Our missing microbes: Short-term antibiotic courses have long-term consequences

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Our missing microbes: Short-term antibiotic courses have long-term consequences
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Martin J. Blaser, MD

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,1 gastroesophageal reflux disease,2 asthma,3 inflammatory bowel disease,4 and, notably, obesity.5 I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.6 While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.7 More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,8 having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,9 who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,10 and their composition comes to resemble that of adults by the age of 3.11

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.12

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.13 For example, in a study in Japanese families, Urita et al14 found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al15 studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.16,17

 

 

USE AND OVERUSE OF ANTIBIOTICS

More than 73 billion antibiotic doses are prescribed worldwide yearly,18 or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.19 Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.20 In the United States, antibiotic use varies by region, with the heaviest use in the South.19,21 It also varies widely among prescribers.22 Jones et al23 examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

  • Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after25
  • Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity26
  • Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.27

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.28

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).29

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.30 If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,31 a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.32 These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.33

In a study in Danish children,34 the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.35 Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,36 not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

References
  1. TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study. Ann NY Acad Sci 2008; 1150:1–13. doi:10.1196/annals.1447.062
  2. El-Serag HB, Sonnenberg A. Associations between different forms of gastro-oesophageal reflux disease. Gut 1997; 41(5):594–599. pmid:9414963
  3. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006; 355(21):2226–2235. doi:10.1056/NEJMra054308
  4. Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology 2017; 152(2):313–321. doi:10.1053/j.gastro.2016.10.020
  5. de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010; 92(5):1257–1264. doi:10.3945/ajcn.2010.29786
  6. Blaser MJ. The theory of disappearing microbiota and the epidemics of chronic disease. Nat Rev Immunol 2017; 17(8):461–463. doi:10.1038/nri.2017.77
  7. Centers for Disease Control and Prevention. National Center for Health Statistics. Obesity and overweight. www.cdc.gov/nchs/fastats/obesity-overweight.htm. Accessed November 6, 2018.
  8. Centers for Disease Control and Prevention. National Center for Health Statistics. Table 59. Obesity among children and adolescents aged 2-19 years, by selected characteristics: United States, selected years 1988–1994 through 2013–2016. www.cdc.gov/nchs/data/hus/2017/059.pdf. Accessed November 6, 2018.
  9. Ochman H, Worobey M, Kuo CH, et al. Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biology 2010; 8(11):e1000546. doi:10.1371/journal.pbio.1000546
  10. Bokulich NA, Chung J, Battaglia T, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Trans Med 2016; 8(343):343ra82. doi:10.1126/scitranslmed.aad7121
  11. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature 2012; 486(7402):222–227. doi:10.1038/nature11053
  12. Blaser MJ. The past and future biology of the human microbiome in an age of extinctions. Cell 2018; 172(6):1173–1177. doi:10.1016/j.cell.2018.02.040
  13. Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 2009; 7(12):887–894. doi:10.1038/nrmicro2245
  14. Urita Y, Watanabe T, Kawagoe N, et al. Role of infected grandmothers in transmission of Helicobacter pylori to children in a Japanese rural town. J Ped Child Health 2013; 49(5):394–398. doi:10.1111/jpc.12191
  15. Clemente JC, Pehrsson EC, Blaser MJ, et al. The microbiome of uncontacted Amerindians. Sci Adv 2015; 1(3). Pii:e1500183. doi:10.1126/sciadv.1500183
  16. Smits SA, Leach J, Sonnenburg ED, et al. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science 2017; 357(6353):802-806. doi:10.1126/science.aan4834
  17. Vangay P, Johnson AJ, Ward TL, et al. US immigration westernizes the human gut microbiome. Cell 2018; 175(4):962–972. doi:10.1016/j.cell.2018.10.029
  18. Van Broeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14(8):742–750. doi:10.1016/S1473-3099(14)70780-7
  19. Hicks LA, Bartoces MG, Roberts RM, et al. US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin Infect Dis 2015; 60(9):1308–1316. doi:10.1093/cid/civ076
  20. Rogawski ET, Platts-Mills JA, Seidman JC, et al. Use of antibiotics in children younger than two years in eight countries: a prospective cohort study. Bull World Health Organ 2017; 95(1):49–61. doi:10.2471/BLT.16.176123
  21. Hicks LA, Taylor TH Jr, Hunkler RJ. U.S. outpatient antibiotic prescribing, 2010; N Engl J Med 2013; 368(15):1461–1462. doi:10.1056/NEJMc1212055
  22. Gerber JS, Prasad PA, Russell LA, et al. Variation in antibiotic prescribing across a pediatric primary care network. J Pediatric Infect Dis Soc 2015; 4(4):297–304. doi:10.1093/jpids/piu086
  23. Jones BE, Sauer B, Jones MM, et al. Variation in outpatient antibiotic prescribing for acute respiratory infections in the veteran population: a cross-sectional study. Ann Intern Med 2015; 163(2):73–80. doi:10.7326/M14-1933
  24. Ternhag A, Hellman J. More on U.S. outpatient antibiotic prescribing, 2010. N Engl J Med 2013; 369(12):1175. doi:10.1056/NEJMc1306863
  25. Mikkelsen KH, Knop FK, Frost M, Hallas J, Pottegard A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J Clin Endocrinol Metab 2015; 100(10):3633–3640. doi:10.1210/jc.2015-2696
  26. Petschow B, Dore J, Hibbert P, et al. Probiotics, prebiotics, and the host microbiome: the science of translation. Ann NY Acad Sci 2013; 1306:1–17. doi:10.1111/nyas.12303
  27. Tasian GE, Jemielita T, Goldfarb DS, et al. Oral antibiotic exposure and kidney stone disease. J Am Soc Nephrol 2018; 29(6):1731–1740. doi:10.1681/ASN.2017111213
  28. Zimmerman DR. Role of subtherapeutic levels of antimicrobials in pig production. J Anim Sci 1986; 62(suppl 3):6–16.
  29. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413):621–626. doi:10.1038/nature11400
  30. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158(4):705–721. doi:10.1016/j.cell.2014.05.052
  31. Nobel YR, Cox LM, Kirigin FF, et al. Metabolic and metagenomics outcomes from early-life pulsed antibiotic treatment. Nat Commun 2015; 6:7486. doi:10.1038/ncomms8486
  32. Ruiz VE, Battaglia T, Kurtz ZD, et al. A single early-in-life macrolide course has lasting effects on murine microbial network topology and immunity. Nat Commun 2017; 8(1):518. doi:10.1038/s41467-017-00531-6
  33. Livanos AE, Greiner TU, Vangay P, et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol 2016; 1(11):16149. doi:10.1038/nmicrobiol.2016.140
  34. Hvilid A, Svanström H, Frish M. Antibiotic use and inflammatory bowel disease in childhood. Gut 2011; 60(1):49–54. doi:10.1136/gut.2010.219683
  35. Schulfer AF, Battaglia T, Alvarez Y, et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol 2018; 3(2):234–242. doi:10.1038/s41564-017-0075-5
  36. Srinivasan A. Antibiotic stewardship: why we must, how we can. Cleve Clin J Med 2017; 84(9):673–679. doi:10.3949/ccjm.84gr.17003
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Martin J. Blaser, MD
Muriel G. and George W. Singer Professor of Translational Medicine; Professor of Microbiology; and Director, Human Microbiome Program, New York University Langone Medical Center, New York, NY

