microbiome_122514

clinical implications of basic research

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Elizabeth G. Phimister, Ph.D., Editor

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Microbiota, Antibiotics, and ObesityTine Jess, M.D.

Obesity is a major health issue worldwide, but the background for this condition is more com-plex than commonly assumed. Dietary and ge-netic factors have but partial roles in the devel-opment of obesity, which is why the focus in recent years has turned to the trillions of mi-crobes 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 pen-icillin in early life induces lasting effects on body composition by altering the intestinal mi-crobiota.

Early life is a critical period both for the es-tablishment 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 develop-ment 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 in-creased total mass and fat mass, increased ecto-pic 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 ex-posure to low-dose penicillin during a specific time window during development may have a sex-specific long-term effect on body composition.

Cox and colleagues went on to study whether treatment with prenatally administered penicil-lin 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 se-lective effects on the microbiota and body mass in particular, fat mass of male mice. Expo-sure 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 fac-tors 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-week-old 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 significant-ly faster rate than did the mice that received mi-crobiota from controls. Recipients of penicillin-altered microbiota also had decreased expression of intestinal immune-response genes, similar to their donors. These results suggest that immu-nologic and metabolic changes are not caused by direct effects of antibiotics but rather by de-rived changes in the gut microbiota.

In humans, similar studies are difficult to conduct. Epidemiologic studies have suggested that interventions that influence the establish-ment of the intestinal microbiota, such as cesare-an section3 and early treatment with antibiotics,4 increase the risk of overweight later in child-hood. Currently, however, there is no direct evi-dence for a causal relationship in humans. And the translation of findings from mouse to hu-

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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 fami-

lies in which obesity is a problem, specific anti-biotic treatment at birth could reverse the ad-verse 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-


Low-Dose Penicillin Exposure

After weaningControlMother exposed

and throughout weaning

Altered microbiotaNormal microbiota

Microbiota transfer to germ-free mice

Mice receiving altered microbiota gainedtotal mass and fat mass at a significantly

faster rate than mice receiving normal microbiota

Normal microbiotaNormal microbiota

Mice receiving altered microbiota gainedtotal 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 simi-lar to that of controls.



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tence of a critical window in early life, when the intestinal microbiota can influence the develop-ment of persisting metabolic traits.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

From the Department of Epidemiology Research, Statens Se-rum Institut, Copenhagen, and the Department of Clinical Epi-demiology, Aalborg University, Aalborg both in Denmark.

1. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014;158:705-21.

2. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter 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 meta-analysis. 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 ad-ministration of antibiotics. Int J Obes (Lond) 2011;35:522-9.

DOI: 10.1056/NEJMcibr1409799Copyright 2014 Massachusetts Medical Society.



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