scholarly journals 1771. Gut Resistome Changes in Response to Prophylactic Antibiotic Administration During Chemotherapy in Children With Acute Lymphoblastic Leukemia

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S66-S66
Author(s):  
Ellie Margolis ◽  
Hana Hakim ◽  
Jiangwei Yao ◽  
Jason Rosch ◽  
Li Tang ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Community Composition ◽  
Resistance Genes ◽  
Gut Microbiome ◽  
Lymphoblastic Leukemia ◽  
Metagenomic Sequencing ◽  
Pediatric Leukemia ◽  
Drug Concentrations ◽  
Stool Samples

Abstract Background Antibiotic resistance harbored in gut microbiome contributes to the emergence of multi–drug-resistant organisms (MDRO). Pediatric leukemia patients typically receive extensive antibiotics and are at higher risk for infection due to MDRO. Methods A prospective cohort of children (n = 242) with acute lymphoblastic leukemia self-collected stool samples at diagnosis and after induction chemothearpy. A third of patients (n = 69) underwent protocol-driven antibiotic prophylaxis: Levofloxacin (LV) given once neutropenia develops. With neutropenic fever patients on prophylaxis stopped LV and all patients received cefepime. Using metagenomic sequencing, we identified bacterial community composition and after alignment to the Comprehensive Antibiotic Resistance Database were able to determine the presence of bacterial resistance genes in 168 stool samples from 49 patients. Results Expected changes in the community composition were discovered with LV prophylaxis, including the loss of many Enterobacteriaceae and Enterococcaceae species, offset by increases in Bacteroides species. Unexpectedly, LV prophylaxis reduced the acquisition of VanA cluster of vancomycin resistance genes and did not increase acquisition of β-lactamase or fluoroquinolone (FQ) resistance gene families. Conclusion LV prophylaxis during leukemia treatment imparts predictable changes in gut bacterial communities but counter intuitively decreases antibiotic resistance in the gut microbiome reservoir. The reduction in VanA cluster of genes is likely due to depletion of Enterococcaceae species via direct killing or loss of synergistic partners. The lack of increase in target (FQ) or off-target resistance suggests that prophylaxis altered community selective pressures or prophylaxis drug concentrations were sufficient to limit the outgrowth of resistant mutants. Disclosures J. Wolf, Karius Inc.: Investigator, Research support.

scholarly journals Antibiotic resistance potential of the healthy preterm infant gut microbiome

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e2928 ◽  
Author(s):  
Graham Rose ◽  
Alexander G. Shaw ◽  
Kathleen Sim ◽  
David J. Wooldridge ◽  
Ming-Shi Li ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Preterm Infant ◽  
Resistance Genes ◽  
Gut Microbiome ◽  
Antibiotic Resistance Genes ◽  
Taxonomic Diversity ◽  
Metagenomic Sequencing ◽  
Important Species ◽  
Antimicrobial Resistance Genes ◽  
Infant Gut Microbiome

Background Few studies have investigated the gut microbiome of infants, fewer still preterm infants. In this study we sought to quantify and interrogate the resistome within a cohort of premature infants using shotgun metagenomic sequencing. We describe the gut microbiomes from preterm but healthy infants, characterising the taxonomic diversity identified and frequency of antibiotic resistance genes detected. Results Dominant clinically important species identified within the microbiomes included C. perfringens, K. pneumoniae and members of the Staphylococci and Enterobacter genera. Screening at the gene level we identified an average of 13 antimicrobial resistance genes per preterm infant, ranging across eight different antibiotic classes, including aminoglycosides and fluoroquinolones. Some antibiotic resistance genes were associated with clinically relevant bacteria, including the identification of mecA and high levels of Staphylococci within some infants. We were able to demonstrate that in a third of the infants the S. aureus identified was unrelated using MLST or metagenome assembly, but low abundance prevented such analysis within the remaining samples. Conclusions We found that the healthy preterm infant gut microbiomes in this study harboured a significant diversity of antibiotic resistance genes. This broad picture of resistances and the wider taxonomic diversity identified raises further caution to the use of antibiotics without consideration of the resident microbial communities.

scholarly journals Gut Microbiome in Survivors of Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1384-1384
Author(s):  
Ronay Thomas ◽  
Wendy Shukwan Wong ◽  
NIccole Piguet ◽  
Jennifer Dean ◽  
Alissa Mills ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Gut Microbiome ◽  
Negative Binomial ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Alpha Diversity ◽  
Metabolic Derangement ◽  
Childhood All ◽  
Stool Samples

