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Antibiotics in early life and obesity

Nature Reviews Endocrinology volume 11, pages 182–190 (2015)Cite this article

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Abstract

The intestinal microbiota can influence host metabolism. When given early in life, agents that disrupt microbiota composition, and consequently the metabolic activity of the microbiota, can affect the body mass of the host by either promoting weight gain or stunting growth. These effects are consistent with the role of the microbiota during development. In this Perspective, we posit that microbiota disruptions in early life can have long-lasting effects on body weight in adulthood. Furthermore, we examine the dichotomy between antibiotic-induced repression and promotion of growth and review the experimental and epidemiological evidence that supports these phenotypes. Considering the characteristics of the gut microbiota in early life as a distinct dimension of human growth and development, as well as comprehending the susceptibility of the microbiota to perturbation, will allow for increased understanding of human physiology and could lead to development of interventions to stem current epidemic diseases such as obesity, type 1 diabetes mellitus and type 2 diabetes mellitus.

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Figure 1: A model of microbiota transmission, maturation and perturbation in early life and possible effects on weight.
Figure 2: Proposed pathways of antibiotic-mediated weight modulation.

References

  1. Costello, E. K., Stagaman, K., Dethlefsen, L., Bohannan, B. J. M. & Relman, D. A. The application of ecological theory toward an understanding of the human microbiome. Science 336, 1255–1262 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Koren, O. et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 150, 470–480 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zeissig, S. & Blumberg, R. S. Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease. Nat. Immunol. 15, 307–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Martin, R. et al. Early life: gut microbiota and immune development in infancy. Benef. Microbes 1, 367–382 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Kalliomäki, M., Collado, M. C., Salminen, S. & Isolauri, E. Early differences in fecal microbiota composition in children may predict overweight. Am. J. Clin. Nutr. 87, 534–538 (2008).

    Article  PubMed  Google Scholar 

  8. Rautava, S., Luoto, R., Salminen, S. & Isolauri, E. Microbial contact during pregnancy, intestinal colonization and human disease. Nat. Rev. Gastroenterol. Hepatol. 9, 565–576 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Ley, R. E., Lozupone, C. A., Hamady, M., Knight, R. & Gordon, J. I. Worlds within worlds: evolution of the vertebrate gut microbiota. Nat. Rev. Microbiol. 6, 776–788 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Seekatz, A. M. & Young, V. B. Clostridium difficile and the microbiota. J. Clin. Invest. 124, 1–8 (2014).

    Article  CAS  Google Scholar 

  11. Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1131 (2006).

    Article  PubMed  Google Scholar 

  13. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Verani, J. R., McGee, L. & Schrag, S. J. Prevention of perinatal group B streptococcal disease—revised guidelines from CDC, 2010. MMWR Recomm. Rep. 59, 1–32 (2010).

    PubMed  Google Scholar 

  15. Blaser, M. J. & Falkow, S. What are the consequences of the disappearing human microbiota? Nat. Rev. Microbiol. 7, 887–894 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Stokholm, J., Sevelsted, A., Bonnelykke, K. & Bisgaard, H. Maternal propensity for infections and risk of childhood asthma: a registry-based cohort study. Lancet Respir. Med. 2, 631–637 (2014).

    Article  PubMed  Google Scholar 

  17. Broe, A., Pottegård, A., Lamont, R. F., Jørgensen, J. S. & Damkier, P. Increasing use of antibiotics in pregnancy during the period 2000–2010: prevalence, timing, category, and demographics. BJOG 121, 988–996 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Vidal, A. C. et al. Associations between antibiotic exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring. Int. J. Obes. 37, 907–913 (2013).

    Article  CAS  Google Scholar 

  19. Jepsen, P. et al. A population-based study of maternal use of amoxicillin and pregnancy outcome in Denmark. Br. J. Clin. Pharmacol. 55, 216–221 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hicks, L. A., Taylor, T. H. & Hunkler, R. J. U.S. outpatient antibiotic prescribing, 2010. N. Engl. J. Med. 368, 1461–1462 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. McCaig, L. F., Besser, R. E. & Hughes, J. M. Trends in antimicrobial prescribing rates for children and adolescents. JAMA 287, 3096–3102 (2002).

    Article  PubMed  Google Scholar 

  22. Grijalva, C. G., Nuorti, J. & Griffin, M. R. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA 302, 758–766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ternhag, A. & Hellman, J. More on U.S. outpatient antibiotic prescribing, 2010. N. Engl. J. Med. 369, 1175–1176 (2013).

    Article  PubMed  Google Scholar 

  24. Hersh, A. L., Jackson, M. A., Hicks, L. A. & American Academy of Pediatrics Committee on Infectious Diseases. Principles of judicious antibiotic prescribing for upper respiratory tract infections in pediatrics. Pediatrics 132, 1146–1154 (2013).

    Article  PubMed  Google Scholar 

  25. Fridkin, S. et al. Vital signs: improving antibiotic use among hospitalized patients. MMWR. Morb. Mortal. Wkly Rep. 63, 194–200 (2014).

