Martin Blaser, MD, doesn't dispute the fact that antibiotics have saved innumerable lives and revolutionized medicine. But when he looks at the global increases in recent decades of non-communicable diseases like diabetes, asthma, and obesity, and the concordant rise in antibiotic use, he sees a troubling connection.
"Something very powerful is going on here," Blaser, a professor of medicine and director of the Human Microbiome Program at NYU School of Medicine, told an audience yesterday at the University of Minnesota. Blaser's talk, titled, "The Dark Side of Antibiotics," was the first in a series of lectures on antibiotic resistance hosted by the University of Minnesota's Consortium on Law and Values in Health, Environment, and the Life Sciences.
For Blaser, author of the book Missing Microbes: How the Overuse of Antibiotics is Fueling our Modern Plagues, the link between antibiotic overuse and the rise in metabolic conditions revolves around the human microbiome—the collection of microorganisms that reside within us. Observational data from human cohort studies and experiments in mice, he believes, provide persuasive evidence that the amount of antibiotics that humans are using—by recent estimates more than 70 billion antibiotic doses annually—are changing the bacterial diversity in the human microbiome, and those changes are contributing to changing physiology.
Antibiotic use in early years
Blaser is particularly interested in the impact of antibiotic exposure in the early years of childhood (ages 0 to 3 years), since that is when the gut microbiome is developing. According to his extrapolations from recent data on US antibiotic usage from the Centers for Disease Control and Prevention (CDC), by the time US children have reached the age of 2, they have received nearly three courses of antibiotics on average.
Antibiotic use in children is similar in Europe and other developed areas of the world. In Pakistan, according to research by the Gates Foundation, children have had nearly 10 courses of antibiotics by age 2.
To demonstrate the potential impact of this early antibiotic exposure, Blaser discussed several observational studies conducted in recent years. In Finland, for example, a study of 15,000 children with allergies to cow's milk and 15,000 controls found that the more antibiotics the children received, the higher the risk of having the allergy. A study of more than a million people in Denmark found a similar association between antibiotic use and risk for type 2 diabetes. And in the United Kingdom, an epidemiologic study of 10,000 children born in the early 1990s found a link between exposure to antibiotics within the first 6 months of life and increased weight gain.
"This suggests that antibiotics are having very powerful metabolic effects, which is not surprising, because they're very powerful drugs," Blaser said.
And these antibiotic-influenced changes to the microbiome, Blaser explained, are getting passed down through generations, because mothers pass on their microbiota to babies. The study of Finnish children with allergies to cow's milk, for example, found that antibiotic use by the mothers of those children before and during pregnancy was associated with an increased risk of children having the allergy. Studies on asthma produced similar results. "There was strong association with exposure of the baby and the baby's microbiome—even before the baby is born—to antibiotics," Blaser said.
As a result, when Blaser looks at CDC maps showing that states in the southern United States have the highest rates of antibiotic use and obesity, he sees a similar correlation.
Searching for causality
While these observational data present a strong case for the association between antibiotic use and metabolic changes, they don't provide evidence of causality. But all one has to do to understand how antibiotics can impact metabolism, Blaser explained, is to look at the real-life experiments on the farm.
"Farmers have been giving antibiotics to their farm animals for decades, for more than 70 years, to change their metabolism, to promote growth" he said. "And what they've found is that the earlier in life they started the antibiotic, the bigger the growth rate."
This realization has led to experiments in mice that have further enhanced understanding of how antibiotic use affects metabolism and weight gain, how it changes microbial diversity, how microbiome changes get passed on to offspring, and how exposure to antibiotics at early stages of life can produce long-term effects.
These experiments, along with the observational data in humans, have led Blaser to conclude that diet and lifestyle aren't the only reasons why we're seeing rising rates of obesity and diabetes all over the globe, both in developed and developing nations. Antibiotic use at all ages, but particularly early in life, is playing a significant role.
"Our view is that antibiotics are having an impact on long-term physiology through microbiota changes," Blaser said. "If the microbiota is impaired, if there's early life antibiotic treatment, then the microbiota are different...early life development is different, and long-term physiology is different."
Restoring the human microbiome
So how do we reverse this trend?
To start, Blaser said, we need to reduce the use of medically important and veterinary antibiotics in food-producing animals. He cited research showing that residues of these antibiotics are showing up in meat and other food products. One study from China found traces of 18 different antibiotics used in human and veterinary medicine in the blood and urine of 58% of Chinese children.
But we also need to reduce antibiotic use in human medicine, Blaser added, by becoming better antibiotic stewards. He pointed to research showing that cumulative antibiotic use in Sweden, across all age-groups, is roughly 40% of what it is in the United States. "Somehow, Swedish doctors seem to be able to solve this problem more efficiently than US doctors," he said. "And as far as I can tell, the Swedes are as healthy as we are."
Blaser's concern is that if we continue at our current levels of antibiotic use, or use increasing amounts of antibiotics, the diversity of the human microbiome is going to continue to decline. But his hope is that we figure out how to stop the decline and maybe even restore that diversity.
Peering into the future of medicine, Blaser foresees a day when pediatricians doing well-baby exams will not only examine babies but also what's in their diapers to see if they have all the microbes they need.
"And if they don't, they're going to reach into their shelves and they're going to give those microbes back."
Feb 7 Consortium on Law and Values news release