Metagenomic insights into the human gut resistome and the forces that shape it.

We show how metagenomic analysis of the human gut antibiotic resistome, compared across large populations and against environmental or agricultural resistomes, suggests a strong anthropogenic cause behind increasing antibiotic resistance in bacteria. This area has been the subject of intense and polarized debate driven by economic and political concerns; therefore such recently available insights address an important need. We derive and compare antibiotic resistomes of human gut microbes from 832 individuals from ten different countries. We observe and describe significant differences between samples from these countries in the gut resistance potential, in line with expectations from antibiotic usage and exposure in medical and food production contexts. Our results imply roles for both of these sources in increased resistance among pathogens in recent history. In contrast, other available metadata such as age, body mass index, sex, or health status have little effect on the antibiotic resistance potential of human gut microbes. Also watch the Video Abstract.

[1]  F. Song,et al.  A systematic review of antibiotic utilization in China. , 2013, The Journal of antimicrobial chemotherapy.

[2]  P. Gastmeier,et al.  Antibiotic consumption and resistance: data from Europe and Germany. , 2013, International journal of medical microbiology : IJMM.

[3]  Jian Wang,et al.  Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota , 2013, Nature Communications.

[4]  Peer Bork,et al.  Country-specific antibiotic use practices impact the human gut resistome , 2013, Genome research.

[5]  C. Saegerman,et al.  Antimicrobial Resistance in the Food Chain: A Review , 2013, International journal of environmental research and public health.

[6]  Fredrik H. Karlsson,et al.  Gut metagenome in European women with normal, impaired and diabetic glucose control , 2013, Nature.

[7]  J. Collins,et al.  Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome , 2013, Nature.

[8]  Gautam Dantas,et al.  Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs , 2013, Front. Microbiol..

[9]  Teresa M. Coque,et al.  Antibiotic resistance shaping multi-level population biology of bacteria , 2013, Front. Microbiol..

[10]  N. Benomar,et al.  Phenotypic and molecular antibiotic resistance profile of Enterococcus faecalis and Enterococcus faecium isolated from different traditional fermented foods. , 2013, Foodborne pathogens and disease.

[11]  Timothy A. Johnson,et al.  Diverse and abundant antibiotic resistance genes in Chinese swine farms , 2013, Proceedings of the National Academy of Sciences.

[12]  Songnian Hu,et al.  Marine Sediment Bacteria Harbor Antibiotic Resistance Genes Highly Similar to Those Found in Human Pathogens , 2013, Microbial Ecology.

[13]  Paul D. Cotter,et al.  Nucleic acid-based approaches to investigate microbial-related cheese quality defects , 2012, Front. Microbio..

[14]  J. Jansson,et al.  Long-term ecological impacts of antibiotic administration on the human intestinal microbiota , 2013, The ISME Journal.

[15]  J. Carlet The gut is the epicentre of antibiotic resistance , 2012, Antimicrobial Resistance and Infection Control.

[16]  Lisa M. Durso,et al.  Distribution and Quantification of Antibiotic Resistant Genes and Bacteria across Agricultural and Non-Agricultural Metagenomes , 2012, PloS one.

[17]  Yongfei Hu,et al.  Functional screening of antibiotic resistance genes from human gut microbiota reveals a novel gene fusion. , 2012, FEMS microbiology letters.

[18]  Mazdak Arabi,et al.  Correlation between upstream human activities and riverine antibiotic resistance genes. , 2012, Environmental science & technology.

[19]  Qiang Feng,et al.  A metagenome-wide association study of gut microbiota in type 2 diabetes , 2012, Nature.

[20]  M. Sommer,et al.  Context matters - the complex interplay between resistome genotypes and resistance phenotypes. , 2012, Current opinion in microbiology.

[21]  Otto X. Cordero,et al.  Ecological Populations of Bacteria Act as Socially Cohesive Units of Antibiotic Production and Resistance , 2012, Science.

[22]  D. Sinderen,et al.  Gut microbiota composition correlates with diet and health in the elderly , 2012, Nature.

[23]  F. Aarestrup Sustainable farming: Get pigs off antibiotics , 2012, Nature.

[24]  Katherine H. Huang,et al.  Structure, Function and Diversity of the Healthy Human Microbiome , 2012, Nature.

[25]  Andrew C. Pawlowski,et al.  Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome , 2012, PloS one.

[26]  M. Borg National cultural dimensions as drivers of inappropriate ambulatory care consumption of antibiotics in Europe and their relevance to awareness campaigns. , 2012, The Journal of antimicrobial chemotherapy.

[27]  Robert D. Stedtfeld,et al.  In-feed antibiotic effects on the swine intestinal microbiome , 2012, Proceedings of the National Academy of Sciences.

