EARLY ANTIBIOTIC EXPOSURE LEADS TO LIFE LONG METABOLIC DISTURBANCE IN MICE
A new study published
in Cell suggests
that antibiotic exposure during a critical window of early development disrupts
the bacterial landscape of the gut, home to trillions of diverse microbes, and
permanently reprograms the body's metabolism, setting up a predisposition to
obesity. Moreover, the study shows that it is altered gut bacteria, rather than
the antibiotics, driving the metabolic effects.
The new study by NYU
Langone Medical Center researchers reveals that mice given lifelong low doses
of penicillin starting in the last week of pregnancy or during nursing were
more susceptible to obesity and metabolic abnormalities than mice exposed to
the antibiotic later in life.
Most intriguing, in
a complementary group of experiments, mice given low doses of penicillin only
during late pregnancy through nursing gained just as much weight as mice
exposed to the antibiotic throughout their lives.
"We found that
when you perturb gut microbes early in life among mice and then stop the
antibiotics, the microbes normalize but the effects on host metabolism are
permanent," says senior author Martin Blaser, MD, the Muriel G. and George
W. Singer Professor of Translational Medicine, director of the NYU Human
Microbiome Program, and professor of microbiology at NYU School of Medicine.
"This supports the idea of a developmental window in which microbes
participate. It's a novel concept, and we're providing direct evidence for
it."
The researchers
stress that more evidence is needed before it can be determined whether
antibiotics lead to obesity in humans, and the present study should not deter
doctors from prescribing antibiotics to children when they are necessary.
"The antibiotic doses used in this study don't mirror what children
get," says Laura M. Cox, PhD, a postdoctoral fellow in Dr. Blaser's
laboratory and the lead author of the study. "But it has identified an
early window in which microbes can influence metabolism, and so further studies
are clearly warranted."
In one experiment in
the study, Dr. Cox administered water with low doses of penicillin to three
groups of mice. One group received antibiotics in the womb during the last week
of pregnancy and continued the medication throughout life. The second group
received the same dose of penicillin after weaning and, like the first group,
continued it throughout life. The third received no antibiotics. "We saw
increased fat mass in both penicillin groups, but it was higher in the mice who
received penicillin starting in the womb," Dr. Cox says. "This showed
that mice are more metabolically vulnerable if they get antibiotics earlier in
life."
The treated mice
also grew fatter than the untreated mice when both were fed a high-fat diet.
"When we put mice on a high-calorie diet, they got fat. When we put mice
on antibiotics, they got fat," explains Dr. Blaser. "But when we put
them on both antibiotics and a high-fat diet, they got very, very fat."
Normally, adult female mice carry three grams of fat. The animals in the study
fed the high-fat diet had five grams of fat. By comparison, the mice who
received antibiotics plus the high-fat chow packed on 10 grams of fat,
accounting for a third of their body weight. The treated rodents were not only
fatter but also suffered elevated levels of fasting insulin, and alterations in
genes related to liver regeneration and detoxification -- effects consistent
with metabolic disorders in obese patients.
This work confirms
and extends landmark research published by Dr. Blaser's lab in 2012 in Nature.
That research showed that mice on a normal diet who were exposed to low doses
of antibiotics throughout life, similar to what occurs in commercial livestock,
packed on 10 to 15 percent more fat than untreated mice and had a markedly
altered metabolism in their liver.
Among the unanswered
questions in that study was whether the metabolic changes were the result of
altered bacteria or antibiotic exposure. This latest study addresses the
question by transferring bacterial populations from penicillin-exposed mice to
specially bred germ-free, antibiotic-free mice, starting at three weeks of age,
which corresponds to infancy just after weaning. The researchers discovered
that mice inoculated with bacteria from the antibiotic-treated donors were
indeed fatter than the germ-free mice inoculated with bacteria from untreated
donors. "This shows us that the altered microbes are driving the obesity
effects, not the antibiotics," says Dr. Cox.
Contrary to a
longstanding hypothesis within the agricultural world that holds that
antibiotics reduce total microbial numbers in the gut, therefore reducing
competition for food and allowing the host organism to grow fatter, the team
found that the penicillin did not, in fact, diminish bacterial abundance. It
did, however, temporarily suppress four distinct organisms early in life during
the critical window of microbial colonization:Lactobacillus, Allobaculum, Candidatus Arthromitus,
and an unnamed member of theRikenellaceae family, which may have important
metabolic and immunological interactions. "We're excited about this
because not only do we want to understand why obesity is occurring, but we also
want to develop solutions," says Dr. Cox. "This gives us four potential
new candidates that might be promising probiotic organisms. We might be able to
give back these organisms after antibiotic treatments."
The researchers
worked with six different mouse models over five years to obtain their results.
To identify bacteria, they used a powerful molecular method that involves
extracting DNA and sequencing a subunit of genetic material called 16S
ribosomal DNA. Altogether, the scientists evaluated 1,007 intestinal samples,
which yielded more than 6 million sequences of bacterial ribosomal genes, the
order of the nucleotides that spell out DNA. Studies like these are possible
because of technological advances in high-throughput sequencing, which allows
scientists to survey microbes in the gut and other parts of the body. The
Genome Technology Center at NYU Langone Medical Center played a key role in
identifying the genetic sequences in the study.
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