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      Infectious Complications Are Associated With Alterations in the Gut Microbiome in Pediatric Patients With Acute Lymphoblastic Leukemia

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          Abstract

          Acute lymphoblastic leukemia is the most common pediatric cancer. Fortunately, survival rates exceed 90%, however, infectious complications remain a significant issue that can cause reductions in the quality of life and prognosis of patients. Recently, numerous studies have linked shifts in the gut microbiome composition to infection events in various hematological malignances including acute lymphoblastic leukemia (ALL). These studies have been limited to observing broad taxonomic changes using 16S rRNA gene profiling, while missing possible differences within microbial functions encoded by individual species. In this study we present the first combined 16S rRNA gene and metagenomic shotgun sequencing study on the gut microbiome of an independent pediatric ALL cohort during treatment. In this study we found distinctive differences in alpha diversity and beta diversity in samples from patients with infectious complications in the first 6 months of therapy. We were also able to find specific species and functional pathways that were significantly different in relative abundance between samples that came from patients with infectious complications. Finally, machine learning models based on patient metadata and bacterial species were able to classify samples with high accuracy (84.09%), with bacterial species being the most important classifying features. This study strengthens our understanding of the association between infection and pediatric acute lymphoblastic leukemia treatment and warrants further investigation in the future.

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          Most cited references15

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          The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.

          Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT. © 2014 by The American Society of Hematology.
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            Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin.

            Invasive and biomaterial-associated infections in humans are often difficult to diagnose and treat. Here, guided by recent advances in clinically relevant optical imaging technologies, we explore the use of fluorescently labelled vancomycin (vanco-800CW) to specifically target and detect infections caused by Gram-positive bacteria. The application potential of vanco-800CW for real-time in vivo imaging of bacterial infections is assessed in a mouse myositis model and a human post-mortem implant model. We show that vanco-800CW can specifically detect Gram-positive bacterial infections in our mouse myositis model, discriminate bacterial infections from sterile inflammation in vivo and detect biomaterial-associated infections in the lower leg of a human cadaver. We conclude that vanco-800CW has a high potential for enhanced non-invasive diagnosis of infections with Gram-positive bacteria and is a promising candidate for early-phase clinical trials.
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              The microbiome and cancer.

              Humans coexist with a vast bacterial, fungal and viral microbiome with which we have coevolved for millions of years. Several long recognized epidemiological associations between particular bacteria and cancer are now understood at the molecular level. At the same time, the arrival of next-generation sequencing technology has permitted a thorough exploration of microbiomes such as that of the human gut, enabling observation of taxonomic and metabolomic relationships between the microbiome and cancer. These studies have revealed causal mechanisms for both microbes within tumours and microbes in other host niches separated from tumours, mediated through direct and immunological mechanisms. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                19 February 2019
                2019
                : 9
                : 28
                Affiliations
                [1] 1Department of Microbiology and Immunology, Dalhousie University , Halifax, NS, Canada
                [2] 2Division of Gastroenterology, Department of Pediatrics, IWK Health Centre , Halifax, NS, Canada
                [3] 3Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center , Amsterdam, Netherlands
                [4] 4Division of Hematology/Oncology, Department of Pediatrics, IWK Health Centre , Halifax, NS, Canada
                [5] 5Department of Pharmacology, Dalhousie University , Halifax, NS, Canada
                Author notes

                Edited by: Shai Bel, Bar-Ilan University, Israel

                Reviewed by: Gil Sharon, California Institute of Technology, United States; Natalia Shulzhenko, Oregon State University, United States

                *Correspondence: Ketan Kulkarni Ketan.Kulkarni@ 123456iwk.nshealth.ca

                This article was submitted to Microbiome in Health and Disease, a section of the journal Frontiers in Cellular and Infection Microbiology

                Article
                10.3389/fcimb.2019.00028
                6389711
                30838178
                dbda6f56-16b3-4e47-bbd0-2661f605a0c7
                Copyright © 2019 Nearing, Connors, Whitehouse, Van Limbergen, Macdonald, Kulkarni and Langille.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 October 2018
                : 29 January 2019
                Page count
                Figures: 6, Tables: 3, Equations: 0, References: 36, Pages: 14, Words: 9710
                Funding
                Funded by: Nova Scotia Health Research Foundation 10.13039/501100000194
                Funded by: Natural Sciences and Engineering Research Council of Canada 10.13039/501100000038
                Funded by: Terry Fox Research Institute 10.13039/501100004376
                Categories
                Cellular and Infection Microbiology
                Original Research

                Infectious disease & Microbiology
                microbiome,genomics,cancer,leukemia,clinical,infection,metagenomics
                Infectious disease & Microbiology
                microbiome, genomics, cancer, leukemia, clinical, infection, metagenomics

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