Biology subjects

Belenky, P.

Publications and source records attributed to Belenky, P..

5 recordsLinked to original sources

bioRxiv2024

MRGM: An enhanced catalog of mouse gut microbial genomes substantially broadening taxonomic and functional landscapes

Mouse gut microbiome research is pivotal for understanding the human gut microbiome, providing insights into disease modeling, host-microbe interactions, and the dietary influence on the gut microbiome. To enhance the translational value of mouse gut microbiome studies, we need detailed and high-quality catalogs of mouse gut microbial genomes. We introduce the Mouse Reference Gut Microbiome (MRGM), a comprehensive catalog with 42,245 non-redundant mouse gut bacterial genomes across 1,524 species. MRGM marks a 40% increase in the known taxonomic diversity of mouse gut microbes, capturing previously underrepresented lineages through refined genome quality assessment techniques. MRGM not only broadens the taxonomic landscape but also enriches the functional landscape of the mouse gut microbiome. Using deep learning, we have elevated the Gene Ontology annotation rate for mouse gut microbial proteins from 3.2% with orthology to 60%, marking an over 18-fold increase. MRGM supports both DNA- and marker-based taxonomic profiling by providing custom databases, surpassing previous catalogs in performance. Finally, taxonomic and functional comparisons between human and mouse gut microbiota reveal diet-driven divergences in their taxonomic composition and functional enrichment. Overall, our study highlights the value of high-quality microbial genome catalogs in advancing our understanding of the co-evolution between gut microbes and their host.

microbiology↗

bioRxiv2021

Candida albicans Isolates 529L and CHN1 Exhibit Stable Colonization of the Murine Gastrointestinal Tract

Candida albicans is a pathobiont that colonizes multiple niches in the body including the gastrointestinal (GI) tract, but is also responsible for both mucosal and systemic infections. Despite its prevalence as a human commensal, the murine GI tract is generally refractory to colonization with the C. albicans reference isolate SC5314. Here, we identify two C. albicans isolates, 529L and CHN1, that stably colonize the murine GI tract in three different animal facilities under conditions where SC5314 is lost from this niche. Analysis of the bacterial microbiota did not show notable differences between mice colonized with the three C. albicans strains. We compared the genotypes and phenotypes of these three strains and identified thousands of SNPs and multiple phenotypic differences, including their ability to grow and filament in response to nutritional cues. Despite striking filamentation differences under laboratory conditions, however, analysis of cell morphology in the GI tract revealed that the three isolates exhibited similar filamentation properties in this in vivo niche. Notably, we found that SC5314 is more sensitive to the antimicrobial peptide CRAMP, and the use of CRAMP-deficient mice increased the ability of SC5314 to colonize the GI tract relative to CHN1 and 529L. These studies provide new insights into how strain-specific differences impact C. albicans traits in the host and advance CHN1 and 529L as relevant strains to study C. albicans pathobiology in its natural host niche. IMPORTANCEUnderstanding how fungi colonize the GI tract is increasingly recognized as highly relevant to human health. The animal models used to study Candida albicans commensalism commonly rely on altering the host microbiome (via antibiotic treatment or defined diets) to establish successful GI colonization by the C. albicans reference isolate SC5314. Here, we characterize two C. albicans isolates that can colonize the murine GI tract without antibiotic treatment and can therefore be used as tools for studying fungal commensalism. Importantly, experiments were replicated in three different animal facilities and utilized three different mouse strains. Differential colonization between fungal isolates was not associated with alterations in the bacterial microbiome but rather with distinct responses to CRAMP, a host antimicrobial peptide. This work emphasizes the importance of C. albicans intra-species variation as well as host anti-microbial defense mechanisms in defining commensal interactions.

microbiology↗

bioRxiv2019

Antimicrobial resistance gene levels are independent of levofloxacin administration but related to abundance of specific pathobionts in dementia patients