Address: Martin J. Blaser, MD, New York University Langone Medical Center, New York, NY 10016; martin.blaser@nyumc.org

Medical Grand Rounds articles are based on edited transcripts from Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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Cleveland Clinic Journal of Medicine - 85(12)
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Type 2 Diabetes ICYMI
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microbiome, gut bacteria, obesity, diabetes, microbial diversity, antibiotics, fecal transplant, Martin Blaser
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Martin J. Blaser, MD
Muriel G. and George W. Singer Professor of Translational Medicine; Professor of Microbiology; and Director, Human Microbiome Program, New York University Langone Medical Center, New York, NY

Address: Martin J. Blaser, MD, New York University Langone Medical Center, New York, NY 10016; martin.blaser@nyumc.org

Medical Grand Rounds articles are based on edited transcripts from Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

Author and Disclosure Information

Martin J. Blaser, MD
Muriel G. and George W. Singer Professor of Translational Medicine; Professor of Microbiology; and Director, Human Microbiome Program, New York University Langone Medical Center, New York, NY

Address: Martin J. Blaser, MD, New York University Langone Medical Center, New York, NY 10016; martin.blaser@nyumc.org

Medical Grand Rounds articles are based on edited transcripts from Medicine Grand Rounds presentations at Cleveland Clinic. They are approved by the author but are not peer-reviewed.

