Fire in the Forest: Adverse Effects of Antibiotics on the Healthy Human Gut Microbiome

Document Type : Narrative Review

Authors

1 School of Dentistry and Oral Health, Griffith University, Queensland, Australia

2 Preventive Oral Health Unit, The National Dental Hospital (Teaching), Colombo, Sri Lanka

Abstract

Antimicrobial resistance, especially the emergence of multidrug-resistant human pathogens, remains a serious public health crisis across the globe. The human gut microbiome regulates essential human functions including digestion, energy metabolism, brain function, and immunity by modulating multiple endocrine, neural, and immune pathways of the host. Increasing evidence shows adverse effects of antibiotics on the community structure and functions of healthy gut microbiomes. Short-term antibiotic treatment is able to change the richness and diversity of species into a long-term dysbiotic state. The colonization of invading pathogens is encouraged because of decreased competitive exclusion. Furthermore, the accumulation of antimicrobial resistant genes in the gut microbiome (gut resistome) facilitates the emergence of multidrug-resistant nosocomial pathogens. In this study, the adverse effects of antibiotics on the gut microbiome are highlighted in terms of dysbiosis and the accumulation of resistance genes. In light of evidence of such adverse impacts, several epidemiological studies have been conducted on traditional culture techniques and 16S rRNA metagenomics to assess the compositional and functional changes occurring in the gut microbiome after exposure to antibiotics. They have failed to agree on specific antibiotic-associated microbiome and its functional redundancy subsequent to exposure to antibiotics. This mini-review describes the composition and role of a healthy microbiome to understand and appraise the value of gut microbiome and summarizes the current understanding of adverse effects of antibiotics on it.

Keywords


  1. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449(7164):804-810. doi:10.1038/nature06244.
  2. Parahitiyawa NB, Scully C, Leung WK, Yam WC, Jin LJ, Samaranayake LP. Exploring the oral bacterial flora: current status and future directions. Oral Dis. 2010;16(2):136-145. doi:10.1111/j.1601-0825.2009.01607.x.
  3. Ling Z, Kong J, Jia P, et al. Analysis of oral microbiota in children with dental caries by PCR-DGGE and barcoded pyrosequencing. Microb Ecol. 2010;60(3):677-690. doi:10.1007/s00248-010-9712-8.
  4. Kilian M, Chapple IL, Hannig M, et al. The oral microbiome - an update for oral healthcare professionals. Br Dent J. 2016;221(10):657-666. doi:10.1038/sj.bdj.2016.865.
  5. Sonnenburg JL, Fischbach MA. Community health care: therapeutic opportunities in the human microbiome. Sci Transl Med. 2011;3(78):78ps12. doi:10.1126/scitranslmed.3001626.
  6. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207-214. doi:10.1038/nature11234.
  7. Huse SM, Ye Y, Zhou Y, Fodor AA. A core human microbiome as viewed through 16S rRNA sequence clusters. PLoS One. 2012;7(6):e34242. doi:10.1371/journal.pone.0034242.
  8. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. doi:10.1042/BCJ20160510.
  9. van Schaik W. The human gut resistome. Philos Trans R Soc Lond B Biol Sci. 2015;370(1670):20140087. doi:10.1098/rstb.2014.0087.
  10. Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016;352(6285):539-544. doi:10.1126/science.aad9378.
  11. Francino MP. Early development of the gut microbiota and immune health. Pathogens. 2014;3(3):769-790. doi:10.3390/pathogens3030769.
  12. Francino MP. Antibiotics and the human gut microbiome: dysbioses and accumulation of resistances. Front Microbiol. 2015;6:1543. doi:10.3389/fmicb.2015.01543.
  13. Kinch MS, Patridge E, Plummer M, Hoyer D. An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Drug Discov Today. 2014;19(9):1283-1287. doi:10.1016/j.drudis.2014.07.005.
  14. O’Neill J. Antimicrobial resistance: tackling a crisis for the health and wealth of nations. The Review on Antimicrobial Resistance. 2014. https://amr-review.org/sites/default/files/AMR%20 Review%20Paper%20-%20Tackling%20a%20crisis%20for%20 the%20health%20and%20wealth%20of%20nations_1.pdf.
  15. Franzosa EA, Hsu T, Sirota-Madi A, et al. Sequencing and beyond: integrating molecular ‘omics’ for microbial community profiling. Nat Rev Microbiol. 2015;13(6):360-372. doi:10.1038/nrmicro3451.
