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Abstract

Among long-stay critically ill patients in the adult intensive care unit (ICU), there are often marked changes in the complexity of the gut microbiota. However, it remains unclear whether such patients might benefit from enhanced surveillance or from interventions targeting the gut microbiota or the pathogens therein. We therefore undertook a prospective observational study of 24 ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses. Two-thirds of the patients experienced a marked drop in gut microbial diversity (to an inverse Simpson’s index of <4) at some stage during their stay in the ICU, often accompanied by the absence or loss of potentially beneficial bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but the administration of other antibiotics, including piperacillin/tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three-quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission of . In some patients, we also saw an increase in the relative abundance of apparent commensal organisms in the gut microbiome, including the archaeal species . In conclusion, we have documented a dramatic absence of microbial diversity and pathogen domination of the gut microbiota in a high proportion of critically ill patients using shotgun metagenomics.

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2019-09-01
2024-03-19
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References

  1. Kim S, Covington A, Pamer EG. The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens. Immunol Rev 2017; 279:90–105 [View Article]
    [Google Scholar]
  2. Feng Q, Chen WD, Wang YD. Gut microbiota: an integral moderator in health and disease. Front Microbiol 2018; 9:151 [View Article]
    [Google Scholar]
  3. Dickson RP. The microbiome and critical illness. Lancet Respir Med 2016; 4:59–72 [View Article]
    [Google Scholar]
  4. Chang SJ, Huang HH. Diarrhea in enterally fed patients: blame the diet?. Curr Opin Clin Nutr Metab Care 2013; 16:588–594 [View Article]
    [Google Scholar]
  5. Lustri BC, Sperandio V, Moreira CG. Bacterial ChAT: intestinal metabolites and signals in host-microbiota-pathogen interactions. Infect Immun 2017; 85: [View Article]
    [Google Scholar]
  6. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018; 555:623–628 [View Article]
    [Google Scholar]
  7. Wischmeyer PE, McDonald D, Knight R. Role of the microbiome, probiotics, and 'dysbiosis therapy' in critical illness. Curr Opin Crit Care 2016; 22:347–353 [View Article]
    [Google Scholar]
  8. Pamer EG. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science 2016; 352:535–538 [View Article]
    [Google Scholar]
  9. Manges AR, Steiner TS, Wright AJ. Fecal microbiota transplantation for the intestinal decolonization of extensively antimicrobial-resistant opportunistic pathogens: a review. Infect Dis 2016; 48:587–592 [View Article]
    [Google Scholar]
  10. Morrow LE, Wischmeyer P. Blurred lines: dysbiosis and probiotics in the ICU. Chest 2017; 151:492–499 [View Article]
    [Google Scholar]
  11. Haak BW, Levi M, Wiersinga WJ. Microbiota-targeted therapies on the intensive care unit. Curr Opin Crit Care 2017; 23:167–174 [View Article]
    [Google Scholar]
  12. Wolff NS, Hugenholtz F, Wiersinga WJ. The emerging role of the microbiota in the ICU. Crit Care 2018; 22:78 [View Article]
    [Google Scholar]
  13. McClave SA, Patel J, Bhutiani N. Should fecal microbial transplantation be used in the ICU?. Curr Opin Crit Care 2018; 24:105–111 [View Article]
    [Google Scholar]