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blaser_missingmicrobes.pdf
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Fecal microbiota transplantation for recurrent C difficile infection: Ready for prime time?
Antibiotic stewardship: Why we must, how we can

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,1 gastroesophageal reflux disease,2 asthma,3 inflammatory bowel disease,4 and, notably, obesity.5 I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.6 While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.7 More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,8 having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,9 who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,10 and their composition comes to resemble that of adults by the age of 3.11

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.12

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.13 For example, in a study in Japanese families, Urita et al14 found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al15 studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.16,17

 

 

USE AND OVERUSE OF ANTIBIOTICS

More than 73 billion antibiotic doses are prescribed worldwide yearly,18 or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.19 Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.20 In the United States, antibiotic use varies by region, with the heaviest use in the South.19,21 It also varies widely among prescribers.22 Jones et al23 examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

  • Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after25
  • Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity26
  • Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.27

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.28

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).29

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.30 If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,31 a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.32 These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.33

In a study in Danish children,34 the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.35 Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,36 not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

Recent years have seen dramatic increases in the prevalences of chronic diseases such as type 1 diabetes,1 gastroesophageal reflux disease,2 asthma,3 inflammatory bowel disease,4 and, notably, obesity.5 I propose the hypothesis that much of this increase may be due to loss of diversity in the bacteria that make our guts their home.6 While multiple causes contribute, much of the blame may be attributed to the use—and overuse—of antibiotics.

FAT AND GETTING FATTER

Today, nearly 40% of US adults are obese, and nearly three-fourths are either obese or overweight.7 More alarming, the prevalence of obesity is also high and getting higher in children and adolescents,8 having increased from 10.0% in 1988–1994 to 17.8% in 2013–2016.

And not just in the United States. Trends in weight have been going up around the world, with a lag of about 30 years between developing countries and industrialized countries.5

OUR BACTERIA, OURSELVES

I believe that the bacteria we carry are not random, but rather have coevolved along with us, passed down from generation to generation in a state of dynamic equilibrium between microbes and host. Evidence supporting this comes from a study by Ochman et al,9 who analyzed the DNA from fecal samples from different hominid species (including Homo sapiens) and found that the phylogenic relationships among the bacteria mirrored those among the apes.

Interacting with each other and with us in complex ways, our bacteria are a diverse community to which we can apply the term microbiome. They are acquired in a standard, choreographed process,10 and their composition comes to resemble that of adults by the age of 3.11

Before modern times, microbes were transferred from mother to child during vaginal birth, from the mother’s breast during nursing, through skin-to-skin contact, and from the mother’s mouth by kissing. Now, widespread cesarean delivery, bottle-feeding, extensive bathing (especially with antibacterial soaps), and especially the use of antibiotics have changed the human ecology and altered transmission and maintenance of ancestral microbes, which affects the composition of the microbiota. The microbes, both good and bad, that are usually acquired early in life are especially important, since they affect a developmentally critical stage.12

Loss of microbial diversity in the mother appears to be cumulative over succeeding generations.13 For example, in a study in Japanese families, Urita et al14 found a decline in the prevalence of Helicobacter pylori colonization from 68.7% in the first generation to 43.4% in the second generation and 12.5% in the third. Clemente et al15 studied the intestinal microbiota in a previously uncontacted group of Yanomami people in the Amazon jungle and found they had the highest diversity of bacteria ever reported in a human group. By comparison, the research team calculated that we in the United States have already lost 50% of our microbial diversity, and 2 other groups, the Guahibo (another Amerindian group) and rural Malawians, were in between. More recent studies are confirming these observations.16,17

 

 

USE AND OVERUSE OF ANTIBIOTICS

More than 73 billion antibiotic doses are prescribed worldwide yearly,18 or about 10 doses for every man, woman, and child on Earth, and the numbers are rising. In the United States 262 million courses were prescribed in 2011, or 842 per 1,000 population.19 Children receive a mean of 2.7 courses by age 2, and 10.9 by age 10. More than 50% of women receive antibiotics during pregnancy or perinatally. This is in addition to an unknown level of exposure from agricultural use of antibiotics.