  16. Moore WE, Holdeman LV. Human fecal flora: the normal flora of 20 Japanese-Hawaiians. Appl Microbiol. 1974;27(5):961-979.
  17. Suau A, Bonnet R, Sutren M, et al. Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl Environ Microbiol. 1999;65(11):4799-4807.
  18. Poretsky R, Rodriguez RL, Luo C, Tsementzi D, Konstantinidis KT. Strengths and limitations of 16S rRNA gene amplicon sequencing in revealing temporal microbial community dynamics. PLoS One. 2014;9(4):e93827. doi:10.1371/journal.pone.0093827.
  19. Mizrahi-Man O, Davenport ER, Gilad Y. Taxonomic classification of bacterial 16S rRNA genes using short sequencing reads: evaluation of effective study designs. PLoS One. 2013;8(1):e53608. doi:10.1371/journal.pone.0053608.
  20. Hugon P, Dufour JC, Colson P, Fournier PE, Sallah K, Raoult D. A comprehensive repertoire of prokaryotic species identified in human beings. Lancet Infect Dis. 2015;15(10):1211-1219. doi:10.1016/S1473-3099(15)00293-5.
  21. Li J, Jia H, Cai X, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol. 2014;32(8):834-841. doi:10.1038/nbt.2942.
  22. Rajilic-Stojanovic M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev. 2014;38(5):996-1047. doi:10.1111/1574-6976.12075.
  23. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104-107. doi:10.1038/nature08780.
  24. Tyakht AV, Kostryukova ES, Popenko AS, et al. Human gut microbiota community structures in urban and rural populations in Russia. Nat Commun. 2013;4:2469. doi:10.1038/ncomms3469.
  25. Jackson MA, Bonder MJ, Kuncheva Z, et al. Detection of stable community structures within gut microbiota co-occurrence networks from different human populations. PeerJ. 2018;6:e4303. doi:10.7717/peerj.4303.
  26. Moya A, Ferrer M. Functional Redundancy-Induced Stability of Gut Microbiota Subjected to Disturbance. Trends Microbiol. 2016;24(5):402-413. doi:10.1016/j.tim.2016.02.002.
  27. Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011;108 Suppl 1:4554- 4561. doi:10.1073/pnas.1000087107.
  28. Perera M, Al-Hebshi NN, Perera I, et al. Inflammatory bacteriome and oral squamous cell carcinoma. J Dent Res. 2018;97(6):725- 732. doi:10.1177/0022034518767118.
  29. Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut. 2006;55(2):205-211. doi:10.1136/gut.2005.073817.
  30. Kassinen A, Krogius-Kurikka L, Makivuokko H, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. 2007;133(1):24- 33. doi:10.1053/j.gastro.2007.04.005.
  31. Scanlan PD, Shanahan F, Clune Y, et al. Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis. Environ Microbiol. 2008;10(3):789-798. doi:10.1111/j.1462-2920.2007.01503.x.
  32. Young VB, Schmidt TM. Antibiotic-associated diarrhea accompanied by large-scale alterations in the composition of the fecal microbiota. J Clin Microbiol. 2004;42(3):1203-1206. doi:10.1128/JCM.42.3.1203-1206.2004.
  33. Greenblum S, Turnbaugh PJ, Borenstein E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci U S A. 2012;109(2):594-599. doi:10.1073/pnas.1116053109.
  34. Musso G, Gambino R, Cassader M. Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care. 2010;33(10):2277-2284. doi:10.2337/dc10-0556.
  35. Marchesi JR, Adams DH, Fava F, et al. The gut microbiota and host health: a new clinical frontier. Gut. 2016;65(2):330-339. doi:10.1136/gutjnl-2015-309990.
  36. Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047-3052. doi:10.1073/pnas.1010529108.
  37. Natividad JM, Verdu EF. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. Pharmacol Res. 2013;69(1):42-51. doi:10.1016/j.phrs.2012.10.007.
  38. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54(9):2325-2340. doi:10.1194/jlr.R036012.
  39. Tomkovich S, Jobin C. Microbiota and host immune responses: a love-hate relationship. Immunology. 2016;147(1):1-10. doi:10.1111/imm.12538.
