Antibiotics in early life alter the murine colonic microbiome and adiposity

Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
Nature (Impact Factor: 41.46). 08/2012; 488(7413):621-6. DOI: 10.1038/nature11400
Source: PubMed


Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.

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Available from: Laura Michelle Cox, Feb 03, 2014
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    • "The composition of gut microbiota is constantly affected by antibiotics, which are routinely administered to treat various infections (Cho et al., 2010; Jernberg et al., 2010; Pérez-Cobas et al., 2012). Clinical research has shown that antibiotics induce diarrhoea (Alam and Mushtaq, 2009) in children and older patients, and could even cause IBD. "
    T Wang · X Hu · S Liang · W Li · X Wu · L Wang · F Jin
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    ABSTRACT: Gut microbiota play a vital role in maintaining the health of the host. Many factors affect gut microbiota; application of broad range antibiotics disturb microbiota, while probiotic application protects the microbiota. To investigate how probiotics alter the physiological and psychological changes induced by antibiotics, we tested the performance of ampicillin-treated rats in the presence or absence of Lactobacillus fermentum strain NS9, in elevated plus maze and Morris water maze. The results showed that NS9 normalised the composition of gut microbiota and alleviated the ampicillin-induced inflammation in the colon. The levels of the mineralocorticoid and N-methyl-D-aspartate receptors were also elevated in the hippocampus of the ampillicin+NS9 treated group. NS9 administration also reduced the anxiety-like behaviour and alleviated the ampicillin-induced impairment in memory retention. These findings suggest that NS9 is beneficial to the host, because it restores the physiological and psychological abnormalities induced by ampicillin. Our results highlight how gut contents regulate the brain, and shed light on the clinical applications of probiotics to treat the side effect of antibiotics and mental disorders.
    Beneficial Microbes 04/2015; DOI:10.3920/BM2014.0177 · 2.61 Impact Factor
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    • "In this study antibiotic treatment from weaning induced significant diminution of microbial populations and taxonomic diversity in the adult mouse gut, which is consistent with previous reports using similar antibiotic regimens in adult mice (Cho et al., 2012; Reikvam et al., 2011; Verdu et al., 2006; Bercik et al., 2011; Zhang et al., 2014). Analysis of remaining gut bacteria in antibiotic-treated mice revealed a significant restructuring of the microbial community characterised by a decrease in the richness of bacterial species. "
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    ABSTRACT: There is growing appreciation for the importance of bacteria in shaping brain development and behaviour. Adolescence and early adulthood are crucial developmental periods during which exposure to harmful environmental factors can have a permanent impact on brain function. Such environmental factors include perturbations of the gut bacteria that may affect gut-brain communication, altering the trajectory of brain development, and increasing vulnerability to psychiatric disorders. Here we assess the effects of gut bacterial depletion from weaning onwards on adult cognitive, social and emotional behaviours and markers of gut-brain axis dysfunction in mice. Mice were treated with a combination of antibiotics from weaning onwards and effects on behaviours and potential brain-gut axis neuromodulators (tryptophan, monoamines, and neuropeptides) and BDNF expression were assessed in adulthood. Antibiotic-treatment depleted and restructured gut microbiota composition of caecal contents and decreased spleen weights in adulthood. Depletion of the gut microbiota from weaning onwards reduced anxiety, induced cognitive deficits, altered dynamics of the tryptophan metabolic pathway, and significantly reduced BDNF, oxytocin and vasopressin expression in the adult brain. Microbiota depletion from weaning onwards by means of chronic treatment with antibiotics in mice impacts on anxiety and cognitive behaviours as well as key neuromodulators of gut-brain communication in a manner that is similar to that reported in germ-free mice. This model may represent a more amenable alternative for germ-free mice in the assessment of microbiota modulation of behaviour. Finally, these data suggest that despite the presence of a normal gut microbiome in early postnatal life, reduced abundance and diversity of the gut microbiota from weaning influences adult behaviours and key neuromodulators of the microbiota-gut-brain axis suggesting that dysregulation of this axis in the post-weaning period may contribute to the pathogenesis of disorders associated with altered anxiety and cognition. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 04/2015; 48. DOI:10.1016/j.bbi.2015.04.004 · 5.89 Impact Factor
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    • "The widespread effects of antibiotics on mitochondrial function need also to be taken into account in clinical practice. Recently, much attention has been drawn to the relevance of microbiota in this respect, as the complete microbiome is estimated to be ten times larger than the number of cells in a human body (10 14 bacteria versus 10 13 cells), possibly explaining why early life exposure to antibiotics severely impacts metabolic traits through disruption of microbial homeostasis (Cho et al., 2012). One should keep in mind, however, that tetracyclines and some other antibiotic classes also inhibit the mitochondria—to be considered as bacteria within our cells—the population of which approximately exceeds the number of bacterial cells by a further order of magnitude (10 15 mitochondria), thus providing a strong platform for adverse effects. "
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    ABSTRACT: In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-on/Tet-off systems. However, the wide range of direct effects of tetracycline use has not been fully appreciated. We show here that these antibiotics induce a mitonuclear protein imbalance through their effects on mitochondrial translation, an effect that likely reflects the evolutionary relationship between mitochondria and proteobacteria. Even at low concentrations, tetracyclines induce mitochondrial proteotoxic stress, leading to changes in nuclear gene expression and altered mitochondrial dynamics and function in commonly used cell types, as well as worms, flies, mice, and plants. Given that tetracyclines are so widely applied in research, scientists should be aware of their potentially confounding effects on experimental results. Furthermore, these results caution against extensive use of tetracyclines in livestock due to potential downstream impacts on the environment and human health. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(10). DOI:10.1016/j.celrep.2015.02.034 · 8.36 Impact Factor
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