  14. Limketkai BN, Hendler S, Ting PS, Parian AM. Fecal microbiota transplantation for the critically ill patient. Nutr Clin Pract 2019; 34:73–79 [View Article]
    [Google Scholar]
  15. Ruppé E, Martin-Loeches I, Rouzé A, Levast B, Ferry T et al. What's new in restoring the gut microbiota in ICU patients? Potential role of faecal microbiota transplantation. Clin Microbiol Infect 2018; 24:803–805 [View Article]
    [Google Scholar]
  16. Dinh A, Fessi H, Duran C, Batista R, Michelon H et al. Clearance of carbapenem-resistant Enterobacteriaceae vs vancomycin-resistant enterococci carriage after faecal microbiota transplant: a prospective comparative study. J Hosp Infect 2018; 99:481–486 [View Article]
    [Google Scholar]
  17. Davido B, Batista R, Fessi H et al. Fecal microbiota transplantation to eradicate vancomycin-resistant enterococci colonization in case of an outbreak. Med Mal Infect 2018
    [Google Scholar]
  18. Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M et al. Post-Antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell 2018; 174:e161406–1423 [View Article]
    [Google Scholar]
  19. Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2012; 55:905–914 [View Article]
    [Google Scholar]
  20. Tamburini FB, Andermann TM, Tkachenko E, Senchyna F, Banaei N et al. Precision identification of diverse bloodstream pathogens in the gut microbiome. Nat Med 2018; 24:1809–1814 [View Article]
    [Google Scholar]
  21. Freedberg DE, Zhou MJ, Cohen ME, Annavajhala MK, Khan S et al. Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection. Intensive Care Med 2018; 44:12031211 [View Article]
    [Google Scholar]
  22. Pallen MJ. Diagnostic metagenomics: potential applications to bacterial, viral and parasitic infections. Parasitology 2014; 141:1856–1862 [View Article]
    [Google Scholar]
  23. Hillmann B, Al-Ghalith GA, Shields-Cutler RR, Zhu Q, Gohl DM et al. Evaluating the information content of shallow shotgun metagenomics. mSystems 2018; 3: [View Article]
    [Google Scholar]
  24. Connor TR, Loman NJ, Thompson S, Smith A, Southgate J et al. CLIMB (the cloud infrastructure for microbial bioinformatics): an online resource for the medical microbiology community. Microb Genom 2016; 2:e000086 [View Article]
    [Google Scholar]
  25. Pal P. 2015; BaseMount: a Linux command line interface for BaseSpace. https://blog.basespace.illumina.com/2015/07/23/basemount-a-linux-command-line-interface-for-basespace/
  26. Andrews S. FastQC: a quality control tool for high throughput sequence data. http://www.bioinformatics.babraham.ac.uk/projects/fastqc
  27. Shen W, Le S, Li Y, Hu F. SeqKit: a Cross-Platform and ultrafast toolkit for FASTA/Q file manipulation. PLoS One 2016; 11:e0163962 [View Article]
    [Google Scholar]
  28. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 2014; 30:2114–2120 [View Article]
    [Google Scholar]
  29. Seemann T. 2015; Snippy: rapid haploid variant calling and core SNP phylogeny. https://github.com/tseemann/snippy
  30. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J et al. The sequence Alignment/Map format and SAMtools. Bioinformatics 2009; 25:2078–2079 [View Article]
    [Google Scholar]
  31. Quinlan AR. BEDTools: the Swiss-Army tool for genome feature analysis. Curr Protoc Bioinformatics 2014; 47:11.12.1–11.1211 [View Article]
    [Google Scholar]
  32. Truong DT, Franzosa EA, Tickle TL, Scholz M, Weingart G et al. MetaPhlAn2 for enhanced metagenomic taxonomic profiling. Nat Methods 2015; 12:902–903 [View Article]
    [Google Scholar]