  40. Rowland I, Gibson G, Heinken A, et al. Gut microbiota functions: metabolism of nutrients and other food components. Eur J Nutr. 2018;57(1):1-24. doi:10.1007/s00394-017-1445-8.
  41. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12(10):661-672. doi:10.1038/nrmicro3344.
  42. Louis P, Scott KP, Duncan SH, Flint HJ. Understanding the effects of diet on bacterial metabolism in the large intestine. J Appl Microbiol. 2007;102(5):1197-1208. doi:10.1111/j.1365-2672.2007.03322.x.
  43. Louis P, Flint HJ. Formation of propionate and butyrate by the human colonic microbiota. Environ Microbiol. 2017;19(1):29-41. doi:10.1111/1462-2920.13589.
  44. Derrien M, Vaughan EE, Plugge CM, de Vos WM. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004;54(Pt 5):1469-1476. doi:10.1099/ijs.0.02873-0.
  45. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016;7(3):189-200. doi:10.1080/19490976.2015.113 4082.
  46. Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol. 2017;18(1):2. doi:10.1186/s12865-016-0187-3.
  47. Correa-Oliveira R, Fachi JL, Vieira A, Sato FT, Vinolo MA. Regulation of immune cell function by short-chain fatty acids. Clin Transl Immunology. 2016;5(4):e73. doi:10.1038/cti.2016.17.
  48. Nagai M, Obata Y, Takahashi D, Hase K. Fine-tuning of the mucosal barrier and metabolic systems using the diet-microbial metabolite axis. Int Immunopharmacol. 2016;37:79-86. doi:10.1016/j.intimp.2016.04.001.
  49. LeBlanc JG, Milani C, de Giori GS, Sesma F, van Sinderen D, Ventura M. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr Opin Biotechnol. 2013;24(2):160- 168. doi:10.1016/j.copbio.2012.08.005.
  50. Martens JH, Barg H, Warren MJ, Jahn D. Microbial production of vitamin B12. Appl Microbiol Biotechnol. 2002;58(3):275-285. doi:10.1007/s00253-001-0902-7.
  51. Pompei A, Cordisco L, Amaretti A, Zanoni S, Matteuzzi D, Rossi M. Folate production by bifidobacteria as a potential probiotic property. Appl Environ Microbiol. 2007;73(1):179-185. doi:10.1128/AEM.01763-06.
  52. Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev. 1997;6 Suppl 1:S43-45. doi:10.1097/00008469-199703001-00009.
  53. Staley C, Weingarden AR, Khoruts A, Sadowsky MJ. Interaction of gut microbiota with bile acid metabolism and its influence on disease states. Appl Microbiol Biotechnol. 2017;101(1):47-64. doi:10.1007/s00253-016-8006-6.
  54. Palau-Rodriguez M, Tulipani S, Isabel Queipo-Ortuno M, Urpi- Sarda M, Tinahones FJ, Andres-Lacueva C. Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes. Front Microbiol. 2015;6:1151. doi:10.3389/fmicb.2015.01151.
  55. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122(1):107- 118. doi:10.1016/j.cell.2005.05.007.
  56. Schnupf P, Gaboriau-Routhiau V, Gros M, et al. Growth and host interaction of mouse segmented filamentous bacteria in vitro. Nature. 2015;520(7545):99-103. doi:10.1038/nature14027.
  57. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066- 9071. doi:10.1073/pnas.1219451110.
  58. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. Low relative abundances of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. in feces of children with autism. Appl Environ Microbiol. 2011;77(18):6718- 6721. doi:10.1128/AEM.05212-11.
  59. Sokol H, Seksik P, Furet JP, et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009;15(8):1183-1189. doi:10.1002/ibd.20903.
  60. Quevrain E, Maubert MA, Michon C, et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut. 2016;65(3):415-425. doi:10.1136/gutjnl-2014-307649.
  61.  Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol. 2007;19(2):59-69. doi:10.1016/j.smim.2006.10.002.
  62. Reunanen J, Kainulainen V, Huuskonen L, et al. Akkermansia muciniphila Adheres to Enterocytes and Strengthens the Integrity of the Epithelial Cell Layer. Appl Environ Microbiol. 2015;81(11):3655-3662. doi:10.1128/AEM.04050-14.
  63. Chen HQ, Yang J, Zhang M, et al. Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL-10 knockout mice. Am J Physiol Gastrointest Liver Physiol. 2010;299(6):G1287-1297. doi:10.1152/ajpgi.00196.2010.