Repeated antibiotic exposure is common in early life, varies widely by country, and is often not medically justified.20 In the United States, antibiotic use varies by region, with the heaviest use in the South.19,21 It also varies widely among prescribers.22 Jones et al23 examined antibiotic prescribing for acute respiratory infections in US veterans and found that the top 10% of physicians gave an antibiotic more than 90% of the time. Physicians in Sweden prescribe about 60% fewer antibiotics than we do in the United States.21,24

Observational data indicate that people who receive antibiotics have a higher risk of chronic diseases later in life, eg:

  • Type 2 diabetes (odds ratio 1.21, 95% confidence interval 1.19–1.23 with 2 to 4 courses, and odds ratio 1.53 (1.50–1.55) with 5 or more courses, up to 15 years after25
  • Obesity: US states with the highest prevalence of antibiotic use also have the highest prevalence of obesity26
  • Kidney stones: prior antibiotic exposure in a large UK study was associated with increased kidney stone risk, for exposures up to 5 years earlier.27

The meat industry has exploited the weight effect for decades, adding subtherapeutic doses of antibiotics to animals’ feed to make them gain weight.28

FINDINGS FROM STUDIES IN MICE

Laboratory studies of the relationship between antibiotic exposure and disease phenotypes in mice have yielded interesting findings.

Mice exposed to antibiotics had more body fat at 10 weeks (32.0%) than control mice (22.9%).29

Low-dose penicillin, started at birth, induces long-lasting effects on the expression of genes involved in immunity and enhances the effect of a high-fat diet in terms of weight gain.30 If the antibiotic exposure is limited to early life, the effect on the microbiota is transient, but the mice still gain weight. If the microbiota from the mice who received penicillin is transferred to germ-free mice, the recipients also become fat, indicating that the bacteria, not the antibiotics per se, cause the weight gain.

In other experiments,31 a series of short, therapeutic doses of antibiotics early in life modeled after those given to children to treat their acute infections caused long-term changes in the composition of the microbiome and in metabolism.

A single course of a macrolide antibiotic also had long-term effects on the microbial population and on the host’s ileal gene expression, T-cell populations, and secretory immunoglobulin A expression.32 These effects were seen only in mice that had a microbiome to begin with, not in germ-free mice, indicating that the antibiotics had their effect through the changes in the microbiome, not directly. But when germ-free mice received a fecal transplant of an impaired microbiome, it was sufficient to affect immunity.

In nonobese diabetic mice, treatment with antibiotics early in life altered the gut microbiome and its metabolic capacities, intestinal gene expression, and T-cell populations, accelerating the onset of type 1 diabetes.33

In a study in Danish children,34 the likelihood of inflammatory bowel disease increased with early-life antibiotic exposure: the more courses the child received, the greater the likelihood of disease. This observation led researchers to wonder if an antibiotic-altered microbiome affects the outcome of inflammatory bowel disease in the next generation.35 Germ-free female mice who received microbiota from mice who had received antibiotics passed the altered microbiome to their pups. Mice lacking the gene for interleukin 10 are genetically susceptible to colitis, and when this experiment was done in mice lacking this gene, the offspring developed markedly more colitis. This indicated the mothers could pass down their altered microbiome to the next generation and that it would affect their risk of disease.

WHAT CAN WE DO?

All physicians must adhere to the principles of antibiotic stewardship,36 not only to prevent the development of resistant strains of pathogens and the overgrowth of potentially dangerous species such as Clostridium difficile, but also, possibly, to prevent the loss of diversity in the human microbiome and thus discourage the development of chronic diseases.

In the future, as we discover more about the microbiome and the optimal mix of bacteria to carry, this information may find practical application in medicine. A pediatrician, for example, may want to analyze a child’s microbiome and, if it is abnormal, administer specific organisms to reshape it.

