sold on grocery store shelves are classified as food, food ingredients, or as dietary supplements, with different guidelines for Food and Drug Administration (FDA) approval. If the probiotics are in something classified as a dietary supplement, their health claims don’t require FDA approval.
When asked about the value of probiotics as a way to counteract the influence of antibiotics, New York University School of Medicine’s Martin Blaser explained it like this: “Most of that is based on wishful thinking and not on science. I think one day there will be useful probiotics that are scientifically tested. Right now, almost everything sold as a so-called probiotic is untested.”
It won’t be simple to replace what we are missing as a result of antibiotics or a host of other external factors, explains Jean-Eric Ghia, the director of Gastrointestinal Basic Biology Research at the IBD Clinical and Research Centre at the University of Manitoba. That’s because our microbiomes are each unique, like a fingerprint. As a result, he says, it seems unlikely that any one probiotic would work for everyone.
Several companies are working to devise probiotics that take all of this complexity into account. For example, MicroBiome Therapeutics is producing pharmaceutical products it says are designed to interact with and manipulate our microbiomes in specific ways. Whole Biome says it is working to generate a comprehensive database of microbiomes, with the goal of creating diagnostics and therapeutics designed to specifically balance each individual’s unique set of microbes. And the Paris-based company Enterome is developing tests and diagnostics aimed at improving the management of microbiome-related diseases, including those affecting the gut, immune system, and metabolism.
So, go on eating your yogurt or taking that supplement for now, especially if it makes you feel better, and stay tuned. A wider array of microbiome-altering products, and hopefully the evidence needed to back them up, should be coming along soon. — K.K.M.