Increasing evidence suggests that the lung microbiome plays an important role in chronic obstructive pulmonary disease (COPD) severity. However, the dynamics of the lung microbiome during COPD exacerbations and its potential role in disease aetiology remain poorly understood.We completed a longitudinal 16S ribosomal RNA survey of the lung microbiome on 476 sputum samples collected from 87 subjects with COPD at four visits defined as stable state, exacerbation, 2 weeks post-therapy and 6 weeks recovery.Our analysis revealed a dynamic lung microbiota where changes appeared to be associated with exacerbation events and indicative of specific exacerbation phenotypes. Antibiotic and steroid treatments appear to have differential effects on the lung microbiome. We depict a microbial interaction network for the lung microbiome and suggest that perturbation of a few bacterial operational taxonomic units, in particular Haemophilus spp., could greatly impact the overall microbial community structure. Furthermore, several serum and sputum biomarkers, in particular sputum interleukin-8, appear to be highly correlated with the structure and diversity of the microbiome.Our study furthers the understanding of lung microbiome dynamics in COPD patients and highlights its potential as a biomarker, and possibly a target, for future respiratory therapeutics. @ERSpublications Lung microbiome changes are associated with COPD exacerbation events and implicated in host inflammatory responses
Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.Trial Registration: www.ClinicalTrials.gov NCT01357876
Saccharomyces cerevisiae is a primary model for studies of transcriptional control, and the specificities of most yeast transcription factors (TFs) have been determined by multiple methods. However, it is unclear which position weight matrices (PWMs) are most useful; for the roughly 200 TFs in yeast, there are over 1200 PWMs in the literature. To address this issue, we created ScerTF, a comprehensive database of 1226 motifs from 11 different sources. We identified a single matrix for each TF that best predicts in vivo data by benchmarking matrices against chromatin immunoprecipitation and TF deletion experiments. We also used in vivo data to optimize thresholds for identifying regulatory sites with each matrix. To correct for biases from different methods, we developed a strategy to combine matrices. These aligned matrices outperform the best available matrix for several TFs. We used the matrices to predict co-occurring regulatory elements in the genome and identified many known TF combinations. In addition, we predict new combinations and provide evidence of combinatorial regulation from gene expression data. The database is available through a web interface at http://ural.wustl.edu/ScerTF. The site allows users to search the database with a regulatory site or matrix to identify the TFs most likely to bind the input sequence.
The soil microbiome can produce, resist, or degrade antibiotics and even catabolize them. While resistance genes are widely distributed in the soil, there is a dearth of knowledge concerning antibiotic catabolism. Here we describe a pathway for penicillin catabolism in four isolates. Genomic and transcriptomic sequencing revealed β-lactamase, amidase, and phenylacetic acid catabolon up-regulation. Knocking out part of the phenylacetic acid catabolon or an apparent penicillin utilization operon (put) resulted in loss of penicillin catabolism in one isolate. A hydrolase from the put operon was found to degrade in vitro benzylpenicilloic acid, the β-lactamase penicillin product. To test the generality of this strategy, an E. coli strain was engineered to co-express a β-lactamase and a penicillin amidase or the put operon, enabling it to grow using penicillin or benzylpenicilloic acid, respectively. Elucidation of additional pathways may allow for bioremediation of antibiotic-contaminated soils and discovery of antibiotic-remodeling enzymes with industrial utility.
e GSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with >32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing of Escherichia coli isolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistant Escherichia coli isolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.) A pproximately 5% of patients admitted to hospitals in the United States develop nosocomial infections that increase not only patient mortality (1) but also hospitalization time and cost of treatment (2, 3). In the United States, Gram-negative bacterial pathogens, such as Escherichia coli, Klebsiella pneumoniae/Klebsiella oxytoca, Pseudomonas aeruginosa, and Acinetobacter baumannii, are responsible for 35% of the most common hospitalacquired infections (HAIs) or conditions, including urinary tract infections (UTIs), pneumonia, and surgical site and bloodstream infections. Furthermore, Ͼ70% of the bacteria causing HAIs are resistant to at least one of the most commonly used antibiotics (4-6). The continuing emergence of resistance has compromised treatment options for Gram-negative bacterial pathogens and forced the use of polymyxins (7), an old antibiotic class with nephrotoxicity issues. Despite the clear need for alternatives to treat these multidrug-resistant life-threatening pathogens, a review of the antibacterial pipeline reveals a scarcity of new antibiotic candidates (8).Aminoacyl-tRNA synthetases (AaRSs) play an essential role in protein synthesis (9) and have been clinically validated to be antibacterial targets of mupirocin (10), an inhibitor of isoleucyltRNA synthetase that has been successfully used since 1985 in the topical treatment of Gram-positive bacterial skin infections (11). Their ubiquitous nature, high degree of conservation within a broad spectrum of bacterial species, and considerable divergence...
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