[28]  Kelly M. McGarvey,et al.  Wide Variation in Antibiotic Resistance Proteins Identified by Functional Metagenomic Screening of a Soil DNA Library , 2012, Applied and Environmental Microbiology.

[29]  J. Martínez,et al.  Bottlenecks in the Transferability of Antibiotic Resistance from Natural Ecosystems to Human Bacterial Pathogens , 2011, Front. Microbio..

[30]  J. E. Rogers,et al.  The Shared Antibiotic Resistome of Soil Bacteria and Human Pathogens , 2012 .

[31]  Otto X. Cordero,et al.  Ecology drives a global network of gene exchange connecting the human microbiome , 2011, Nature.

[32]  Heather K. Allen,et al.  Antibiotics in Feed Induce Prophages in Swine Fecal Microbiomes , 2011, mBio.

[33]  J. Martiny,et al.  Functional Metagenomics Reveals Previously Unrecognized Diversity of Antibiotic Resistance Genes in Gulls , 2011, Front. Microbio..

[34]  S. Levy,et al.  Food Animals and Antimicrobials: Impacts on Human Health , 2011, Clinical Microbiology Reviews.

[35]  G. B. Golding,et al.  Antibiotic resistance is ancient , 2011, Nature.

[36]  Michael R Gillings,et al.  Gene flow, mobile genetic elements and the recruitment of antibiotic resistance genes into Gram-negative pathogens. , 2011, FEMS microbiology reviews.

[37]  T. Stanton,et al.  Chlortetracycline-Resistant Intestinal Bacteria in Organically Raised and Feral Swine , 2011, Applied and Environmental Microbiology.

[38]  Maite Muniesa,et al.  Bacteriophages Carrying Antibiotic Resistance Genes in Fecal Waste from Cattle, Pigs, and Poultry , 2011, Antimicrobial Agents and Chemotherapy.

[39]  H. Goossens,et al.  Society's failure to protect a precious resource: antibiotics , 2011, The Lancet.

[40]  J. Kuehl,et al.  The Gut as Reservoir of Antibiotic Resistance: Microbial Diversity of Tetracycline Resistance in Mother and Infant , 2011, PloS one.

[41]  Heike Schmitt,et al.  Antibiotic resistance gene spread due to manure application on agricultural fields. , 2011, Current opinion in microbiology.

[42]  R. Aminov Horizontal Gene Exchange in Environmental Microbiota , 2011, Front. Microbio..

[43]  G. Perozzi,et al.  Antibiotic resistance determinants in the interplay between food and gut microbiota , 2011, Genes & Nutrition.

[44]  K. Yuen,et al.  Extensive dissemination of CTX-M-producing Escherichia coli with multidrug resistance to 'critically important' antibiotics among food animals in Hong Kong, 2008-10. , 2011, The Journal of antimicrobial chemotherapy.

[45]  S. Oliver,et al.  Impact of antibiotic use in adult dairy cows on antimicrobial resistance of veterinary and human pathogens: a comprehensive review. , 2011, Foodborne pathogens and disease.

[46]  E. Kristiansson,et al.  Pyrosequencing of Antibiotic-Contaminated River Sediments Reveals High Levels of Resistance and Gene Transfer Elements , 2011, PloS one.

[47]  Charles W. Knapp,et al.  Antibiotic Resistance Gene Abundances Associated with Waste Discharges to the Almendares River near Havana, Cuba , 2010, Environmental science & technology.

[48]  J. Sofos,et al.  Characterization and transferability of class 1 integrons in commensal bacteria isolated from farm and nonfarm environments. , 2010, Foodborne pathogens and disease.

[49]  Cecilia Jernberg,et al.  Long-term impacts of antibiotic exposure on the human intestinal microbiota. , 2010, Microbiology.

[50]  Yong-guan Zhu,et al.  Abundance and diversity of tetracycline resistance genes in soils adjacent to representative swine feedlots in China. , 2010, Environmental science & technology.

[51]  D. Mackay,et al.  Comparison of the sales of veterinary antibacterial agents between 10 European countries. , 2010, The Journal of antimicrobial chemotherapy.

[52]  J. Steurer [Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients]. , 2010, Praxis.

[53]  A. So,et al.  Tackling antibiotic resistance , 2010, BMJ : British Medical Journal.

[54]  Alastair D Hay,et al.  Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis , 2010, BMJ : British Medical Journal.

[55]  Heather K. Allen,et al.  Call of the wild: antibiotic resistance genes in natural environments , 2010, Nature Reviews Microbiology.

[56]  Anders F. Andersson,et al.  Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome , 2010, PloS one.

[57]  P. Bork,et al.  A human gut microbial gene catalogue established by metagenomic sequencing , 2010, Nature.

[58]  A. Brisabois,et al.  Organic and conventional fruits and vegetables contain equivalent counts of Gram-negative bacteria expressing resistance to antibacterial agents. , 2010, Environmental microbiology.