References
  1. TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study. Ann NY Acad Sci 2008; 1150:1–13. doi:10.1196/annals.1447.062
  2. El-Serag HB, Sonnenberg A. Associations between different forms of gastro-oesophageal reflux disease. Gut 1997; 41(5):594–599. pmid:9414963
  3. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006; 355(21):2226–2235. doi:10.1056/NEJMra054308
  4. Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology 2017; 152(2):313–321. doi:10.1053/j.gastro.2016.10.020
  5. de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010; 92(5):1257–1264. doi:10.3945/ajcn.2010.29786
  6. Blaser MJ. The theory of disappearing microbiota and the epidemics of chronic disease. Nat Rev Immunol 2017; 17(8):461–463. doi:10.1038/nri.2017.77
  7. Centers for Disease Control and Prevention. National Center for Health Statistics. Obesity and overweight. www.cdc.gov/nchs/fastats/obesity-overweight.htm. Accessed November 6, 2018.
  8. Centers for Disease Control and Prevention. National Center for Health Statistics. Table 59. Obesity among children and adolescents aged 2-19 years, by selected characteristics: United States, selected years 1988–1994 through 2013–2016. www.cdc.gov/nchs/data/hus/2017/059.pdf. Accessed November 6, 2018.
  9. Ochman H, Worobey M, Kuo CH, et al. Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biology 2010; 8(11):e1000546. doi:10.1371/journal.pbio.1000546
  10. Bokulich NA, Chung J, Battaglia T, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Trans Med 2016; 8(343):343ra82. doi:10.1126/scitranslmed.aad7121
  11. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature 2012; 486(7402):222–227. doi:10.1038/nature11053
  12. Blaser MJ. The past and future biology of the human microbiome in an age of extinctions. Cell 2018; 172(6):1173–1177. doi:10.1016/j.cell.2018.02.040
  13. Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 2009; 7(12):887–894. doi:10.1038/nrmicro2245
  14. Urita Y, Watanabe T, Kawagoe N, et al. Role of infected grandmothers in transmission of Helicobacter pylori to children in a Japanese rural town. J Ped Child Health 2013; 49(5):394–398. doi:10.1111/jpc.12191
  15. Clemente JC, Pehrsson EC, Blaser MJ, et al. The microbiome of uncontacted Amerindians. Sci Adv 2015; 1(3). Pii:e1500183. doi:10.1126/sciadv.1500183
  16. Smits SA, Leach J, Sonnenburg ED, et al. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science 2017; 357(6353):802-806. doi:10.1126/science.aan4834
  17. Vangay P, Johnson AJ, Ward TL, et al. US immigration westernizes the human gut microbiome. Cell 2018; 175(4):962–972. doi:10.1016/j.cell.2018.10.029
  18. Van Broeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14(8):742–750. doi:10.1016/S1473-3099(14)70780-7
  19. Hicks LA, Bartoces MG, Roberts RM, et al. US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin Infect Dis 2015; 60(9):1308–1316. doi:10.1093/cid/civ076
  20. Rogawski ET, Platts-Mills JA, Seidman JC, et al. Use of antibiotics in children younger than two years in eight countries: a prospective cohort study. Bull World Health Organ 2017; 95(1):49–61. doi:10.2471/BLT.16.176123
  21. Hicks LA, Taylor TH Jr, Hunkler RJ. U.S. outpatient antibiotic prescribing, 2010; N Engl J Med 2013; 368(15):1461–1462. doi:10.1056/NEJMc1212055
  22. Gerber JS, Prasad PA, Russell LA, et al. Variation in antibiotic prescribing across a pediatric primary care network. J Pediatric Infect Dis Soc 2015; 4(4):297–304. doi:10.1093/jpids/piu086
  23. Jones BE, Sauer B, Jones MM, et al. Variation in outpatient antibiotic prescribing for acute respiratory infections in the veteran population: a cross-sectional study. Ann Intern Med 2015; 163(2):73–80. doi:10.7326/M14-1933
  24. Ternhag A, Hellman J. More on U.S. outpatient antibiotic prescribing, 2010. N Engl J Med 2013; 369(12):1175. doi:10.1056/NEJMc1306863
  25. Mikkelsen KH, Knop FK, Frost M, Hallas J, Pottegard A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J Clin Endocrinol Metab 2015; 100(10):3633–3640. doi:10.1210/jc.2015-2696
  26. Petschow B, Dore J, Hibbert P, et al. Probiotics, prebiotics, and the host microbiome: the science of translation. Ann NY Acad Sci 2013; 1306:1–17. doi:10.1111/nyas.12303
