Biology subjects

Bar, N.

Publications and source records attributed to Bar, N..

3 recordsLinked to original sources

bioRxiv2018

Prolonged Antibiotic Treatment Generates a Fluoroquinolone Resistant Gut Microbiome and Collateral Multi-Drug Resistance

One Sentence SummaryThe majority of the gut microbiome develops antibiotic resistance via point-mutations in addition to collateral resistance whereas its density is only moderately decreased following long-term antibiotic treatment.\n\nABSTRACTAntibiotic resistance in bacterial pathogens represents a growing threat to modern medicine. Limitation of lengthy and broad-spectrum antibacterial treatment regimens is generally recommended. Nevertheless, some conditions may require prolonged antibiotic treatment. The effects of such treatments on bacterial communities, specifically their resistome, is yet unknown. Here, we followed a unique cohort of patients with ulcerative colitis who underwent total large bowel resection and the formation of an ileal pouch from their normal small bowel. The majority of these patients tend to develop inflammation of this previously normal small bowel, known as \"pouchitis\". Pouchitis is commonly treated with repeated or prolonged courses of broad-spectrum antibiotics. By using metagenomics of faecal samples obtained longitudinally from patients treated with antibiotics for prolonged periods, we hereby show that the majority of their gut commensal bacteria develop antibiotic resistance by point-mutations. In addition, some bacterial species had acquired multidrug resistance loci with genes that confer resistance to the drug used in the treatment (ciprofloxacin) but co-localized with genes encoding extended-spectrum {beta}-lactamases and other resistance-conferring enzymes. We further show that bacterial density in faecal samples is only modestly reduced despite the long-term antibiotic treatment, thereby questioning the current rationale that antibiotic efficacy in treating pouch inflammation is due to the reduction of bacterial load. This study reveals the impact and dynamics of prolonged antibiotic treatment on human gut microbiomes and provides insights that may guide the development of future IBD therapies. It also provides novel insights into bacterial community recovery after cessation of such prolonged treatment, and highlights the increased risk of spreading mobile antibiotic resistance.

microbiology↗

bioRxiv2018

Universal cancer tasks, evolutionary tradeoffs, and the functions of driver mutations

Recent advances have led to an appreciation of the vast molecular diversity of cancer. Detailed data has enabled powerful methods to sort tumors into groups with benefits for prognosis and treatment. We are still missing, however, a general theoretical framework to understand the diversity of tumor gene-expression and mutations. To address this, we present a framework based on multi-task evolution theory, using the fact that tumors evolve in the body, and that tumors are faced with multiple tasks that contribute to their fitness. In accordance with the theory, we find that tradeoff between tasks constrains tumor gene-expression to a continuum bounded by a polyhedron. The vertices of the polyhedron are gene-expression profiles each specializing in one task, allowing the tasks to be identified. We find five universal cancer tasks across tissue-types: cell-division, biomass & energy, lipogenesis, immune-interaction and invasion & tissue remodeling. Tumors whose gene-expression lies close to a vertex are task specialists. We find evidence that such specialists are more sensitive to drugs that interfere with this task. We find that driver mutations, but not passenger mutations, tune gene-expression towards specialization in specific tasks. This approach can integrate additional types of molecular data into a theoretically-based framework for understanding tumor diversity.

cancer biology↗

bioRxiv2017

Environmental factors dominate over host genetics in shaping human gut microbiota composition

Human gut microbiome composition is shaped by multiple host intrinsic and extrinsic factors, but the relative contribution of host genetic compared to environmental factors remains elusive. Here, we genotyped a cohort of 696 healthy individuals from several distinct ancestral origins and a relatively common environment, and demonstrate that there is no statistically significant association between microbiome composition and ethnicity, single nucleotide polymorphisms (SNPs), or overall genetic similarity, and that only 5 of 211 (2.4%) previously reported microbiome-SNP associations replicate in our cohort. In contrast, we find similarities in the microbiome composition of genetically unrelated individuals who share a household. We define the term biome-explainability as the variance of a host phenotype explained by the microbiome after accounting for the contribution of human genetics. Consistent with our finding that microbiome and host genetics are largely independent, we find significant biome-explainability levels of 16-33% for body mass index (BMI), fasting glucose, high-density lipoprotein (HDL) cholesterol, waist circumference, waist-hip ratio (WHR), and lactose consumption. We further show that several human phenotypes can be predicted substantially more accurately when adding microbiome data to host genetics data, and that the contribution of both data sources to prediction accuracy is largely additive. Overall, our results suggest that human microbiome composition is dominated by environmental factors rather than by host genetics.

genetics↗