  64. Petersson J, Schreiber O, Hansson GC, et al. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol. 2011;300(2):G327- 333. doi:10.1152/ajpgi.00422.2010.
  65. Freitas M, Cayuela C, Antoine JM, Piller F, Sapin C, Trugnan G. A heat labile soluble factor from Bacteroides thetaiotaomicron VPI- 5482 specifically increases the galactosylation pattern of HT29- MTX cells. Cell Microbiol. 2001;3(5):289-300. doi:10.1046/j.1462-5822.2001.00113.x.
  66. Baumler AJ, Sperandio V. Interactions between the microbiota and pathogenic bacteria in the gut. Nature. 2016;535(7610):85-93. doi:10.1038/nature18849.
  67. Mandal S, Mishra S, Mandal PK. Microbiome and Antimicrobial Resistance: A Mini Review. J Biotechnol Bioeng. 2017;1(1):14-16.
  68. Hawkey PM. The growing burden of antimicrobial resistance. J Antimicrob Chemother. 2008;62 Suppl 1:i1-9. doi:10.1093/jac/dkn241.
  69. Hegarty JW, Guinane CM, Ross RP, Hill C, Cotter PD. Bacteriocin production: a relatively unharnessed probiotic trait? F1000Res. 2016;5:2587. doi:10.12688/f1000research.9615.1.
  70. Aminov RI. The role of antibiotics and antibiotic resistance in nature. Environ Microbiol. 2009;11(12):2970-2988. doi:10.1111/j.1462-2920.2009.01972.x.
  71. Martinez JL. Antibiotics and antibiotic resistance genes in natural environments. Science. 2008;321(5887):365-367. doi:10.1126/science.1159483.
  72. Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J. Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol. 2010;8(4):251-259. doi:10.1038/nrmicro2312.
  73. Martinez JL. General principles of antibiotic resistance in bacteria. Drug Discov Today Technol. 2014;11:33-39. doi:10.1016/j.ddtec.2014.02.001.
  74. Hall BG, Barlow M. Evolution of the serine beta-lactamases: past, present and future. Drug Resist Updat. 2004;7(2):111-123. doi:10.1016/j.drup.2004.02.003.
  75. Relman DA. The human microbiome: ecosystem resilience and health. Nutr Rev. 2012;70 Suppl 1:S2-9. doi:10.1111/j.1753-4887.2012.00489.x.
  76. Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6(11):e280. doi:10.1371/journal.pbio.0060280.
  77. Ubeda C, Taur Y, Jenq RR, et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest. 2010;120(12):4332-4341. doi:10.1172/JCI43918.
  78. Madan JC, Salari RC, Saxena D, et al. Gut microbial colonisation in premature neonates predicts neonatal sepsis. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F456-462. doi:10.1136/fetalneonatal-2011-301373.
  79. Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term ecological impacts of antibiotic administration on the human intestinal microbiota. Isme j. 2007;1(1):56-66. doi:10.1038/ismej.2007.3.
  80. Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010;156(Pt 11):3216-3223. doi:10.1099/mic.0.040618-0.
  81. Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One. 2010;5(3):e9836. doi:10.1371/journal.pone.0009836.
  82. Perez-Cobas AE, Gosalbes MJ, Friedrichs A, et al. Gut microbiota disturbance during antibiotic therapy: a multi-omic approach. Gut. 2013;62(11):1591-1601. doi:10.1136/gutjnl-2012-303184.
  83. Ferreyra JA, Wu KJ, Hryckowian AJ, Bouley DM, Weimer BC, Sonnenburg JL. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe. 2014;16(6):770-777. doi:10.1016/j. chom.2014.11.003.
  84. Ng KM, Ferreyra JA, Higginbottom SK, et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature. 2013;502(7469):96-99. doi:10.1038/nature12503.
  85. Hernandez E, Bargiela R, Diez MS, et al. Functional consequences of microbial shifts in the human gastrointestinal tract linked to antibiotic treatment and obesity. Gut Microbes. 2013;4(4):306- 315. doi:10.4161/gmic.25321.
  86. Song HJ, Shim KN, Jung SA, et al. Antibiotic-associated diarrhea: candidate organisms other than Clostridium difficile. Korean J Intern Med. 2008;23(1):9-15. doi:10.3904/kjim.2008.23.1.9.