  27. Tasian GE, Jemielita T, Goldfarb DS, et al. Oral antibiotic exposure and kidney stone disease. J Am Soc Nephrol 2018; 29(6):1731–1740. doi:10.1681/ASN.2017111213
  28. Zimmerman DR. Role of subtherapeutic levels of antimicrobials in pig production. J Anim Sci 1986; 62(suppl 3):6–16.
  29. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413):621–626. doi:10.1038/nature11400
  30. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158(4):705–721. doi:10.1016/j.cell.2014.05.052
  31. Nobel YR, Cox LM, Kirigin FF, et al. Metabolic and metagenomics outcomes from early-life pulsed antibiotic treatment. Nat Commun 2015; 6:7486. doi:10.1038/ncomms8486
  32. Ruiz VE, Battaglia T, Kurtz ZD, et al. A single early-in-life macrolide course has lasting effects on murine microbial network topology and immunity. Nat Commun 2017; 8(1):518. doi:10.1038/s41467-017-00531-6
  33. Livanos AE, Greiner TU, Vangay P, et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol 2016; 1(11):16149. doi:10.1038/nmicrobiol.2016.140
  34. Hvilid A, Svanström H, Frish M. Antibiotic use and inflammatory bowel disease in childhood. Gut 2011; 60(1):49–54. doi:10.1136/gut.2010.219683
  35. Schulfer AF, Battaglia T, Alvarez Y, et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol 2018; 3(2):234–242. doi:10.1038/s41564-017-0075-5
  36. Srinivasan A. Antibiotic stewardship: why we must, how we can. Cleve Clin J Med 2017; 84(9):673–679. doi:10.3949/ccjm.84gr.17003
References
  1. TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study. Ann NY Acad Sci 2008; 1150:1–13. doi:10.1196/annals.1447.062
  2. El-Serag HB, Sonnenberg A. Associations between different forms of gastro-oesophageal reflux disease. Gut 1997; 41(5):594–599. pmid:9414963
  3. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006; 355(21):2226–2235. doi:10.1056/NEJMra054308
  4. Kaplan GG, Ng SC. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology 2017; 152(2):313–321. doi:10.1053/j.gastro.2016.10.020
  5. de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr 2010; 92(5):1257–1264. doi:10.3945/ajcn.2010.29786
  6. Blaser MJ. The theory of disappearing microbiota and the epidemics of chronic disease. Nat Rev Immunol 2017; 17(8):461–463. doi:10.1038/nri.2017.77
  7. Centers for Disease Control and Prevention. National Center for Health Statistics. Obesity and overweight. www.cdc.gov/nchs/fastats/obesity-overweight.htm. Accessed November 6, 2018.
  8. Centers for Disease Control and Prevention. National Center for Health Statistics. Table 59. Obesity among children and adolescents aged 2-19 years, by selected characteristics: United States, selected years 1988–1994 through 2013–2016. www.cdc.gov/nchs/data/hus/2017/059.pdf. Accessed November 6, 2018.
  9. Ochman H, Worobey M, Kuo CH, et al. Evolutionary relationships of wild hominids recapitulated by gut microbial communities. PLoS Biology 2010; 8(11):e1000546. doi:10.1371/journal.pbio.1000546
  10. Bokulich NA, Chung J, Battaglia T, et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci Trans Med 2016; 8(343):343ra82. doi:10.1126/scitranslmed.aad7121
  11. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature 2012; 486(7402):222–227. doi:10.1038/nature11053
  12. Blaser MJ. The past and future biology of the human microbiome in an age of extinctions. Cell 2018; 172(6):1173–1177. doi:10.1016/j.cell.2018.02.040
  13. Blaser MJ, Falkow S. What are the consequences of the disappearing human microbiota? Nat Rev Microbiol 2009; 7(12):887–894. doi:10.1038/nrmicro2245
  14. Urita Y, Watanabe T, Kawagoe N, et al. Role of infected grandmothers in transmission of Helicobacter pylori to children in a Japanese rural town. J Ped Child Health 2013; 49(5):394–398. doi:10.1111/jpc.12191
  15. Clemente JC, Pehrsson EC, Blaser MJ, et al. The microbiome of uncontacted Amerindians. Sci Adv 2015; 1(3). Pii:e1500183. doi:10.1126/sciadv.1500183
  16. Smits SA, Leach J, Sonnenburg ED, et al. Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania. Science 2017; 357(6353):802-806. doi:10.1126/science.aan4834
  17. Vangay P, Johnson AJ, Ward TL, et al. US immigration westernizes the human gut microbiome. Cell 2018; 175(4):962–972. doi:10.1016/j.cell.2018.10.029
  18. Van Broeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14(8):742–750. doi:10.1016/S1473-3099(14)70780-7
