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D.L.K. is an inventor on patents licensed to Symbiotic Biotherapies
by Brigham and Women’s Hospital and Harvard Medical School
related to PSA of B. fragilis and its use as an immunomodulator for
treating immune-mediated diseases. D.L.K. and R.S.B. are paid
consultants for Symbiotic Biotherapies. R.S.B. is supported by NIH
grant DK44319 and the Harvard Digestive Diseases Center
(DK0034854). D.L.K is supported by NIH grant R21 AI090102 and
the U.S. Department of Defense (W81XWH-15-1-0368).
Antibiotic use and its consequences
for the normal microbiome
Martin J. Blaser1,2,3
Anti-infectives, including antibiotics, are essentially different from all other drugs; they
not only affect the individual to whom they are given but also the entire community,
through selection for resistance to their own action. Thus, their use resides at the
intersection of personal and public health. Antibiotics can be likened to a four-edged
sword against bacteria. The first two edges of the antibiotic sword were identified
immediately after their discovery and deployment in that they not only benefit an
individual in treating their infection but also benefit the community in preventing the
spread of that infectious agent. The third edge was already recognized by Alexander
Fleming in 1945 in his Nobel acceptance speech, which warned about the cost to the
community of antibiotic resistance that would inevitably evolve and be selected for
during clinical practice. We have seen this cost mount up, as resistance curtails or
precludes the activities of some of our most effective drugs for clinically important
infections. But the fourth edge of the antibiotic sword remained unappreciated until
recently, i.e., the cost that an antibiotic exerts on an individual’s own health via the
collateral damage of the drug on bacteria that normally live on or in healthy humans:
our microbiota. These organisms, their genes, metabolites, and interactions with one
another, as well as with their host collectively, represent our microbiome. Our
relationship with these symbiotic bacteria is especially important during the early years
of life, when the adult microbiome has not yet formed.
For 70 years, antibiotics have been a pillar of medicine and are being used worldwide on an enormous scale. In many countries, anti- biotic use exceeds one course per capita per year. In 2010, the top seven antibiotic classes
were consumed in an estimated 70 billion individual doses, which equates to about 10 pills, capsules,
or teaspoons for every man, woman, and child on
earth (1), an annual rate that appears to be rising.
This magnitude of use is based at least in part on
the perception, among both health professionals
and the public, that antibiotics are completely safe.
We all are aware of mild, self-limited problems,
such as rashes and drug reactions, and doctors
know about serious but very rare side effects, yet
at a functional level, most of us consider these
risks so close to zero that they do not usually factor into the equation about use. There also is the
cost of antibiotic resistance, but because it predominantly affects the community rather than
the treated individual, its avoidance does not
usually affect clinical judgments about whether
or not treatment should be given. Parents would
rather have their ill child treated with a drug they
see as safe and effective than worry about the impact of that single course on the future of humankind, and their doctors generally agree.
However, this construct of essentially complete
personal safety is illusory. Shortly after antibiotics
began to be used to treat ill people and animals,
farmers discovered that adding low doses of anti-
biotics to the food or water of their livestock would
promote their growth; the earlier in life the expo-
sure began, the more profound the effect (2). This
observation alone provides an important clue that
antibiotic exposure affects metabolic development.
Antibiotic use has been widespread because it
leads to growth promotion and, therefore, increased
profit for farmers. But does this massive decades-
long worldwide “experiment” on the farm teach
us anything about human health? Is it possible
that the antibiotics that we give our children ear-
ly in life to treat their infections—whether severe
(uncommon) or mild (very common)—are influ-
encing a critical window in the development of
their own metabolism?
In recent years, scientists have been exploring
this question, with mostly consistent results. Observational, clinical, and epidemiologic studies
focused on young children are providing a growing
body of evidence that antibiotic exposure is associated with increased risk for a variety of diseases
including obesity, types 1 and 2 diabetes, inflammatory bowel diseases, celiac disease, allergies,
and asthma [see (3, 4) for examples]. Experimental models are providing increasing evidence that
these associations are not just correlative but are
causal. Studies in mice have found that antibiotic
exposure, by disrupting the development of the
early-life microbiome, which often causes loss of
species and strain diversity (i.e., biodiversity loss),
leads to metabolic perturbations that affect adiposity and bone growth and alter normal immunologic development (5, 6).
A variety of evidence indicates that the risks
appear greatest for young children (7). Paradoxically,
1Division of Translational Medicine, Department of Medicine,
New York University Langone Medical Center (NYULMC),
New York, NY 10016, USA. 2Department of Microbiology,
NYULMC, New York, NY 10016, USA. 3Department of
Veterans Affairs New York Harbor Medical Center, New York,
NY 10010, USA.