BackgroundThe issue of antimicrobial resistance continues to grow worldwide, and long-term care facilities are significant reservoirs of antimicrobial-resistant organisms, in part due to high frequency of antimicrobial use. Patients with advanced dementia are particularly vulnerable to multidrug-resistant organism acquisition and antimicrobial overuse, which has negative consequences for the gut microbiome and can contribute to the selection and propagation of antimicrobial resistance genes. In this study, we longitudinally examined a group of advanced dementia patients treated with the fluoroquinolone antimicrobial levofloxacin, finding a correlation between abundance of pathogens and antimicrobial resistance genes, which we confirmed in a larger cohort of subjects with advanced dementia.\n\nResultsWe observed significant inter- and intra-subject heterogeneity in the composition of the microbiota of the longitudinal levofloxacin cohort, suggesting temporal instability. Within this dataset, we did not find significant impacts of levofloxacin on the diversity, composition, function, or resistome of the gut microbiota of this population. However, we were able to link the antimicrobial resistance gene burden in a sample with the relative abundance of several pathobionts - particularly Escherichia coli, Proteus mirabilis, and Enterococcus faecalis, as well as less-prevalent species including Providencia stuartii and Staphylococcus haemolyticus. Furthermore, we used metagenomic assembly and binning to demonstrate that these species had higher genomic resistance gene levels than common gut commensals, and we were able to predict antimicrobial resistance gene burden from the relative abundances of these species in a separate, larger cohort from the same population.\n\nConclusionsWe found that the relative abundances of several pathobionts were correlated with and were even predictive of the level of antimicrobial resistance genes in corresponding samples, and that these species carried high levels of resistances genes in their assembled genomes. In order to test this observation, we utilized a larger metagenomics dataset from a similar population and confirmed the association between pathobiont abundance and antimicrobial resistance genes. Given the high frequency with which these species were found at high levels in this population and the underlying vulnerability to infection with multidrug resistant organisms of advanced dementia patients, attention to microbial blooms of these species may be warranted. Additionally, in this study, we were able to utilize genomic assembly from metagenomic data to more definitively associate antimicrobial resistance gene levels with specific assembled species; as this technology continues to develop, assembly could prove to be a valuable method to monitor both specific resistance genes and blooms of multidrug-resistant organisms.

microbiology↗

bioRxiv2019

Consumption of a Western-style diet modulates the response of the murine gut microbiome to ciprofloxacin

Dietary composition and antibiotic use are known to have major impacts on the structure and function of the gut microbiome, often resulting in dysbiosis. Despite this, little research has been done to explore the role of host diet as a determinant of antibiotic-induced microbiome disruption. Here, we utilize a multi-omic approach to characterize the impact of Western-style diet consumption on ciprofloxacin-induced changes to gut microbiome community structure and transcriptional activity. We found that mice consuming a Western-style diet experienced a greater expansion of Firmicutes following ciprofloxacin treatment than those eating a control diet. At the transcriptional level, we found that ciprofloxacin induced a reduction in the abundance of TCA cycle transcripts on both diets, suggesting that carbon metabolism plays a key role in the response of the gut microbiome to this antibiotic. Despite this shared response, we observed extensive differences in the response of the microbiota to ciprofloxacin on each diet. In particular, at the whole-community level we detected an increase in starch degradation, glycolysis, and pyruvate fermentation following antibiotic treatment in mice on the Western diet, which we did not observe in mice on the control diet. Similarly, we observed diet-specific changes in the transcriptional activity of two important commensal bacteria, Akkermansia muciniphila and Bacteroides thetaiotaomicron, involving diverse cellular processes such as nutrient acquisition, stress responses, and capsular polysaccharide (CPS) biosynthesis. These findings demonstrate that host diet plays a key role in determining the extent of disruption of microbiome composition and function induced by antibiotic treatment. ImportanceWhile both diet and antibiotics are individually known to have profound impacts on gut microbiome composition, little work has been done to examine the effect of these two factors combined. A number of negative health outcomes, including diabetes and obesity, are associated with diets high in simple sugars in fats but low in host-indigestible fiber, and some of these outcomes may be mediated by the gut microbiome. Likewise, treatment with broad-spectrum antibiotics and the resulting dysbiosis is associated with many of the same detrimental side effects. Previous work has shown that nutrient availability, as influenced by host diet, plays an important role in determining the extent of antibiotic-induced disruption to the gut microbiome. Due to the growing incidence of disorders related to antibiotic-induced dysbiosis, it is essential to determine how the prevalence of high fat and sugar "Western"-style diets impacts the response of the microbiome to antibiotics.

microbiology↗

bioRxiv2018

Metabolism-Induced Oxidative Stress and DNA Damage Selectively Trigger Genome Instability in Polyploid Cells

Understanding the forces impacting genome stability is important for diverse processes such as tumorigenesis and reproductive biology. The pathogenic yeast Candida albicans displays unusual genome dynamics in which tetraploid cells, but not diploid cells, become unstable when grown on a glucose-rich pre-sporulation medium. Here, we reveal that C. albicans polyploid cells are metabolically hyperactive on this medium as evidenced by increased expression of metabolic genes as well as higher rates of fermentation and oxidative respiration. These cells also show elevated levels of reactive oxygen species (ROS), activate the ROS-responsive transcription factor Cap1, and accrue DNA double-strand breaks. Suppression of ROS levels reduced oxidative stress, DNA damage and chromosome instability. These studies reveal how metabolic flux can generate endogenous ROS, triggering DNA damage and genome instability in polyploid, but not diploid, cells. We discuss parallels with metabolism-induced instability in cancer cells and propose that ROS-induced DNA damage could have facilitated ploidy cycling in eukaryotes prior to the evolution of meiosis.

microbiology↗