  19. Hicks LA, Bartoces MG, Roberts RM, et al. US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin Infect Dis 2015; 60(9):1308–1316. doi:10.1093/cid/civ076
  20. Rogawski ET, Platts-Mills JA, Seidman JC, et al. Use of antibiotics in children younger than two years in eight countries: a prospective cohort study. Bull World Health Organ 2017; 95(1):49–61. doi:10.2471/BLT.16.176123
  21. Hicks LA, Taylor TH Jr, Hunkler RJ. U.S. outpatient antibiotic prescribing, 2010; N Engl J Med 2013; 368(15):1461–1462. doi:10.1056/NEJMc1212055
  22. Gerber JS, Prasad PA, Russell LA, et al. Variation in antibiotic prescribing across a pediatric primary care network. J Pediatric Infect Dis Soc 2015; 4(4):297–304. doi:10.1093/jpids/piu086
  23. Jones BE, Sauer B, Jones MM, et al. Variation in outpatient antibiotic prescribing for acute respiratory infections in the veteran population: a cross-sectional study. Ann Intern Med 2015; 163(2):73–80. doi:10.7326/M14-1933
  24. Ternhag A, Hellman J. More on U.S. outpatient antibiotic prescribing, 2010. N Engl J Med 2013; 369(12):1175. doi:10.1056/NEJMc1306863
  25. Mikkelsen KH, Knop FK, Frost M, Hallas J, Pottegard A. Use of antibiotics and risk of type 2 diabetes: a population-based case-control study. J Clin Endocrinol Metab 2015; 100(10):3633–3640. doi:10.1210/jc.2015-2696
  26. Petschow B, Dore J, Hibbert P, et al. Probiotics, prebiotics, and the host microbiome: the science of translation. Ann NY Acad Sci 2013; 1306:1–17. doi:10.1111/nyas.12303
  27. Tasian GE, Jemielita T, Goldfarb DS, et al. Oral antibiotic exposure and kidney stone disease. J Am Soc Nephrol 2018; 29(6):1731–1740. doi:10.1681/ASN.2017111213
  28. Zimmerman DR. Role of subtherapeutic levels of antimicrobials in pig production. J Anim Sci 1986; 62(suppl 3):6–16.
  29. Cho I, Yamanishi S, Cox L, et al. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413):621–626. doi:10.1038/nature11400
  30. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014; 158(4):705–721. doi:10.1016/j.cell.2014.05.052
  31. Nobel YR, Cox LM, Kirigin FF, et al. Metabolic and metagenomics outcomes from early-life pulsed antibiotic treatment. Nat Commun 2015; 6:7486. doi:10.1038/ncomms8486
  32. Ruiz VE, Battaglia T, Kurtz ZD, et al. A single early-in-life macrolide course has lasting effects on murine microbial network topology and immunity. Nat Commun 2017; 8(1):518. doi:10.1038/s41467-017-00531-6
  33. Livanos AE, Greiner TU, Vangay P, et al. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol 2016; 1(11):16149. doi:10.1038/nmicrobiol.2016.140
  34. Hvilid A, Svanström H, Frish M. Antibiotic use and inflammatory bowel disease in childhood. Gut 2011; 60(1):49–54. doi:10.1136/gut.2010.219683
  35. Schulfer AF, Battaglia T, Alvarez Y, et al. Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice. Nat Microbiol 2018; 3(2):234–242. doi:10.1038/s41564-017-0075-5
  36. Srinivasan A. Antibiotic stewardship: why we must, how we can. Cleve Clin J Med 2017; 84(9):673–679. doi:10.3949/ccjm.84gr.17003
Issue
Cleveland Clinic Journal of Medicine - 85(12)
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Cleveland Clinic Journal of Medicine - 85(12)
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928-930
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928-930
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Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
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Cleveland Clinic Journal of Medicine
Type 2 Diabetes ICYMI
Topics
Infectious Diseases
Obesity
Gastroenterology
Diabetes
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Our missing microbes: Short-term antibiotic courses have long-term consequences
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Our missing microbes: Short-term antibiotic courses have long-term consequences
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microbiome, gut bacteria, obesity, diabetes, microbial diversity, antibiotics, fecal transplant, Martin Blaser
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microbiome, gut bacteria, obesity, diabetes, microbial diversity, antibiotics, fecal transplant, Martin Blaser
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