[59]  Charles W. Knapp,et al.  Evidence of increasing antibiotic resistance gene abundances in archived soils since 1940. , 2010, Environmental science & technology.

[60]  J. Davies,et al.  Origins and Evolution of Antibiotic Resistance , 1996, Microbiology and Molecular Biology Reviews.

[61]  I. Karunasagar,et al.  Human health consequences of use of antimicrobial agents in aquaculture. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[62]  P. Stone,et al.  Economic burden of healthcare-associated infections: an American perspective , 2009, Expert review of pharmacoeconomics & outcomes research.

[63]  M. Quail,et al.  Distribution of tetracycline and erythromycin resistance genes among human oral and fecal metagenomic DNA. , 2009, Microbial drug resistance.

[64]  G. Church,et al.  Functional Characterization of the Antibiotic Resistance Reservoir in the Human Microflora , 2009, Science.

[65]  Alfred Pühler,et al.  Detection of 140 clinically relevant antibiotic-resistance genes in the plasmid metagenome of wastewater treatment plant bacteria showing reduced susceptibility to selected antibiotics. , 2009, Microbiology.

[66]  F. Aarestrup,et al.  World Health Organization ranking of antimicrobials according to their importance in human medicine: A critical step for developing risk management strategies for the use of antimicrobials in food production animals. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[67]  A. Rajić,et al.  Associations between reported on-farm antimicrobial use practices and observed antimicrobial resistance in generic fecal Escherichia coli isolated from Alberta finishing swine farms. , 2009, Preventive veterinary medicine.

[68]  E. Gotuzzo,et al.  Antibiotic resistance in a very remote Amazonas community. , 2009, International journal of antimicrobial agents.

[69]  Heather K. Allen,et al.  Functional metagenomics reveals diverse β-lactamases in a remote Alaskan soil , 2009, The ISME Journal.

[70]  Karen P. Scott,et al.  Tetracycline Resistome of the Organic Pig Gut , 2009, Applied and Environmental Microbiology.

[71]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[72]  Mihai Pop,et al.  ARDB—Antibiotic Resistance Genes Database , 2008, Nucleic Acids Res..

[73]  Reflection paper on the use of third and fourth generation cephalosporins in food producing animals in the European Union: development of resistance and impact on human and animal health. , 2009, Journal of veterinary pharmacology and therapeutics.

[74]  H. Heuer,et al.  Piggery manure used for soil fertilization is a reservoir for transferable antibiotic resistance plasmids. , 2008, FEMS microbiology ecology.

[75]  R. Marre,et al.  Changes in Escherichia coli resistance patterns during and after antibiotic therapy: a longitudinal study among outpatients in Germany. , 2008, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[76]  Gerard D. Wright,et al.  Expanding the soil antibiotic resistome: exploring environmental diversity. , 2007, Current opinion in microbiology.

[77]  Keith Mitchelson,et al.  Use of a DNA Microarray for Simultaneous Detection of Antibiotic Resistance Genes among Staphylococcal Clinical Isolates , 2007, Journal of Clinical Microbiology.

[78]  Sudeshna Ghosh,et al.  The effects of subtherapeutic antibiotic use in farm animals on the proliferation and persistence of antibiotic resistance among soil bacteria , 2007, The ISME Journal.

[79]  Gerard D. Wright The antibiotic resistome: the nexus of chemical and genetic diversity , 2007, Nature Reviews Microbiology.

[80]  J. Cots,et al.  Effect of intervention promoting a reduction in antibiotic prescribing by improvement of diagnostic procedures: a prospective, before and after study in general practice , 2006, European Journal of Clinical Pharmacology.

[81]  Peter Mullany,et al.  Determining the antibiotic resistance potential of the indigenous oral microbiota of humans using a metagenomic approach. , 2006, FEMS microbiology letters.

[82]  J. Davies Are antibiotics naturally antibiotics? , 2006, Journal of Industrial Microbiology and Biotechnology.

[83]  D. Hughes,et al.  Sampling the Antibiotic Resistome , 2006, Science.

[84]  A. Sundsfjord,et al.  Prevalence, Persistence, and Molecular Characterization of Glycopeptide-Resistant Enterococci in Norwegian Poultry and Poultry Farmers 3 to 8 Years after the Ban on Avoparcin , 2006, Applied and Environmental Microbiology.

[85]  G. Barlow,et al.  Is antibiotic resistance a problem? A practical guide for hospital clinicians , 2005, Postgraduate Medical Journal.

[86]  P. Collignon,et al.  The routine use of antibiotics to promote animal growth does little to benefit protein undernutrition in the developing world. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[87]  Robert S. Dittus,et al.  Trends in antibiotic prescribing for adults in the United States—1995 to 2002 , 2005, Journal of General Internal Medicine.

