Bloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection

BackgroundClostridium difficile infection (CDI) is the leading infectious cause of nosocomial diarrhea. Hospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive antibiotics and other medications that can disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance. Using whole metagenome shotgun sequencing, we examined the diversity and composition of the fecal microbiota in a prospective cohort study of 98 hospitalized patients.ResultsFour patients had asymptomatic C. difficile colonization, and four patients developed CDI. We observed dramatic shifts in the structure of the gut microbiota during hospitalization. In contrast to CDI cases, asymptomatic patients exhibited elevated relative abundance of potentially protective bacterial taxa in their gut at the onset of C. difficile colonization. Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium; species within these genera have previously been shown to enhance resistance to CDI via the production of secondary bile acids. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Family XI Incertae Sedis, a bacterial family that has been previously associated with decreased CDI risk.ConclusionsThis study underscores the detrimental impact of antibiotics as well as other medications, particularly laxatives, on the intestinal microbiota and suggests that co-colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI.

[1]  L. Peterson,et al.  Development of a rapid and efficient restriction endonuclease analysis typing system for Clostridium difficile and correlation with other typing systems , 1993, Journal of clinical microbiology.

[2]  D. Gerding,et al.  Is there a relationship between vancomycin-resistant enterococcal infection and Clostridium difficile infection? , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[3]  M. Samore,et al.  Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea , 1998, The Lancet.

[4]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[5]  L. Rice,et al.  Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. , 2000, The New England journal of medicine.

[6]  C E Nord,et al.  Effect of antimicrobial agents on the ecological balance of human microflora. , 2001, The Lancet. Infectious diseases.

[7]  B. Currie,et al.  Evidence for Biliary Excretion of Vancomycin into Stool during Intravenous Therapy: Potential Implications for Rectal Colonization with Vancomycin-Resistant Enterococci , 2004, Antimicrobial Agents and Chemotherapy.

[8]  L. Lanthier,et al.  Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  E. Kuijper,et al.  Emergence of Clostridium difficile-associated disease in North America and Europe. , 2006, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[10]  C. Donskey,et al.  Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[11]  Carlene A. Muto,et al.  Antimicrobial-associated risk factors for Clostridium difficile infection. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[12]  C. Kelly,et al.  Clostridium difficile--more difficult than ever. , 2008, The New England journal of medicine.

[13]  N. Socci,et al.  Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. , 2010, The Journal of clinical investigation.

[14]  Matthias Meyer,et al.  Illumina sequencing library preparation for highly multiplexed target capture and sequencing. , 2010, Cold Spring Harbor protocols.

[15]  Limin Fu,et al.  Artificial and natural duplicates in pyrosequencing reads of metagenomic data , 2010, BMC Bioinformatics.

[16]  Marcel Martin.  Cutadapt removes adapter sequences from high-throughput sequencing reads , 2011 .

[17]  W. D. de Vos,et al.  Intestinal Microbiota in Healthy Adults: Temporal Analysis Reveals Individual and Common Core and Relation to Intestinal Symptoms , 2011, PloS one.

[18]  A. Ananthakrishnan.  Clostridium difficile infection: epidemiology, risk factors and management , 2011, Nature Reviews Gastroenterology &Hepatology.

[19]  Risk factors for Clostridium difficile toxin-positive diarrhea: a population-based prospective case–control study , 2012, European Journal of Clinical Microbiology & Infectious Diseases.

[20]  Bernard Henrissat,et al.  Metabolic Reconstruction for Metagenomic Data and Its Application to the Human Microbiome , 2012, PLoS Comput. Biol..

[21]  Yongan Zhao,et al.  RAPSearch2: a fast and memory-efficient protein similarity search tool for next-generation sequencing data , 2011, Bioinform..

[22]  David A Stephens,et al.  Reductions in intestinal Clostridiales precede the development of nosocomial Clostridium difficile infection , 2013, Microbiome.

[23]  M. Kleerebezem,et al.  Laxative treatment with polyethylene glycol decreases microbial primary bile salt dehydroxylation and lipid metabolism in the intestine of rats. , 2013, American journal of physiology. Gastrointestinal and liver physiology.

[24]  Daniel J. Wilson,et al.  Diverse sources of C. difficile infection identified on whole-genome sequencing. , 2013, The New England journal of medicine.

[25]  Jacques Ravel,et al.  Microbiome, demystifying the role of microbial communities in the biosphere , 2013, Microbiome.

[26]  J. Clemente,et al.  The Long-Term Stability of the Human Gut Microbiota , 2013 .

[27]  P. Gérard.  Metabolism of Cholesterol and Bile Acids by the Gut Microbiota , 2013, Pathogens.

[28]  Ashwin N Ananthakrishnan,et al.  Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections , 2013, The American Journal of Gastroenterology.

[29]  P. Savelkoul,et al.  Rectal Swabs for Analysis of the Intestinal Microbiota , 2014, PloS one.

[30]  N. Chia,et al.  Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility , 2014, Microbiome.

[31]  T. Simuni,et al.  A Review of the Clinical Evidence for Complementary and Alternative Therapies in Parkinson’s Disease , 2014, Current Treatment Options in Neurology.

[32]  C. Vincent,et al.  Excretion of Host DNA in Feces Is Associated with Risk of Clostridium difficile Infection , 2015, Journal of immunology research.

[33]  Lisa G Winston,et al.  Burden of Clostridium difficile Infection in the United States , 2015 .

[34]  Antonio Ramos,et al.  Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C. difficile infection: a randomized clinical trial. , 2015, JAMA.

[35]  Duy Tin Truong,et al.  MetaPhlAn2 for enhanced metagenomic taxonomic profiling , 2015, Nature Methods.

[36]  E. Mylonakis,et al.  Colonization With Toxinogenic C. difficile Upon Hospital Admission, and Risk of Infection: A Systematic Review and Meta-Analysis , 2015, The American Journal of Gastroenterology.

[37]  Nora C. Toussaint,et al.  Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial. , 2015, Gastroenterology.

[38]  Erratum to: Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility , 2016, Microbiome.