Abstract Purpose Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood and has a high treatment success rate. However, survivors of childhood ALL have a high prevalence of chronic medical illnesses, such as metabolic syndrome. Dysbiosis in the gut microbiome is associated with metabolic derangement and disease risk. Chemotherapy and antibiotics increase gut microbiome dysbiosis. We tested the hypothesis that ALL treatment can cause alterations in the gut microbiome that persist in survivorship. Method Stool samples were collected on fecal occult blood test cards from 38 survivors between 2-18 years of age who were >1 year off therapy for ALL. 16 stool samples from healthy siblings age 2-18 years were collected from 14 families as controls. Clinical data including anthropometrics, antibiotic use, and probiotic use were collected. DNA was extracted and sequenced using a modified Illumina 16S Metagenomics Sequencing Library Preparation protocol for analysis of hypervariable region V4. A single rarefaction was performed at 4,897 removing 2 samples with low mapped read counts. Alpha and beta (Bray) diversities were calculated; Wilcoxon rank-sum test was used to compare the alpha diversities between groups, as well as the beta diversities within and between groups. Wilcoxon signed-rank test was used to compare the alpha diversity between survivors and their matched siblings. Finally, read counts for each Operational Taxonomic Unit (OTU) was normalized and tested for differential abundance using edgeR, assuming a negative binomial model. Results Significant differences in the abundance of taxa were found, with the most notable being the depletion of Faecalibacterium in survivors (FDR= 0.0004). Figure 1 shows a heatmap with the complete linkage clustering method on the Euclidean distance using the 13 OTUs with statistically significant (FDR<0.05) differences between survivors and siblings (Table 1). When compared to their respective siblings, survivors exhibited decreased alpha diversity using four metrics (Observed, Shannon, Simpson, Fisher), but these results did not meet statistical significance. Significant differences were not observed in alpha diversity within survivors between different clinical categories (antibiotic usage, probiotic usage, disease risk, age at diagnosis and time off treatment). Stool microbiome was more similar within a family than between families (P = 0.00079). Conclusion Differences in the relative abundance of certain taxa were found between survivors and siblings. Specifically, Fecalibacterium was depleted in survivors, which has also been previously observed in older populations of childhood ALL survivors. This study shows that these microbiome changes are present in ALL survivors during childhood, and should be evaluated longitudinally for association with the chronic medical illnesses seen in ALL survivors in adulthood. Early interventions to restore the gut microbiome in ALL patients may potentially ameliorate the risk of long-term adverse health outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Metagenomic Sequencing Analysis of the Effects of Colistin Sulfate on the Pig Gut Microbiome

2021 ◽  
Vol 8 ◽  
Author(s):  
Ling Guo ◽  
Dan Zhang ◽  
Shulin Fu ◽  
Jiacheng Zhang ◽  
Xiaofang Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Antibiotic Resistance ◽  
Microbial Diversity ◽  
Resistance Genes ◽  
Gut Microbiome ◽  
Antibiotic Resistance Genes ◽  
Protein Processing ◽  
Control Group ◽  
Metagenomic Sequencing ◽  
Microbiome Composition

The gut microbiome plays important roles in maintaining host health, and inappropriate use of antibiotics can cause imbalance, which may contribute to serious disease. However, despite its promise, using metagenomic sequencing to explore the effects of colistin on gut microbiome composition in pig has not been reported. Herein, we evaluated the roles of colistin in gut microbiome modulation in pigs. Metagenomic analysis demonstrated that overall microbial diversity was higher in the colistin group compared with the control group. Antibiotic Resistance Genes Database analysis demonstrated that following colistin treatment, expression levels of tsnr, ant6ia, tetq, oleb, norm, ant3ia, and mexh were significantly upregulated, indicating that colistin may induce transformation of antibiotic resistance genes. Colistin also affected the microbiome distribution patterns at both genus and phylum levels. In addition, at the species level, colistin significantly reduced the abundance of Prevotella copri, Phascolarctobacterium succinatutens, and Prevotella stercorea and enhanced the abundance of Treponema succinifaciens and Acidaminococcus fermentans compared to the control group. Gene Ontology analysis demonstrated that following treatment with colistin, metabolic process, cellular process, and single-organism process were the dominant affected terms. Kyoto Encyclopedia of Genes and Genomes analysis showed that oxidative phosphorylation, protein processing in endoplasmic reticulum, various types of N-glycan biosynthesis, protein processing in endoplasmic reticulum, pathogenic Escherichia coli infection, and mitogen-activated protein kinase signaling pathway–yeast were the dominant signaling pathways in the colistin group. Overall, our results suggested that colistin affects microbial diversity and may modulate gut microbiome composition in pig, potentially providing novel strategy or antibiotic rationalization pertinent to human and animal health.