  87. Vincent JL. Nosocomial infections in adult intensive-care units. Lancet. 2003;361(9374):2068-2077. doi:10.1016/S0140-6736(03)13644-6.
  88. Rice LB. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis. 2008;197(8):1079- 1081. doi:10.1086/533452.
  89. Card RM, Warburton PJ, MacLaren N, Mullany P, Allan E, Anjum MF. Application of microarray and functional-based screening methods for the detection of antimicrobial resistance genes in the microbiomes of healthy humans. PLoS One. 2014;9(1):e86428. doi:10.1371/journal.pone.0086428.
  90. Field W, Hershberg R. Alarmingly high segregation frequencies of quinolone resistance alleles within human and animal microbiomes are not explained by direct clinical antibiotic exposure. Genome Biol Evol. 2015;7(6):1743-1757. doi:10.1093/gbe/evv102.
  91. Forslund K, Sunagawa S, Kultima JR, et al. Country-specific antibiotic use practices impact the human gut resistome. Genome Res. 2013;23(7):1163-1169. doi:10.1101/gr.155465.113.
  92. Hu Y, Yang X, Qin J, et al. Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota. Nat Commun. 2013;4:2151. doi:10.1038/ncomms3151.
  93. de Vries LE, Valles Y, Agerso Y, et al. The gut as reservoir of antibiotic resistance: microbial diversity of tetracycline resistance in mother and infant. PLoS One. 2011;6(6):e21644. doi:10.1371/journal.pone.0021644.
  94. Sommer MOA, Dantas G, Church GM. Functional characterization of the antibiotic resistance reservoir in the human microflora. Science. 2009;325(5944):1128-1131. doi:10.1126/science.1176950.
  95. Buelow E, Gonzalez TB, Versluis D, et al. Effects of selective digestive decontamination (SDD) on the gut resistome. J Antimicrob Chemother. 2014;69(8):2215-2223. doi:10.1093/jac/dku092.
  96. Perez-Cobas AE, Artacho A, Knecht H, et al. Differential effects of antibiotic therapy on the structure and function of human gut microbiota. PLoS One. 2013;8(11):e80201. doi:10.1371/journal.pone.0080201.
  97. Ghosh TS, Gupta SS, Nair GB, Mande SS. In silico analysis of antibiotic resistance genes in the gut microflora of individuals from diverse geographies and age-groups. PLoS One. 2013;8(12):e83823. doi:10.1371/journal.pone.0083823.
  98. Shoemaker NB, Vlamakis H, Hayes K, Salyers AA. Evidence for extensive resistance gene transfer among Bacteroides spp. and among Bacteroides and other genera in the human colon. Appl Environ Microbiol. 2001;67(2):561-568. doi:10.1128/AEM.67.2.561-568.2001.
  99. Bahl MI, Sorensen SJ, Hansen LH, Licht TR. Effect of tetracycline on transfer and establishment of the tetracycline-inducible conjugative transposon Tn916 in the guts of gnotobiotic rats. Appl Environ Microbiol. 2004;70(2):758-764. doi:10.1128/AEM.70.2.758-764.2004.
  100. Alpert CA, Mater DD, Muller MC, Ouriet MF, Duval-Iflah Y, Corthier G. Worst-case scenarios for horizontal gene transfer from Lactococcus lactis carrying heterologous genes to Enterococcus faecalis in the digestive tract of gnotobiotic mice. Environ Biosafety Res. 2003;2(3):173-180. doi:10.1051/ebr:2003010.
  101. Whittle G, Shoemaker NB, Salyers AA. The role of Bacteroides conjugative transposons in the dissemination of antibiotic resistance genes. Cell Mol Life Sci. 2002;59(12):2044-2054. doi:10.1007/s000180200004.
  102. Furuya EY, Lowy FD. Antimicrobial-resistant bacteria in the community setting. Nat Rev Microbiol. 2006;4(1):36-45. doi:10.1038/nrmicro1325.
  103. Nordgard L, Brusetti L, Raddadi N, Traavik T, Averhoff B, Nielsen KM. An investigation of horizontal transfer of feed introduced DNA to the aerobic microbiota of the gastrointestinal tract of rats. BMC Res Notes. 2012;5:170. doi:10.1186/1756-0500-5-170.
  104. Aagaard K, Petrosino J, Keitel W, et al. The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters. FASEB J. 2013;27(3):1012-1022. doi:10.1096/fj.12-220806.