    PubMed  PubMed Central  Google Scholar 

  26. Lee, G. C. et al. Outpatient antibiotic prescribing in the United States: 2000 to 2010. BMC Med. 12, 96 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hersh, A. L., Shapiro, D. J., Pavia, A. T. & Shah, S. S. Antibiotic prescribing in ambulatory pediatrics in the United States. Pediatrics 128, 1053–1061 (2011).

    Article  PubMed  Google Scholar 

  28. Gerber, J. S. et al. Variation in antibiotic prescribing across a pediatric primary care network. J. Pediatric Infect. Dis. Soc. http://dx.doi.org/10.1093/jpids/piu086.

  29. Donoghue, D. J. Antibiotic residues in poultry tissues and eggs: human health concerns? Poult. Sci. 82, 618–621 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Andersson, D. I. & Hughes, D. Microbiological effects of sublethal levels of antibiotics. Nat. Rev. Microbiol. 12, 465–478 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Yang, S. & Carlson, K. Evolution of antibiotic occurrence in a river through pristine, urban and agricultural landscapes. Water Res. 37, 4645–4656 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Buzby, J. C. International trade and food safety: economic theory and case studies. United States Department of Agriculture Economic Research Service, [online] (2003).

    Google Scholar 

  33. [No authors listed] United States National Residue Program for Meat, Poultry, and Egg Products: 2011 Residue Sample Results. [online] (2013).

  34. Marshall, B. M. & Levy, S. B. Food animals and antimicrobials: impacts on human health. Clin. Microbiol. Rev. 24, 718–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ternak, G. Antibiotics may act as growth/obesity promoters in humans as an inadvertent result of antibiotic pollution? Med. Hypotheses 64, 14–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Riley, L. W., Raphael, E. & Faerstein, E. Obesity in the United States–dysbiosis from exposure to low-dose antibiotics? Front. Public Health 1, 69 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. National Research Council (US) Committee on Drug Use in Food Animals. The use of drugs in food animals: benefits and risks (National Academies Press (US), 1999).

  38. [No authors listed] New animal drugs and new animal drug combination products administered in or on medicated feed or drinking water of food-producing animals: recommendations for drug sponsors for voluntarily aligning product use conditions with GFI #209 [online], (2013).

  39. Nelson, R. FDA action on animal antibiotics could still have loopholes. Lancet Infect. Dis. 14, 376–377 (2014).

    Article  PubMed  Google Scholar 

  40. Cordle, M. K. USDA regulation of residues in meat and poultry products. J. Anim. Sci. 66, 413–433 (1988).

    Article  CAS  PubMed  Google Scholar 

  41. Done, H. Y. & Halden, R. U. Reconnaissance of 47 antibiotics and associated microbial risks in seafood sold in the United States. J. Hazard. Mater. http://dx.doi.org/10.1016/j.jhazmat.2014.08.075.

  42. Taylor, J. H. & Gordon, W. S. Growth-promoting activity for pigs of inactivated penicillin. Nature 176, 312–313 (1955).

    Article  CAS  PubMed  Google Scholar 

  43. Jukes, T. H. & Williams, W. L. Nutritional effects of antibiotics. Pharmacol. Rev. 5, 381–420 (1953).

    CAS  PubMed  Google Scholar 

  44. Gaskins, H. R., Collier, C. T. & Anderson, D. B. Antibiotics as growth promotants: mode of action. Anim. Biotechnol. 13, 29–42 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Butaye, P., Devriese, L. & Haesebrouck, F. Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria. Clin. Microbiol. Rev. 16, 175–188 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Muir, L. A. Mode of action of exogenous substances on animal growth—an overview. J. Anim. Sci. 61 (Suppl. 2), 154–180 (1985).

    Article  Google Scholar 

  47. Coates, M. E., Fuller, R., Harrison, G. F., Lev, M. & Suffolk, S. F. A comparison of the growth of chicks in the Gustafsson germ-free apparatus and in a conventional environment, with and without dietary supplements of penicillin. Br. J. Nutr. 17, 141–150 (1963).

    Article  CAS  PubMed  Google Scholar 

  48. Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Cho, I. et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 488, 621–626 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dubos, R., Schaedler, R. W. & Costello, R. L. The effect of antibacterial drugs on the weight of mice. J. Exp. Med. 117, 245–257 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cox, L. M. & Blaser, M. J. Pathways in microbe-induced obesity. Cell Metab. 17, 883–894 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jiang, H. Q., Bos, N. A. & Cebra, J. J. Timing, localization, and persistence of colonization by segmented filamentous bacteria in the neonatal mouse gut depend on immune status of mothers and pups. Infect. Immun. 69, 3611–3617 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yin, Y. et al. Comparative analysis of the distribution of segmented filamentous bacteria in humans, mice and chickens. ISME J. 7, 615–621 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Davis, C. P. & Savage, D. C. Effect of penicillin on the succession, attachment, and morphology of segmented, filamentous microbes in the murine small bowel. Infect. Immun. 13, 180–188 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Rune, I. et al. Ampicillin-improved glucose tolerance in diet-induced obese C57BL/6N Tac mice is age dependent. J. Diabetes Res. 2013, 1–13 (2013).