scholarly journals Combined effects of composting and antibiotic administration on cattle manure–borne antibiotic resistance genes

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ishi Keenum ◽  
Robert K. Williams ◽  
Partha Ray ◽  
Emily D. Garner ◽  
Katharine F. Knowlton ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Antibiotic Resistance Genes ◽  
Land Application ◽  
Multidimensional Analysis ◽  
Small Scale ◽  
Antibiotic Administration ◽  
Metagenomic Sequencing ◽  
Combined Effects ◽  
Bacterial Microbiota

Abstract Background Research is needed to delineate the relative and combined effects of different antibiotic administration and manure management practices in either amplifying or attenuating the potential for antibiotic resistance to spread. Here, we carried out a comprehensive parallel examination of the effects of small-scale (> 55 °C × 3 days) static and turned composting of manures from dairy and beef cattle collected during standard antibiotic administration (cephapirin/pirlimycin or sulfamethazine/chlortetracycline/tylosin, respectively), versus from untreated cattle, on “resistomes” (total antibiotic resistance genes (ARGs) determined via shotgun metagenomic sequencing), bacterial microbiota, and indicator ARGs enumerated via quantitative polymerase chain reaction. To gain insight into the role of the thermophilic phase, compost was also externally heated to > 55 °C × 15 days. Results Progression of composting with time and succession of the corresponding bacterial microbiota was the overarching driver of the resistome composition (ANOSIM; R = 0.424, p = 0.001, respectively) in all composts at the small-scale. Reduction in relative abundance (16S rRNA gene normalized) of total ARGs in finished compost (day 42) versus day 0 was noted across all conditions (ANOSIM; R = 0.728, p = 0.001), except when externally heated. Sul1, intI1, beta-lactam ARGs, and plasmid-associated genes increased in all finished composts as compared with the initial condition. External heating more effectively reduced certain clinically relevant ARGs (blaOXA, blaCARB), fecal coliforms, and resistome risk scores, which take into account putative pathogen annotations. When manure was collected during antibiotic administration, taxonomic composition of the compost was distinct according to nonmetric multidimensional analysis and tet(W) decayed faster in the dairy manure with antibiotic condition and slower in the beef manure with antibiotic condition. Conclusions This comprehensive, integrated study revealed that composting had a dominant effect on corresponding resistome composition, while little difference was noted as a function of collecting manure during antibiotic administration. Reduction in total ARGs, tet(W), and resistome risk suggested that composting reduced some potential for antibiotic resistance to spread, but the increase and persistence of other indicators of antibiotic resistance were concerning. Results indicate that composting guidelines intended for pathogen reduction do not necessarily provide a comprehensive barrier to ARGs or their mobility prior to land application and additional mitigation measures should be considered.

scholarly journals The Infant Gut Resistome is Associated with E. coli and Early-life Exposures

2020 ◽  
Author(s):  
Rebecca M. Lebeaux ◽  
Modupe O. Coker ◽  
Erika F. Dade ◽  
Thomas J. Palys ◽  
Hilary G. Morrison ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Relative Risk ◽  
Relative Abundance ◽  
Gut Microbiome ◽  
Early Life ◽  
The United States ◽  
Delivery Mode ◽  
Metagenomic Sequencing ◽  
E Coli ◽  
Early Life Exposures