[88]  J. Dibner,et al.  Antibiotic growth promoters in agriculture: history and mode of action. , 2005, Poultry science.

[89]  H. Goossens,et al.  Outpatient antibiotic use in Europe and association with resistance: a cross-national database study , 2005, The Lancet.

[90]  J. Handelsman,et al.  Uncultured soil bacteria are a reservoir of new antibiotic resistance genes. , 2004, Environmental microbiology.

[91]  J. Banfield,et al.  Community structure and metabolism through reconstruction of microbial genomes from the environment , 2004, Nature.

[92]  Ron Jones,et al.  Does the use of antibiotics in food animals pose a risk to human health? A critical review of published data. , 2003, The Journal of antimicrobial chemotherapy.

[93]  M. Teuber,et al.  Acquired antibiotic resistance in lactic acid bacteria from food , 1999, Antonie van Leeuwenhoek.

[94]  K. Carlson,et al.  Evolution of antibiotic occurrence in a river through pristine, urban and agricultural landscapes. , 2003, Water research.

[95]  H. Wegener Antibiotics in animal feed and their role in resistance development. , 2003, Current opinion in microbiology.

[96]  I. Phillips,et al.  The European ban on growth-promoting antibiotics and emerging consequences for human and animal health. , 2003, The Journal of antimicrobial chemotherapy.

[97]  S. Russell,et al.  The effect of airsacculitis on bird weights, uniformity, fecal contamination, processing errors, and populations of Campylobacter spp. and Escherichia coli. , 2003, Poultry science.

[98]  D. Pugh The EU precautionary bans of animal feed additive antibiotics. , 2002, Toxicology letters.

[99]  O. Cars,et al.  A European study on the relationship between antimicrobial use and antimicrobial resistance. , 2002, Emerging infectious diseases.

[100]  S. Levy,et al.  Carriage of antibiotic-resistant fecal bacteria in Nepal reflects proximity to Kathmandu. , 2001, The Journal of infectious diseases.

[101]  Y. Benjamini,et al.  THE CONTROL OF THE FALSE DISCOVERY RATE IN MULTIPLE TESTING UNDER DEPENDENCY , 2001 .

[102]  O. Cars,et al.  Variation in antibiotic use in the European Union , 2001, The Lancet.

[103]  H. Vlamakis,et al.  Evidence for Extensive Resistance Gene Transfer amongBacteroides spp. and among Bacteroides and Other Genera in the Human Colon , 2001, Applied and Environmental Microbiology.

[104]  H. Ochman,et al.  Long-Term Shifts in Patterns of Antibiotic Resistance in Enteric Bacteria , 2000, Applied and Environmental Microbiology.

[105]  M. Barton,et al.  Antibiotic use in animal feed and its impact on human healt , 2000, Nutrition Research Reviews.

[106]  W. Witte,et al.  Selective pressure by antibiotic use in livestock. , 2000, International journal of antimicrobial agents.

[107]  E. Stobberingh,et al.  Epidemiology of resistance to antibiotics. Links between animals and humans. , 2000, International journal of antimicrobial agents.

[108]  Michel G. Bergeron,et al.  Correlation between the Resistance Genotype Determined by Multiplex PCR Assays and the Antibiotic Susceptibility Patterns of Staphylococcus aureus andStaphylococcus epidermidis , 2000, Antimicrobial Agents and Chemotherapy.

[109]  I. Phillips The use of bacitracin as a growth promoter in animals produces no risk to human health. , 1999, The Journal of antimicrobial chemotherapy.

[110]  M. Teuber Spread of antibiotic resistance with food-borne pathogens , 1999, Cellular and Molecular Life Sciences CMLS.

[111]  P. Hjortdahl,et al.  Influence of prescription patterns in general practice on anti-microbial resistance in Norway. , 1999, The British journal of general practice : the journal of the Royal College of General Practitioners.

[112]  R. Anderson,et al.  The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[113]  E. Cundliffe How antibiotic-producing organisms avoid suicide. , 1989, Annual review of microbiology.

[114]  W. Witte,et al.  Spread of plasmid‐mediated nourseothricin resistance due to antibiotic use in animal husbandry , 1986, Journal of basic microbiology.

[115]  M. L. Cohen,et al.  Animal-to-man transmission of antimicrobial-resistant Salmonella: investigations of U.S. outbreaks, 1971-1983. , 1984, Science.

[116]  N. Datta,et al.  Conjugative plasmids in bacteria of the ‘pre-antibiotic’ era , 1983, Nature.

[117]  S. Levy,et al.  Changes in intestinal flora of farm personnel after introduction of a tetracycline-supplemented feed on a farm. , 1976, The New England journal of medicine.

[118]  J Davies,et al.  Aminoglycoside antibiotic-inactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[119]  S. Waksman,et al.  History of the word 'antibiotic'. , 1973, Journal of the history of medicine and allied sciences.