Evolution and Population Dynamics of Clonal Complex 152 Community-Associated Methicillin-Resistant Staphylococcus aureus.

Since the late 1990s, changes in the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) were recognized with the emergence of community-associated MRSA (CA-MRSA). CA-MRSA belonging to clonal complex 152 (CC152), carrying the small staphylococcal cassette chromosome mec (SCCmec) type V and encoding the Panton-Valentine leukocidin (PVL), has been observed in Europe. The aim of this study was to investigate its origin, evolution, and dissemination. Whole-genome sequencing was performed on a global collection of 149 CC152 isolates spanning 20 years (93 methicillin-susceptible S. aureus [MSSA] and 56 MRSA isolates). Core genome phylogeny, Bayesian inference, in silico resistance analyses, and genomic characterization were applied. Phylogenetic analysis revealed two major distinct clades, one dominated by MSSA and the other populated only by MRSA. The MSSA isolates were predominately from sub-Saharan Africa, whereas MRSA was almost exclusively from Europe. The European MRSA isolates all harbored an SCCmec type V (5C2&5) element, whereas other SCCmec elements were sporadically detected in MRSA from the otherwise MSSA-dominated clade, including SCCmec types IV (2B), V (5C2), and XIII (9A). In total, 93% of the studied CC152 isolates were PVL positive. Bayesian coalescent inference suggests an emergence of the European CC152-MRSA in the 1990s, while the CC152 lineage dates back to the 1970s. The CA-MRSA CC152 clone mimics the European CC80 CA-MRSA lineage by its emergence from a PVL-positive MSSA ancestor from North Africa or Europe. The CC152 lineage has acquired SCCmec several times, but acquisition of SCCmec type V (5C2&5) seems associated with expansion of MRSA CC152 in Europe.IMPORTANCE Understanding the evolution of CA-MRSA is important in light of the increasing importance of this reservoir in the dissemination of MRSA. Here, we highlight the story of the CA-MRSA CC152 lineage using whole-genome sequencing on an international collection of CC152. We show that the evolution of this lineage is novel and that antibiotic usage may have the potential to select for the phage-encoded Panton-Valentine leukocidin. The diversity of the strains correlated highly to geography, with higher level of resistance observed among the European MRSA isolates. The mobility of the SCCmec element is mandatory for the emergence of novel MRSA lineages, and we show here distinct acquisitions, one of which is linked to the successful clone found throughout Europe today

Fecal microbiota profiles in treatment-naïve pediatric inflammatory bowel disease – associations with disease phenotype, treatment, and outcome

Purpose: Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-naïve IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes. Patients and methods: Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohn’s disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map ™ technology at diagnosis and after therapy in IBD patients. Results: Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (P&lt;0.001). Only Prevotella was more abundant in patients (P&lt;0.01). IBD patients with ileocolitis or total colitis had more Ruminococcus gnavus (P=0.02) than patients with colonic CD or left-sided UC. CD patients with upper gastrointestinal manifestations had higher Veillonella abundance (P&lt;0.01). IBD patients (58%) who received biologic therapy had lower baseline Firmicutes and Mycoplasma hominis abundance (P&lt;0.01) than conventionally treated. High Proteobacteria abundance was associated with stricturing/penetrating CD, surgery (P&lt;0.01), and nonmucosal healing (P&lt;0.03). Low Faecalibacterium prausnitzii abundance was associated with prior antibiotic therapy (P=0.001), surgery (P=0.02), and nonmucosal healing (P&lt;0.03). After therapy, IBD patients had unchanged dysbiosis. Conclusion: Fecal microbiota profiles differentiated IBD and non-IBD symptomatic children from healthy children, but displayed similar dysbiosis in IBD and non-IBD symptomatic patients. Pretreatment fecal microbiota profiles may be of prognostic value and aid in treatment individu-alization in pediatric IBD as severe dysbiosis was associated with an extensive, complicated phenotype, biologic therapy, and nonmucosal healing. The dysbiosis persisted after therapy, regardless of treatments and mucosal healing.</p

Fecal microbiota profiles in treatment-na&iuml;ve pediatric inflammatory bowel disease &ndash; associations with disease phenotype, treatment, and outcome