Abstract Background: Antibiotic resistance is an increasing threat to human health. The human gut microbiome harbors a collection of bacterial antimicrobial resistance genes (ARGs) known as the resistome. The factors associated with establishment of the resistome in early life are not well understood and clarifying these factors would inform strategies to decrease antibiotic resistance. We investigated the early-life exposures and taxonomic signatures associated with resistome development over the first year of life in a large, prospective cohort in the United States. Shotgun metagenomic sequencing was used to profile both microbial composition and ARGs in stool samples collected at 6 weeks and 1 year of age from infants enrolled in the New Hampshire Birth Cohort Study. Negative binomial regression and statistical modeling was used to examine infant factors such as sex, delivery mode, feeding method, gestational age, antibiotic exposure, and infant gut microbiome composition in relation to the diversity and relative abundance of ARGs.Results: Metagenomic sequencing was performed on paired samples from 195 full term (at least 37 weeks’ gestation) and 15 late preterm (33-36 weeks’ gestation) infants. 6-week samples compared to 1-year samples had 4.37 times (95% CI: 3.54-5.39) the rate of harboring ARGs. The majority of ARGs that were at a greater relative abundance at 6 weeks (chi-squared p < 0.01) worked through the mechanism of antibiotic efflux (i.e., by pumping antibiotics out of the cell). The overall relative abundance of the resistome was strongly correlated with Proteobacteria (Spearman correlation = 78.9%) and specifically E. coli (62.2%) relative abundance in the gut microbiome. Among infant characteristics, delivery mode was most strongly associated with the diversity and relative abundance of ARGs. Infants born via cesarean delivery had a higher risk of harboring unique ARGs [relative risk = 1.12 (95% CI: 0.97 – 1.29)] as well as a having an increased risk for overall ARG relative abundance [relative risk = 1.43 (95% CI: 1.12 – 1.84)] at 1 year compared to infants born vaginally. Additionally, 6 specific ARGs were at a greater relative abundance in infants delivered by cesarean section compared to vaginally delivered infants across both time points. Conclusions: Our findings suggest that the developing infant gut resistome may be alterable by early-life exposures. Establishing the extent to which infant characteristics and early-life exposures impact the resistome can ultimately lead to interventions that decrease the transmission of ARGs and thus the possibility of antibiotic resistant life threatening infections.

Abundance, diversity and mobility potential of antibiotic resistance genes in pristine Tibetan Plateau soil as revealed by soil metagenomics

2020 ◽  
Vol 96 (10) ◽  
Author(s):  
Bo Li ◽  
Zeng Chen ◽  
Fan Zhang ◽  
Yongqin Liu ◽  
Tao Yan
Keyword(s):  
Antibiotic Resistance ◽  
Microbial Diversity ◽  
Resistance Genes ◽  
Antibiotic Resistance Genes ◽  
Soil Samples ◽  
16S Rrna Genes ◽  
Rrna Genes ◽  
Metagenomic Sequencing ◽  
Clinical Issue ◽  
Abundance And Diversity

ABSTRACT Widespread occurrence of antibiotic resistance genes (ARGs) has become an important clinical issue. Studying ARGs in pristine soil environments can help to better understand the intrinsic soil resistome. In this study, 10 soil samples were collected from a high elevation and relatively pristine Tibetan area, and metagenomic sequencing and bioinformatic analyses were conducted to investigate the microbial diversity, the abundance and diversity of ARGs and the mobility potential of ARGs as indicated by different mobile genetic elements (MGEs). A total of 48 ARG types with a relative abundance of 0.05–0.28 copies of ARG/copy of 16S rRNA genes were detected in Tibetan soil samples. The observed ARGs were mainly associated with antibiotics that included glycopeptide and rifamycin; the most abundant ARGs were vanRO and vanSO. Low abundance of MGEs and potentially plasmid-related ARGs indicated a low horizontal gene transfer risk of ARGs in the pristine soil. Pearson correlation and redundancy analyses showed that temperature and total organic carbon were the major environmental factors controlling both microbial diversity and ARG abundance and diversity.

scholarly journals Horizontal transfer of antibiotic resistance genes in the human gut microbiome

2020 ◽  
Vol 53 ◽  
pp. 35-43 ◽  
Author(s):  
Ross S McInnes ◽  
Gregory E McCallum ◽  
Lisa E Lamberte ◽  
Willem van Schaik
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Gut Microbiome ◽  
Horizontal Transfer ◽  
Antibiotic Resistance Genes ◽  
Human Gut ◽  
Human Gut Microbiome

scholarly journals The Effect of Probiotics Supplementation on the Gut Microbiome of Healthy Dogs Assessed Using Metagenomic Sequencing: A Randomized Control Trial

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1591-1591
Author(s):  
Jirayu Tanprasertsuk ◽  
Justin Shmalberg ◽  
Aashish Jha ◽  
LeeAnn Perry ◽  
Ryan Honaker
Keyword(s):  
Health Outcomes ◽  
Gut Microbiome ◽  
Randomized Control Trial ◽  
Gastrointestinal Diseases ◽  
Metagenomic Sequencing ◽  
Β Diversity ◽  
Α Diversity ◽  
Stool Samples ◽  
Healthy Dogs ◽  
Randomized Control

Abstract Objectives Dogs share similar gut microbiome (GM) with humans, making them a great model for investigating the effects of probiotics (PR) on GM and health. This randomized control trial examined changes in MB and health outcomes in household dogs after PR supplementation. Methods All dogs recruited were fed human grade cooked food ≥ 1 mo, not fed any cultured food, PR, prebiotics, or on antibiotics ≥ 3 mo, and absent of major diseases. Dogs were randomized to receive a daily dose of PR (20 billion CFU of L. reuteri, P. acidilactici, E. faecium, L. acidophilus, B. animalis, L. fermentum, L. rhamnosus) or placebo (PL) for 4 weeks. Owners completed a health survey and collected stool samples at baseline and 4 weeks after the intervention in both groups. Additional stool samples were collected 2 weeks after stopping the PR in the PR group. GM profiling was performed with metagenomic sequencing. Results Twenty three dogs in the PR and 19 dogs in the PL group completed the trial (5.6 ± 3.0 y, 69% male). PR had no effect on α-diversity. As compared to baseline, changes in β-diversity at the species level in 4.3% of GM were significantly affected by PR at week 4 (P &lt; 0.001) but not at week 6. A significant increase (adj P &lt; 0.01) for ≥ 2-fold in abundance was observed at week 4 as compared to baseline for 41 bacterial taxa, 29 (71%) of which belong in the Lactobacillus genus. The abundance of E. coli also decreased at week 4 in the PR group (2.8 folds, adj P &lt; 0.01). The abundance of these taxa returned to baseline at week 6. Such changes in diversity or abundance were not observed with PL. Dogs fed PR tended to be at a lower risk of diarrhea during the trial (0% vs 16%, P = 0.08). No change in other health outcomes was observed. Conclusions Oral PR supplementation has a small but significant effect on GM in healthy dogs. Findings warrant further investigation with longer duration in populations at a higher risk of gastrointestinal diseases. Funding Sources NomNomNow Inc.

Characterizing the Global Transcriptional Effects of TEL-AML1-Fusion in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3794-3794
Author(s):  
Susanna Teppo ◽  
Kaisa J Teittinen ◽  
Toni Grönroos ◽  
Keijo Viiri ◽  
Minna Kaikkonen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Acute Lymphoblastic Leukemia ◽  
Rna Polymerase Ii ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Constitutive Expression ◽  
Enrichment Analysis ◽  
Leukemic Cell ◽  
Pediatric Leukemia ◽  
Transcriptional Changes

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer affecting thousands of children worldwide each year. Most patients are cured but only after long chemotherapy treatment and still 15 % of them relapse. Therefore, better understanding of the molecular biology behind the disease is fundamental. TEL-AML1 fusion - comprised of two transcription factors important in hematopoiesis regulation - is the most frequent genetic variation found in 25 % of pediatric ALL-patients. The translocation occurs during pregnancy and is suggested to serve as a “first hit” enabling secondary changes that lead to cancer formation. Despite its frequency, genetic targets of this aberrant transcription factor are unclear, and its function in leukemia initiation and progression remains elusive. Here we aim at solving the genome-wide effects of TEL-AML1 on transcription using pre-B-leukemic cell models. After a time-series induction of wild-type or DNA-binding compromised mutated TEL-AML1, or a constitutive expression of shRNA silencing the fusion, the cells were studied using global nuclear run-on sequencing (GRO-seq). GRO-seq technology can map RNA polymerase II location and identify actively transcribed coding and non-coding genes and their directionality. Thus, GRO-seq provides a snapshot of global active transcription and was used here to identify bona fide targets of the TEL-AML1-fusion protein. In addition to transcriptional changes in known genes, we identified a notable number of novel transcripts including antisense-, lincRNA-, and microRNAs. We also characterized genomic locations where the fusion functions as a direct regulator by taking advantage of non-coding RNA transcripts known as enhancer RNAs. Furthermore, we performed transcription factor motif enrichment analysis on these active regulatory eRNA regions. The results uncover early transcriptional changes induced by TEL-AML1-fusion and may reveal critical steps in leukemia initiation and development. The findings also highlight the importance of non-coding RNAs in the pathogenesis of pediatric leukemia. Disclosures No relevant conflicts of interest to declare.

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