Biology subjects

Zhernakova, A.

Publications and source records attributed to Zhernakova, A..

26 records · Page 2Linked to original sources

bioRxiv2021

Discovery, diversity and functional associations of crAss-like phages in human gut metagenomes from four Dutch cohorts

The crAss-like phages are a diverse group of related viruses that includes one of the most abundant viruses of the human gut. To explore their diversity and functional role in human population and clinical cohorts, we analyzed gut metagenomic data collected from more than 2000 individuals from the Netherlands. We discovered 125 novel species-level and 32 novel genus-level clusters of crAss-like phages, all belonging to five previously recognized groups associated with the human gut. Analysis of their genomic features revealed that closely related crAss-like phages can possess strikingly divergent regions responsible for transcription, presumably acquired through recombination. Prediction of crAss-like phage hosts pointed primarily to bacteria of the phylum Bacteroidetes, consistent with previous reports. Finally, we explored the temporal stability of crAss-like phages over a 4-year period and identified associations between the abundance of crAss-like phages and several human phenotypes, including depletion of crAss-like phages in inflammatory bowel disease patients. HighlightsO_LI125 tentative new species of crAss-like phages were discovered C_LIO_LIClosely related crAss-like phages often possess highly divergent transcription gene modules possibly acquired via recombination C_LIO_LICrAss-like fraction of the human gut virome remains relatively stable over the period of 4 years C_LIO_LIPrevalence of crAss-like phages in the human gut is associated with several metabolic, dietary and health phenotypes C_LIO_LIGut crAss-like phages are depleted in inflammatory bowel disease patients C_LI

microbiology↗

bioRxiv2021

Gut microbial structural variations as determinants of human bile acid metabolism

Bile acids (BAs) facilitate intestinal fat absorption and act as important signaling molecules in host{square}gut microbiota crosstalk. BA-metabolizing pathways in the microbial community have been identified, but how the highly variable genomes of gut bacteria interact with host BA metabolism remains largely unknown. We characterized 8,282 structural variants (SVs) of 55 bacterial species in the gut microbiomes of 1,437 individuals from two Dutch cohorts and performed a systematic association study with 39 plasma BA parameters. Both variations in SV-based continuous genetic makeup and discrete subspecies showed correlations with BA metabolism. Metagenome-wide association analysis identified 797 replicable associations between bacterial SVs and BAs and SV regulators that mediate the effects of lifestyle factors on BA metabolism. This is the first large-scale microbial genetic association analysis to demonstrate the impact of bacterial SVs on human BA composition, and highlights the potential of targeting gut microbiota to regulate BA metabolism through lifestyle intervention.

microbiology↗

bioRxiv2021

A systematic analysis of metabolic pathways in the human gut microbiota

The gut microbiota produce hundreds of small molecules, many of which modulate host physiology. Although efforts have been made to identify biosynthetic genes for secondary metabolites, the chemical output of the gut microbiome consists predominantly of primary metabolites. Here, we systematically profile primary metabolic genes from the gut microbiome, identifying 19,885 gene clusters in 4,240 high-quality microbial genomes. We find marked differences in pathway distribution among phyla, reflecting distinct strategies for energy capture. These data explain taxonomic differences in short-chain fatty acid production and suggest a characteristic metabolic niche for each taxon. Analysis of 1,135 subjects from a Dutch population-based cohort shows that the level of 14 microbiome-derived metabolites in plasma is almost completely uncorrelated with the metagenomic abundance of the corresponding biosynthetic genes, revealing a crucial role for pathway-specific gene regulation and metabolite flux. This work is a starting point for understanding differences in how bacterial taxa contribute to the chemistry of the microbiome.

bioinformatics↗

bioRxiv2020

Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

Host genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function within the Dutch Microbiome Project, a population cohort of 7,738 individuals from the northern Netherlands. Two robust, study-wide significant (p<1.89x10-10) signals near the LCT and ABO genes were found to affect multiple microbial taxa and pathways, and were replicated in two independent cohorts. The LCT locus associations were modulated by lactose intake, while those at ABO reflected participant secretor status determined by FUT2 genotype. Eighteen other loci showed suggestive evidence (p<5x10-8) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome.

genetics↗

bioRxiv2020

The Dutch Microbiome Project defines factors that shape the healthy gut microbiome

The gut microbiome is associated with diverse diseases, but the universal signature of an (un)healthy microbiome remains elusive and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. To fill this gap, we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We then correlated this to 241 host and environmental factors, including physical and mental health, medication use, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is primarily shaped by environment and cohousing. Only [~]13% of taxa are heritable, which are enriched with highly prevalent and health-associated bacteria. By identifying 2,856 associations between microbiome and health, we find that seemingly unrelated diseases share a common signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, of which numerous early-life and current factors are particularly linked to the microbiome. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.

microbiology↗

bioRxiv2019

Predicting biological age based on the BBMRI-NL 1H-NMR metabolomics repository

The blood metabolome incorporates cues from the environment as well as the hosts genetic background, potentially offering a holistic view of an individuals health status. We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individuals biological age. Exploration in independent cohorts demonstrates that being judged older by ones metabolome, as compared to ones chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.

epidemiology↗

bioRxiv2019

Relationship between gut microbiota and circulating metabolites in population-based cohorts

Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. As recent development in metabolomics allows classifying the lipoprotein particles into more details, we aimed to examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance (1H-NMR) technology in 2,309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort in whom gut microbiota was profiled using 16S rRNA gene sequencing. The relationship between gut microbiota and metabolites was assessed by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. Our analysis revealed association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, amino acids, and acute phase reaction markers. These observations provide novel insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.

epidemiology↗

bioRxiv2019

Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Microbiomes are vast communities of microbes and viruses that populate all natural ecosystems. Viruses have been considered the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared to other environments. Here we investigate the origin, evolution, and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboratory, we obtained DNA sequences of crAssphage from over one-third of the worlds countries, and showed that its phylogeography is locally clustered within countries, cities, and individuals. We also found colinear crAssphage-like genomes in both Old-World and New-World primates, challenging genomic mosaicism and suggesting that the association of crAssphage with primates may be millions of years old. We conclude that crAssphage is a benign globetrotter virus that may have co-evolved with the human lineage and an integral part of the normal human gut virome.

microbiology↗