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      Pretreatment gut microbiome predicts chemotherapy-related bloodstream infection

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          Abstract

          Background

          Bacteremia, or bloodstream infection (BSI), is a leading cause of death among patients with certain types of cancer. A previous study reported that intestinal domination, defined as occupation of at least 30 % of the microbiota by a single bacterial taxon, is associated with BSI in patients undergoing allo-HSCT. However, the impact of the intestinal microbiome before treatment initiation on the risk of subsequent BSI remains unclear. Our objective was to characterize the fecal microbiome collected before treatment to identify microbes that predict the risk of BSI.

          Methods

          We sampled 28 patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic stem cell transplantation (HSCT) prior to administration of chemotherapy and characterized 16S ribosomal RNA genes using high-throughput DNA sequencing. We quantified bacterial taxa and used techniques from machine learning to identify microbial biomarkers that predicted subsequent BSI.

          Results

          We found that patients who developed subsequent BSI exhibited decreased overall diversity and decreased abundance of taxa including Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella. Using machine-learning methods, we developed a BSI risk index capable of predicting BSI incidence with a sensitivity of 90 % at a specificity of 90 % based only on the pretreatment fecal microbiome.

          Conclusions

          These results suggest that the gut microbiota can identify high-risk patients before HSCT and that manipulation of the gut microbiota for prevention of BSI in high-risk patients may be a useful direction for future research. This approach may inspire the development of similar microbiome-based diagnostic and prognostic models in other diseases.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13073-016-0301-4) contains supplementary material, which is available to authorized users.

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          Most cited references25

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          Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease.

          Specific members of the intestinal microbiota dramatically affect inflammatory bowel disease (IBD) in mice. In humans, however, identifying bacteria that preferentially affect disease susceptibility and severity remains a major challenge. Here, we used flow-cytometry-based bacterial cell sorting and 16S sequencing to characterize taxa-specific coating of the intestinal microbiota with immunoglobulin A (IgA-SEQ) and show that high IgA coating uniquely identifies colitogenic intestinal bacteria in a mouse model of microbiota-driven colitis. We then used IgA-SEQ and extensive anaerobic culturing of fecal bacteria from IBD patients to create personalized disease-associated gut microbiota culture collections with predefined levels of IgA coating. Using these collections, we found that intestinal bacteria selected on the basis of high coating with IgA conferred dramatic susceptibility to colitis in germ-free mice. Thus, our studies suggest that IgA coating identifies inflammatory commensals that preferentially drive intestinal disease. Targeted elimination of such bacteria may reduce, reverse, or even prevent disease development. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Comparative Analysis of Human Gut Microbiota by Barcoded Pyrosequencing

            Humans host complex microbial communities believed to contribute to health maintenance and, when in imbalance, to the development of diseases. Determining the microbial composition in patients and healthy controls may thus provide novel therapeutic targets. For this purpose, high-throughput, cost-effective methods for microbiota characterization are needed. We have employed 454-pyrosequencing of a hyper-variable region of the 16S rRNA gene in combination with sample-specific barcode sequences which enables parallel in-depth analysis of hundreds of samples with limited sample processing. In silico modeling demonstrated that the method correctly describes microbial communities down to phylotypes below the genus level. Here we applied the technique to analyze microbial communities in throat, stomach and fecal samples. Our results demonstrate the applicability of barcoded pyrosequencing as a high-throughput method for comparative microbial ecology.
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              Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation.

              Bacteremia is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear whether changes in the intestinal microbiota during allo-HSCT contribute to the development of bacteremia. We examined the microbiota of patients undergoing allo-HSCT, and correlated microbial shifts with the risk of bacteremia. Fecal specimens were collected longitudinally from 94 patients undergoing allo-HSCT, from before transplant until 35 days after transplant. The intestinal microbiota was characterized by 454 pyrosequencing of the V1-V3 region of bacterial 16S ribosomal RNA genes. Microbial diversity was estimated by grouping sequences into operational taxonomic units and calculating the Shannon diversity index. Phylogenetic classification was obtained using the Ribosomal Database Project classifier. Associations of the microbiota with clinical predictors and outcomes were evaluated. During allo-HSCT, patients developed reduced diversity, with marked shifts in bacterial populations inhabiting the gut. Intestinal domination, defined as occupation of at least 30% of the microbiota by a single predominating bacterial taxon, occurred frequently. Commonly encountered dominating organisms included Enterococcus, Streptococcus, and various Proteobacteria. Enterococcal domination was increased 3-fold by metronidazole administration, whereas domination by Proteobacteria was reduced 10-fold by fluoroquinolone administration. As a predictor of outcomes, enterococcal domination increased the risk of Vancomycin-resistant Enterococcus bacteremia 9-fold, and proteobacterial domination increased the risk of gram-negative rod bacteremia 5-fold. During allo-HSCT, the diversity and stability of the intestinal flora are disrupted, resulting in domination by bacteria associated with subsequent bacteremia. Assessment of fecal microbiota identifies patients at highest risk for bloodstream infection during allo-HCST.
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                Author and article information

                Contributors
                Emmanuel.MONTASSIER@chu-nantes.fr
                algh0022@umn.edu
                ward@umn.edu
                stephane.corvec@chu-nantes.fr
                gastinne.thomas@chu-nantes.fr
                gilles.potel@chu-nantes.fr
                philippe.moreau@chu-nantes.fr
                mfcochet@hotmail.com
                eric.batard@chu-nantes.fr
                dknights@umn.edu
                Journal
                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                1756-994X
                28 April 2016
                28 April 2016
                2016
                : 8
                : 49
                Affiliations
                [ ]Université de Nantes, EA 3826 Thérapeutiques cliniques et expérimentales des infections. Faculté de médecine, 1 Rue G Veil, Nantes, 44000 France
                [ ]Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455 USA
                [ ]Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455 USA
                [ ]Biotechnology Institute, University of Minnesota, St. Paul, MN 55108 USA
                [ ]Nantes University Hospital, Microbiology Laboratory, Nantes, France
                [ ]Hematology Department, Nantes University Hospital, Nantes, France
                Article
                301
                10.1186/s13073-016-0301-4
                4848771
                27121964
                3ce9c4e0-ea17-42ce-b54e-69db35df56c6
                © Montassier et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 January 2016
                : 11 April 2016
                Funding
                Funded by: French National Society of Gastroenterology
                Award ID: Robert Tournut Award
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Molecular medicine
                bloodstream infection,chemotherapy,intestinal microbiome,prediction
                Molecular medicine
                bloodstream infection, chemotherapy, intestinal microbiome, prediction

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