    Article  CAS  Google Scholar 

  64. Carvalho, B. M. et al. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia 55, 2823–2834 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Membrez, M. et al. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J. 22, 2416–2426 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Murphy, E. F. et al. Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut 62, 220–226 (2013).

    Article  PubMed  Google Scholar 

  67. Morel, F. B. et al. Can. Antibiotic treatment in preweaning rats alter body composition in adulthood? Neonatology 103, 182–189 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rabot, S. et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, 4948–4959 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Fleissner, C. K. et al. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br. J. Nutr. 104, 919–929 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Ajslev, T. A., Andersen, C. S., Gamborg, M., Sørensen, T. I. A. & 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. 35, 522–529 (2011).

    Article  CAS  Google Scholar 

  72. Trasande, L. et al. Infant antibiotic exposures and early-life body mass. Int. J. Obes. 37, 16–23 (2013).

    Article  CAS  Google Scholar 

  73. Azad, M. B., Bridgman, S. L., Becker, A. B. & Kozyrskyj, A. L. Infant antibiotic exposure and the development of childhood overweight and central adiposity. Int. J. Obes. 38, 1290–1298 (2014).

    Article  CAS  Google Scholar 

  74. Bailey, L. C. et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr. 168, 1063–1069 (2014).

    Article  PubMed  Google Scholar 

  75. Murphy, R. et al. Antibiotic treatment during infancy and increased body mass index in boys: an international cross-sectional study. Int. J. Obes. 38, 115–119 (2013).

    Google Scholar 

  76. Blustein, J. et al. Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. Int. J. Obes. 37, 900–906 (2013).

    Article  CAS  Google Scholar 

  77. Huh, S. Y. et al. Delivery by caesarean section and risk of obesity in preschool age children: a prospective cohort study. Arch. Dis. Child. 97, 610–616 (2012).

    Article  PubMed  Google Scholar 

  78. Luoto, R., Kalliomäki, M., Laitinen, K. & Isolauri, E. The impact of perinatal probiotic intervention on the development of overweight and obesity: follow-up study from birth to 10 years. Int. J. Obes. 34, 1531–1537 (2010).

    Article  CAS  Google Scholar 

  79. Angelakis, E., Merhej, V. & Raoult, D. Related actions of probiotics and antibiotics on gut microbiota and weight modification. Lancet Infect. Dis. 13, 889–899 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Hill, C. et al. Expert consensus document: The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).

    Article  PubMed  Google Scholar 

  81. Huovinen, P. Bacteriotherapy: the time has come. BMJ 323, 353–354 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Dominguez-Bello, M. G., Blaser, M. J., Ley, R. E. & Knight, R. Development of the human gastrointestinal microbiota and insights from high-throughput sequencing. Gastroenterol. 140, 1713–1719 (2011).

    Article  CAS  Google Scholar 

  83. Dethlefsen, L., Huse, S., Sogin, M. L. & Relman, D. A. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6, e280 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Paine, R. T., Tegner, M. J. & Johnson, E. A. Compounded perturbations yield ecological surprises. Ecosystems 1, 535–545 (1998).

    Article  Google Scholar 

  85. Stokholm, J. et al. Antibiotic use during pregnancy alters the commensal vaginal microbiota. Clin. Microbiol. Infect. 20, 629–635 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Matamoros, S., Gras-Leguen, C., Le Vacon, F., Potel, G. & de La Cochetiere, M. F. Development of intestinal microbiota in infants and its impact on health. Trends Microbiol. 21, 167–173 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Dubos, R., Schaedler, R. W. & Stephens, M. The effect of antibacterial drugs on the fecal flora of mice. J. Exp. Med. 117, 231–243 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jain, N. & Walker, W. A. Diet and host–microbial crosstalk in postnatal intestinal immune homeostasis. Nat. Rev. Gastroenterol. Hepatol. http://dx.doi.org/10.1038/nrgastro.2014.153.

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Acknowledgements

This was supported in part by grant T-RO1-DK090989 from the NIH, as well as funding from the Diane Belfer Program in Human Microbial Ecology and the Knapp and Ziff Family foundations.

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  1. Department of Medicine, New York University School of Medicine, VA Medical Centre, Room 6026W, 423 East 23rd Street, New York, 10010, NY, USA

    Laura M. Cox & Martin J. Blaser

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  1. Laura M. Cox
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L.M.C. and M.J.B. contributed equally to all aspects of the article.

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Correspondence to Martin J. Blaser.

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Cox, L., Blaser, M. Antibiotics in early life and obesity. Nat Rev Endocrinol 11, 182–190 (2015). https://doi.org/10.1038/nrendo.2014.210

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