  33. R-Core-Team R: A language and environment for statistical computing Vienna, Austria: R Foundation for Statistical Computing; 2018
    [Google Scholar]
  34. Pinheiro J, Bates D, DebRoy S, Sarkar D. R-Core-Team 2018; nlme: linear and nonlinear mixed effects models. R package version 3.1-137 https://CRAN.R-project.org/package=nlme
    [Google Scholar]
  35. Li D, Luo R, Liu CM, Leung CM, Ting HF et al. MEGAHIT v1.0: a fast and scalable metagenome assembler driven by advanced methodologies and community practices. Methods 2016; 102:3–11 [View Article]
    [Google Scholar]
  36. Eren AM, Esen Özcan C, Quince C, Vineis JH, Morrison HG et al. Anvi'o: an advanced analysis and visualization platform for 'omics data. PeerJ 2015; 3:e1319 [View Article]
    [Google Scholar]
  37. Hyatt D, Chen GL, Locascio PF, Land ML, Larimer FW et al. Prodigal: prokaryotic gene recognition and translation initiation site identification. BMC Bioinformatics 2010; 11:119 [View Article]
    [Google Scholar]
  38. Potter SC, Luciani A, Eddy SR, Park Y, Lopez R et al. HMMER web server: 2018 update. Nucleic Acids Res 2018; 46:W200–W204 [View Article]
    [Google Scholar]
  39. Kim D, Song L, Breitwieser FP, Salzberg SL. Centrifuge: rapid and sensitive classification of metagenomic sequences. Genome Res 2016; 26:1721–1729 [View Article]
    [Google Scholar]
  40. Parks DH, Imelfort M, Skennerton CT, Hugenholtz P, Tyson GW. CheckM: assessing the quality of microbial genomes recovered from isolates, single cells, and metagenomes. Genome Res 2015; 25:1043–1055 [View Article]
    [Google Scholar]
  41. Waterhouse RM, Seppey M, Simão FA, Manni M, Ioannidis P et al. BUSCO applications from quality assessments to gene prediction and phylogenomics. Mol Biol Evol 2017 [View Article]
    [Google Scholar]
  42. Seeman T. 2018; ABRicate. https://github.com/tseemann/abricate
  43. Gloor GB, Hummelen R, Macklaim JM, Dickson RJ, Fernandes AD et al. Microbiome profiling by Illumina sequencing of combinatorial sequence-tagged PCR products. PLoS One 2010; 5:e15406 [View Article]
    [Google Scholar]
  44. Seemann T. Prokka: rapid prokaryotic genome annotation. Bioinformatics 2014; 30:2068–2069 [View Article]
    [Google Scholar]
  45. Okonechnikov K, Conesa A, García-Alcalde F. Qualimap 2: advanced multi-sample quality control for high-throughput sequencing data. Bioinformatics 2016; 32:292–294 [View Article]
    [Google Scholar]
  46. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol 1990; 215:403–410 [View Article]
    [Google Scholar]
  47. Rodriguez-R LM, Konstantinidis KT. The enveomics collection: a toolbox for specialized analyses of microbial genomes and metagenomes. PeerJ Preprints 2016e1900v1
    [Google Scholar]
  48. Alikhan NF, Petty NK, Ben Zakour NL, Beatson SA. Blast ring image generator (BRIG): simple prokaryote genome comparisons. BMC Genomics 2011; 12:402 [View Article]
    [Google Scholar]
  49. Buelow E, Bayjanov JR, Majoor E, Willems RJ, Bonten MJ et al. Limited influence of hospital wastewater on the microbiome and resistome of wastewater in a community sewerage system. FEMS Microbiol Ecol 2018; 94: [View Article]
    [Google Scholar]
  50. Zaborin A, Smith D, Garfield K, Quensen J, Shakhsheer B et al. Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness. MBio 2014; 5:e01361–14 [View Article]
    [Google Scholar]
  51. McDonald D, Ackermann G, Khailova L, Baird C, Heyland D et al. Extreme dysbiosis of the microbiome in critical illness. mSphere 2016; 1:207 [View Article]
    [Google Scholar]