Christine Olbj&oslash;rn,1,2 Milada Cvancarova Sm&aring;stuen,3 Espen Thiis-Evensen,4 Britt Nakstad,1,2 Morten Harald Vatn,5 J&oslash;rgen Jahnsen,2,6 Petr Ricanek,2,6 Simen Vatn,2,6 Aina EF Moen,5 Tone M Tann&aelig;s,5 Jonas C Lindstr&oslash;m,7 Johan D S&ouml;derholm,8 Jonas Halfvarson,9 Fernando Gomoll&oacute;n,10 Christina Cas&eacute;n,11 Magdalena K Karlsson,11 Rahul Kalla,12 Alex T Adams,12,13 Jack Satsangi,12,13 G&oslash;ri Perminow14 1Department of Pediatric and Adolescent Medicine, Akershus University Hospital, L&oslash;renskog, Norway; 2Institute of Clinical Medicine, Campus Ahus, University of Oslo, Oslo, Norway; 3Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway; 4Department of Gastroenterology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 5Department of Clinical Molecular Biology (EpiGen), Division of Medicine, Akershus University Hospital, L&oslash;renskog, and University of Oslo, Oslo, Norway; 6Department of Gastroenterology, Akerhus University Hospital, L&oslash;renskog, Norway; 7Institute of Clinical Medicine, University of Oslo, Health Services Research Unit, Akershus University Hospital, L&oslash;renskog, Norway; 8Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Link&ouml;ping University, Link&ouml;ping, Sweden; 9Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Link&ouml;ping University, Link&ouml;ping, Sweden; 10Digestive Diseases Unit, IIS Arag&oacute;n, Zaragoza, Spain; 11Genetic-Analysis AS, Oslo, Norway; 12Gastrointestinal Unit, Centre for Genomics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; 13Translational Gastroenterology Unit, Experimental Medicine Division, University of Oxford, Oxford, UK; 14Department of Pediatrics, Oslo University Hospital, Ullev&aring;l, Oslo, Norway Purpose: Imbalance in the microbiota, dysbiosis, has been identified in inflammatory bowel disease (IBD). We explored the fecal microbiota in pediatric patients with treatment-na&iuml;ve IBD, non-IBD patients with gastrointestinal symptoms and healthy children, its relation to IBD subgroups, and treatment outcomes.Patients and methods: Fecal samples were collected from 235 children below 18 years of age. Eighty children had Crohn&rsquo;s disease (CD), 27 ulcerative colitis (UC), 3 IBD unclassified, 50 were non-IBD symptomatic patients, and 75 were healthy. The bacterial abundance of 54 predefined DNA markers was measured with a 16S rRNA DNA-based test using GA-Map&trade; technology at diagnosis and after therapy in IBD patients.Results: Bacterial abundance was similarly reduced in IBD and non-IBD patients in 51 of 54 markers compared to healthy patients (P&lt;0.001). Only Prevotella was more abundant in patients (P&lt;0.01). IBD patients with ileocolitis or total colitis had more Ruminococcus gnavus (P=0.02) than patients with colonic CD or left-sided UC. CD patients with upper gastrointestinal manifestations had higher Veillonella abundance (P&lt;0.01). IBD patients (58%) who received biologic therapy had lower baseline Firmicutes and Mycoplasma hominis abundance (P&lt;0.01) than conventionally treated. High Proteobacteria abundance was associated with stricturing/penetrating CD, surgery (P&lt;0.01), and nonmucosal healing (P&lt;0.03). Low Faecalibacterium prausnitzii abundance was associated with prior antibiotic therapy (P=0.001), surgery (P=0.02), and nonmucosal healing (P&lt;0.03). After therapy, IBD patients had unchanged dysbiosis.Conclusion: Fecal microbiota profiles differentiated IBD and non-IBD symptomatic children from healthy children, but displayed similar dysbiosis in IBD and non-IBD symptomatic patients. Pretreatment fecal microbiota profiles may be of prognostic value and aid in treatment individualization in pediatric IBD as severe dysbiosis was associated with an extensive, complicated phenotype, biologic therapy, and nonmucosal healing. The dysbiosis persisted after therapy, regardless of treatments and mucosal healing. Keywords: dysbiosis, Crohn&rsquo;s disease, ulcerative colitis, Proteobacteria, biologic therapy, Faecalibacterium prausnitzi

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression