The

n e w e ng l a n d j o u r na l

of

m e dic i n e

clinical implications of basic research

Elizabeth G. Phimister, Ph.D., Editor

Microbiota, Antibiotics, and Obesity

Tine Jess, M.D.
Obesity is a major health issue worldwide, but
the background for this condition is more complex than commonly assumed. Dietary and genetic factors have but partial roles in the development of obesity, which is why the focus in
recent years has turned to the trillions of microbes residing in the human intestine and their
possible effect on energy harvest and metabolic
signaling. A study by Cox and colleagues1
showed that the administration of low-dose penicillin in early life induces lasting effects on
body composition by altering the intestinal microbiota.
Early life is a critical period both for the establishment of the intestinal microbiota and for
metabolic development. The authors previously
found that subtherapeutic antibiotic treatment
of young mice altered their microbiota and body
composition.2 However, the question remained
whether age at the commencement of antibiotic
treatment played a specific role in the development of obesity and whether obesity persists in
the long term, after treatment. In a more recent
study, Cox and colleagues found that mice are
particularly vulnerable to exposure to low-dose
penicillin during a critical time window around
birth.1 Male mice whose mothers were treated
with penicillin before the birth of the pups and
throughout the weaning process had a markedly
altered body composition in adulthood, with increased total mass and fat mass, increased ectopic fat deposition, increased hepatic expression
of genes involved in adipogenesis, decreased
bone mineral content, and increased bone area.
By contrast, the body composition of adult male
mice who had received penicillin after weaning
and of female mice who had received penicillin
at either phase of development (just before birth
or after weaning) was more similar to that of
controls. The results suggest that even transient
changes to the microbiota caused by limited exposure to low-dose penicillin during a specific
time window during development may have a sexspecific long-term effect on body composition.
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Cox and colleagues went on to study whether

treatment with prenatally administered penicillin added to the effect of a high-fat diet in the
development of obesity. Low-dose penicillin and
high-fat diet were found to have independent selective effects on the microbiota and body mass
in particular, fat mass of male mice. Exposure to penicillin also resulted in substantially
more fat mass in female mice fed a high-fat diet,
as compared with penicillin-exposed female mice
fed a low-fat diet. Penicillin and a high-fat diet
in combination, but not separately, increased
fasting insulin levels. These findings underscore
that the development of obesity depends on more
than diet and genes. The identification of factors that modify the intestinal microbiota may
help us to understand why individual persons have
different vulnerabilities to high calorie intake.
Finally, Cox and colleagues examined whether
the penicillin-moderated gut microbiota would
have similar effects on body composition and
metabolism if transferred to germ-free mice.
Cecal microbiota were transferred from 18-weekold controls and penicillin-treated mice to
3-week-old germ-free mice (Fig. 1). The young
mice that received penicillin-altered microbiota
gained total mass and fat mass at a significantly faster rate than did the mice that received microbiota from controls. Recipients of penicillinaltered microbiota also had decreased expression
of intestinal immune-response genes, similar to
their donors. These results suggest that immunologic and metabolic changes are not caused
by direct effects of antibiotics but rather by derived changes in the gut microbiota.
In humans, similar studies are difficult to
conduct. Epidemiologic studies have suggested
that interventions that influence the establishment of the intestinal microbiota, such as cesarean section3 and early treatment with antibiotics,4
increase the risk of overweight later in childhood. Currently, however, there is no direct evidence for a causal relationship in humans. And
the translation of findings from mouse to hu-

n engl j med 371;26nejm.orgdecember 25, 2014

The New England Journal of Medicine

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clinical implications of basic research

Low-Dose Penicillin Exposure

Control

Mother exposed
and throughout weaning

After weaning

Normal microbiota

Altered microbiota

Microbiota transfer to germ-free mice

Mice receiving altered microbiota gained

total mass and fat mass at a significantly
faster rate than mice receiving normal microbiota

Figure 1. Timing of Low-Dose Penicillin Treatment and Risk of Obesity.

Cox and colleagues1 transferred cecal microbiota from 18-week-old controls and penicillin-treated mice to 3-week-old germ-free mice to
investigate the effects on body composition and metabolism. Mice that received penicillin-altered microbiota gained total mass and fat
mass at a significantly faster rate than did mice that received microbiota from controls. Mice whose mothers were treated with penicillin
before the birth of the pups and throughout the weaning process had a markedly altered body composition in adulthood, with increased
total and fat mass, increased ectopic fat deposition, increased hepatic expression of genes involved in adipogenesis, decreased bone
mineral content, and increased bone area. The body composition of adult male mice who had received penicillin after weaning was similar to that of controls.

man is challenging. Although humans may be

vulnerable to early treatment with antibiotics,
sex differences may not be the same as in mice
and the length of the critical time window may
be different. Furthermore, the magnitude of the
effect of antibiotics on obesity in humans needs
to be weighed against the beneficial effects of
clinically indicated treatment with antibiotics in
infancy. It may even be speculated that in famin engl j med 371;26

lies in which obesity is a problem, specific antibiotic treatment at birth could reverse the adverse effect of obesogenic microbiota transferred
from mother to infant during delivery.
Obesity and its causes are a puzzle; each
piece makes our understanding of the causative
factors more complete. The study by Cox and
colleagues represents a valuable piece in the
puzzle in that it provides evidence for the exis-

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2527

clinical implications of basic research

tence of a critical window in early life, when the

intestinal microbiota can influence the development of persisting metabolic traits.

From the Department of Epidemiology Research, Statens Serum Institut, Copenhagen, and the Department of Clinical Epidemiology, Aalborg University, Aalborg both in Denmark.

the murine colonic microbiome and adiposity. Nature 2012;488:

621-6.
3. Li HT, Zhou YB, Liu JM. The impact of cesarean section on
offspring overweight and obesity: a systematic review and metaanalysis. Int J Obes (Lond) 2013;37:893-9.
4. Ajslev TA, Andersen CS, Gamborg M, Srensen TI, Jess T.
Childhood overweight after establishment of the gut microbiota:
the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes (Lond) 2011;35:522-9.

1. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal

DOI: 10.1056/NEJMcibr1409799

Disclosure forms provided by the author are available with the

full text of this article at NEJM.org.

microbiota during a critical developmental window has lasting

metabolic consequences. Cell 2014;158:705-21.

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2. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter

Copyright 2014 Massachusetts Medical Society.

n engl j med 371;26nejm.orgdecember 25, 2014

The New England Journal of Medicine

Downloaded from nejm.org by BRADFORD KNEY on January 4, 2015. For personal use only. No other uses without permission.
Copyright 2014 Massachusetts Medical Society. All rights reserved.