  52. Palleja A, Mikkelsen KH, Forslund SK, Kashani A, Allin KH et al. Recovery of gut microbiota of healthy adults following antibiotic exposure. Nat Microbiol 2018; 3:1255–1265 [View Article]
    [Google Scholar]
  53. Hildebrand F, Moitinho-Silva L, Blasche S, Jahn MT, Gossmann TI et al. Antibiotics-induced monodominance of a novel gut bacterial order. Gut 2019gutjnl-2018-317715 [View Article]
    [Google Scholar]
  54. Dubourg G, Lagier JC, Armougom F, Robert C, Audoly G et al. High-Level colonisation of the human gut by Verrucomicrobia following broad-spectrum antibiotic treatment. Int J Antimicrob Agents 2013; 41:149–155 [View Article]
    [Google Scholar]
  55. Khelaifia S, Lagier JC, Nkamga VD, Guilhot E, Drancourt M et al. Aerobic culture of methanogenic archaea without an external source of hydrogen. Eur J Clin Microbiol Infect Dis 2016; 35:985–991 [View Article]
    [Google Scholar]
  56. Traore SI, Khelaifia S, Armstrong N, Lagier JC, Raoult D. Isolation and culture of Methanobrevibacter smithii by co-culture with hydrogen-producing bacteria on agar plates. Clin Microbiol Infect 2019 [View Article]
    [Google Scholar]
  57. Grine G, Lotte R, Chirio D, Chevalier A, Raoult D et al. Co-Culture of Methanobrevibacter smithii with enterobacteria during urinary infection. EBioMedicine 2019; 43:333–337 [View Article]
    [Google Scholar]
  58. Grine G, Drouet H, Fenollar F, Bretelle F, Raoult D et al. Detection of Methanobrevibacter smithii in vaginal samples collected from women diagnosed with bacterial vaginosis. Eur J Clin Microbiol Infect Dis 2019
    [Google Scholar]
  59. Shaw TD, Fairley DJ, Schneiders T, Pathiraja M, Hill RLR et al. The use of high-throughput sequencing to investigate an outbreak of glycopeptide-resistant Enterococcus faecium with a novel quinupristin-dalfopristin resistance mechanism. Eur J Clin Microbiol Infect Dis 2018; 37:959–967 [View Article]
    [Google Scholar]
  60. Lee RS, Gonçalves da Silva A, Baines SL, Strachan J, Ballard S et al. The changing landscape of vancomycin-resistant Enterococcus faecium in Australia: a population-level genomic study. J Antimicrob Chemother 2018; 73:3268–3278 [View Article]
    [Google Scholar]
  61. Zhou X, Chlebowicz MA, Bathoorn E, Rosema S, Couto N et al. Elucidating vancomycin-resistant Enterococcus faecium outbreaks: the role of clonal spread and movement of mobile genetic elements. J Antimicrob Chemother 2018; 73:3259–3267 [View Article]
    [Google Scholar]
  62. Hayakawa M, Asahara T, Henzan N, Murakami H, Yamamoto H et al. Dramatic changes of the gut flora immediately after severe and sudden insults. Dig Dis Sci 2011; 56:2361–2365 [View Article]
    [Google Scholar]
  63. Ojima M, Motooka D, Shimizu K, Gotoh K, Shintani A et al. Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients. Dig Dis Sci 2016; 61:1628–1634 [View Article]
    [Google Scholar]
  64. Yeh A, Rogers MB, Firek B, Neal MD, Zuckerbraun BS et al. Dysbiosis across multiple body sites in critically ill adult surgical patients. Shock 2016; 46:649–654 [View Article]
    [Google Scholar]
  65. Buelow E, Bello González TDJ, Fuentes S, de Steenhuijsen Piters WAA, Lahti L et al. Comparative gut microbiota and resistome profiling of intensive care patients receiving selective digestive tract decontamination and healthy subjects. Microbiome 2017; 5:88 [View Article]
    [Google Scholar]
  66. Raymond F, Ouameur AA, Déraspe M, Iqbal N, Gingras H et al. The initial state of the human gut microbiome determines its reshaping by antibiotics. Isme J 2016; 10:707–720 [View Article]
    [Google Scholar]
