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Possible antibiotics side effects include later obesity, via gut microbiome

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By Anette Breindl
Science Editor

One of the biggest side effects of antibiotics may come not at the time of treatment, but years later. Scientists have shown that treatment with antibiotics early in life permanently altered the metabolism of mice, predisposing them to obesity.

The effects showed up long after treatment – in the mouse equivalency of middle age – but once they appeared, they were there to stay.

The study, corresponding author Martin Blaser of New York University Langone Medical Center told BioWorld Today, was "designed to understand the biological role of early life antibiotics in metabolism."

A few years ago, Blaser and his colleagues published a study showing that "giving mice antibiotics early in life made them fat." Such animals are also insulin resistant and have other metabolic symptoms.

The current work, which appeared in the Aug. 14, 2014, issue of Cell, is both a confirmation and an extension of those earlier studies, teasing out the temporal relationship between antibiotics and obesity and demonstrating that it is changes in the microbiome, rather than the antibiotics themselves, that lead to rotund rodents.

The effects of antibiotics on metabolism occur with a time lag. Even when antibiotics exposure occurred at birth, "the weight gain doesn't show up until middle age," Blaser said.

Treatment did not need to be constant. Four weeks of antibiotic exposure, started early, caused as much weight gain as longer-term treatment.

But "if we start [treatment] at birth, it's much more profound than if we start at four weeks of age."

Antibiotics exposure changed the composition of the gut microbiome. It has been known for some years that the composition of the microbiome affects an individual's susceptibility to weight gain, as well as other aspects of their physiology. (See BioWorld Today, Jan. 3, 2007, and Feb. 19, 2014.)

But the metabolic effects showed up after those composition changes appeared to have come and gone.

A month after antibiotics treatment ended, Blaser said, "the microbiome was back to normal. But the mice still became fat."

Despite the fact that the microbiome was normal in terms of its gross composition, the team showed that it was the culprit in the metabolic changes that the team observed. When Blaser and his team transplanted the gut microbiome of antibiotics-exposed mice, "the microbes alone were sufficient" to cause weight gain in animals that had never themselves received antibiotics.

Overall, Blaser said, the work "is consistent with the idea that early life antibiotics increase the risk of obesity in older children" – a relationship that has also been demonstrated in epidemiological studies.

Blaser and his colleagues are following up on multiple aspects of their study; they have identified multiple pathways in the intestine whose altered activities might contribute to the permanent metabolic alterations that long outlast the antibiotic treatment.

They are also testing what time window exists for preventing the permanent metabolic effects of early life exposure to antibiotics – what Blaser termed a "window of restoration."

The results are yet another indictment of indiscriminate use of antibiotics, though first author Laura Cox pointed out in a prepared statement that "the antibiotic doses used in this study don't mirror what children get."

Even if the dosing used in the study did mirror human treatments, "if a kid is really sick, of course they need antibiotics," Blaser said.

But the study is a warning that "antibiotics have costs that we are not accounting for."

A full reckoning of costs and benefits, he said, would show that antibiotics are used in many instances where there benefits are marginal, or may even be outweighed by their long-term costs.

In one sense, pointing out that antibiotics are overused is stating the obvious. Public health experts have been warning for years that the world is at the beginning of a new post-antibiotics era. (See BioWorld Today, July 3, 2014.)

So far, though, the knowledge that antibiotics are overused in principle has not led to widespread changes at the front lines, where the feverish child, the concerned parent and the time-pressed doctor with the prescribing pad meet.

The new results, though, may be more likely than concerns about drug resistance to get doctors and parents to change their behavior, because the negative consequences accrue to the same individual who is taking the drugs, rather than to some hypothetical anonymous future person who does not have access to antibiotics because of resistance issues.

"It's well recognized that we are overusing antibiotics," Blaser said. "It's just that doctors and parents think that their child is the exception."