  67. Lankelma JM, van Vught LA, Belzer C, Schultz MJ, van der Poll T et al. Critically ill patients demonstrate large interpersonal variation in intestinal microbiota dysregulation: a pilot study. Intensive Care Med 2017; 43:59–68 [View Article]
    [Google Scholar]
  68. Lamarche D, Johnstone J, Zytaruk N, Clarke F, Hand L et al. Microbial dysbiosis and mortality during mechanical ventilation: a prospective observational study. Respir Res 2018; 19:220 [View Article]
    [Google Scholar]
  69. Livanos AE, Snider EJ, Whittier S, Chong DH, Wang TC et al. Rapid gastrointestinal loss of clostridial clusters IV and XIVa in the ICU associates with an expansion of gut pathogens. PLoS One 2018; 13:e0200322 [View Article]
    [Google Scholar]
  70. Thiemann S, Smit N, Strowig T. Antibiotics and the intestinal microbiome : individual responses, resilience of the ecosystem, and the susceptibility to infections. Curr Top Microbiol Immunol 2016; 398:123–146 [View Article]
    [Google Scholar]
  71. Lange K, Buerger M, Stallmach A, Bruns T. Effects of antibiotics on gut microbiota. Dig Dis 2016; 34:260–268 [View Article]
    [Google Scholar]
  72. Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest 2014; 124:4212–4218 [View Article]
    [Google Scholar]
  73. Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut 2016; 65:1906–1915 [View Article]
    [Google Scholar]
  74. Bradley SJ, Wilson AL, Allen MC, Sher HA, Goldstone AH et al. The control of hyperendemic glycopeptide-resistant Enterococcus spp. on a haematology unit by changing antibiotic usage. J Antimicrob Chemother 1999; 43:261–266 [View Article]
    [Google Scholar]
  75. Wilcox MH. Gastrointestinal disorders and the critically Ill. Clostridium difficile infection and pseudomembranous colitis. Best Pract Res Clin Gastroenterol 2003; 17:475–493
    [Google Scholar]
  76. Props R, Kerckhof FM, Rubbens P, De Vrieze J, Hernandez Sanabria E et al. Absolute quantification of microbial taxon abundances. Isme J 2017; 11:584–587 [View Article]
    [Google Scholar]
  77. Vandeputte D, Kathagen G, D’hoe K, Vieira-Silva S, Valles-Colomer M et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature 2017; 551:507–511 [View Article]
    [Google Scholar]
  78. Ruppé E, Ghozlane A, Tap J, Pons N, Alvarez A-S et al. Prediction of the intestinal resistome by a three-dimensional structure-based method. Nat Microbiol 2019; 4:112–123 [View Article]
    [Google Scholar]
  79. Khelaifia S, Drancourt M. Susceptibility of archaea to antimicrobial agents: applications to clinical microbiology. Clin Microbiol Infect 2012; 18:841–848 [View Article]
    [Google Scholar]
  80. Stewart RD, Auffret MD, Warr A, Wiser AH, Press MO et al. Assembly of 913 microbial genomes from metagenomic sequencing of the cow rumen. Nat Commun 2018; 9:870 [View Article]
    [Google Scholar]
  81. Kaleko M, Bristol JA, Hubert S, Parsley T, Widmer G et al. Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Anaerobe 2016; 41:58–67 [View Article]
    [Google Scholar]
  82. de Gunzburg J, Ghozlane A, Ducher A, Le Chatelier E, Duval X et al. Protection of the human gut microbiome from antibiotics. J Infect Dis 2018; 217:628–636 [View Article]
    [Google Scholar]
  83. Taur Y, Coyte K, Schluter J, Robilotti E, Figueroa C et al. Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci Transl Med 2018; 10:eaap9489 [View Article]
    [Google Scholar]
  84. Bilinski J, Grzesiowski P, Sorensen N, Madry K, Muszynski J et al. Fecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study. Clin Infect Dis 2017; 65:364–370 [View Article]
    [Google Scholar]
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