Biology subjects

Kurilshikov, A.

Publications and source records attributed to Kurilshikov, A..

16 recordsLinked to original sources

bioRxiv2026

Comprehensive profiling of infant gut virome assembly reveals associations with eczema and wheeze

Infancy is a critical developmental window during which the gut ecosystem assembles and helps train the immune system, thereby setting trajectories for lifelong health. Bacteria and viruses are equally numerous in this early ecosystem, yet the gut viromes composition, dynamics, and health relevance remain poorly understood. Here, we show that the infant gut virome is diverse, dynamic, and linked to health outcomes. We performed comprehensive virome profiling of 1,110 longitudinal fecal samples from 314 mother-infant pairs from the Dutch birth cohort Lifelines NEXT using both virus-like particle enrichment (VLP) and total metagenomic sequencing (MGS). We find only 18.9% compositional overlap between the VLP- and MGS-metaviromes, with VLP recovering the active virome and most novel species and MGS predominantly capturing temperate phages. By combining both methods, we identified 8,348 novel virus species spanning diverse hosts, from bacteria to humans, and all major viral genome types (dsDNA, ssDNA, and RNA). We find that bacteriophages frequently encode metabolic functions, including genes related to B vitamin metabolism. We further observe that the development of the infant gut virome is shaped by both host factors, including delivery mode and feeding practices, and continuous switching of temperate phage lifecycles. Notably, the relative abundance of induced temperate phages is also associated with eczema development within the first year of life. Together, these findings establish the infant gut virome as a dynamic and clinically relevant component of early-life microbial development and highlight how comprehensive dual-method profiling is a necessary framework for future virome research.

microbiology↗

bioRxiv2026

Pregnancy and Early-Life Gut Virome in the Lifelines NEXT cohort:Origin, Persistence, Influencing Factors and Health Implications

The human gut virome is a key modulator of gut microbial ecology and function, yet its role in early gut ecosystem development remains poorly understood. Here, we profiled the DNA virome from 4,523 fecal and 91 breastmilk metagenomes from 714 mother-infant pairs in the Dutch birth cohort Lifelines NEXT. This analysis generated a catalog of 31,205 unique vOTUs, with 31,019 detected in fecal and 248 in breastmilk samples, including 16,540 not previously reported in other databases. We find that the maternal virome is largely stable, in contrast to the infant viromes rapid diversification over time. We also identify delivery and feeding modes as major drivers of infant virome developmental trajectories, with additional influences of maternal parity, infections during pregnancy, socioeconomic factors, gestational age and infant birth weight. Notably, increased viral diversity was associated with the infant developing a food allergy. Strain-level virome profiling confirmed the maternal gut as the primary source of viruses for the infant gut, with increased sharing rates in vaginally delivered infants and with breastmilk as a secondary reservoir. We demonstrate that temperate phages frequently co-transmit with their bacterial hosts and identify multiple protein families associated with anti-defense functions enriched among maternally shared viruses. Finally, we show that DNA adenine N6-methyltransferase hin1523, together with widely active diversity-generating retroelements, promote long-term viral persistence in the infant and maternal gut. Together, these findings establish the origin, dynamics and modulating factors of the infant gut virome, along with the genetic strategies supporting its persistence in the gut ecosystem.

microbiology↗

bioRxiv2024

Negativeome in Early-Life Virome Studies: Characterization and Decontamination

Environmental contamination complicates the study of low-biomass microbial communities like the human gut virome. In 1,321 early-life gut viromes and 55 negative controls (NCs) from four datasets, we identified viral contaminants and their prevalence across studies. Samples and NCs were indistinguishable in genomic and ecological features, with 71.5% of samples sharing at least one identical strain with NCs. This work demonstrates the efficacy of strain-aware decontamination for preserving biological signals.

bioinformatics↗

bioRxiv2024

Dynamics and determinants of the gut mobilome in early life

As mobile genetic elements (MGE) are critical yet understudied determinants of gut microbiome composition, we characterized the gut virome and plasmidome in 195 samples from 28 mother-infant dyads delivered by caesarean section. Infant mobilome increased in richness over the first 6 postnatal weeks, demonstrating high individual-specificity and temporal stability, establishing a personal persistent mobilome. Formula-fed infants exhibited greater mobilome richness than breastfed infants, with plasmid composition influenced by antibiotic exposure and birth weight. Plasmids constituted a significant reservoir of antibiotic resistance genes (ARG), with around 5% of infant gut plasmid taxonomic units carrying ARG. Notably, ARG profiles did not differ with antibiotic exposure at birth. We found that mother-infant sharing of viral and plasmid strains primarily occurred after 6 months of age. Overall, our integrative analysis offers novel insights into the dynamics, modulation, origin, and clinical implications of MGE in the developing gut microbiome.

genomics↗

bioRxiv2023

Linking the gut microbiome to host DNA methylation by a discovery and replication epigenome-wide association study

Both gene methylation and the gut microbiome are partially determined by host genetics and partially by environment. We investigated the relations between gene methylation in blood and the abundance of common gut bacteria profiled by 16s rRNA gene sequencing in two population-based Dutch cohorts: LifeLines-Deep (LLD, n = 616, discovery) and the Netherlands Twin Register (NTR, n = 296, replication). In LLD, we also explored microbiome composition using data generated by shotgun metagenomic sequencing (n = 683). We then investigated if genetic and environmental factors can explain the methylation-microbiota associations in a set of 78 associated CpG-taxa pairs from the EWAS meta-analysis. In both cohorts, blood and stool samples were collected within 2 weeks of each other. Methylation was profiled in blood samples using the Illumina 450K array. Methylation and microbiome analysis pipelines were harmonized across cohorts. Epigenome-wide association study (EWAS) of microbial features were analysed using linear regression with adjustment for technical covariates. Discovery and replication analysis using 16s data identified two independent CpGs associated with the genus Eggerthella: cg16586104 (Pmeta-analysis = 3.21 x 10-11) and cg12234533 (Pmeta-analysis = 4.29 x 10-10). While we did not find human genetic variants that could explain the associated CpG-taxa/pathway pairs, we show that microbiome can mediate the effect of environmental factors on epigenetics. In this first association study linking epigenome to microbiome, we found and replicated the associations of two CpGs to the abundance of genus Eggerthella and identified microbiome as a mediator of the exposome.

genomics↗

bioRxiv2023

Mother-Infant Gut Viruses and their Bacterial Hosts: Transmission Patterns and Dynamics during Pregnancy and Early Life

Early development of the gut ecosystem is crucial for lifelong health. While infant gut bacterial communities have been studied extensively, the infant gut virome remains under-explored. We longitudinally assessed the composition of gut viruses and their bacterial hosts in 322 total metagenomes and 205 metaviromes from 30 mothers during and after pregnancy and from their 32 infants during their first year of life. While the maternal gut virome composition remained stable during late pregnancy and after birth, the infant gut virome was dynamic in the first year of life and contained a higher abundance of active temperate phages compared to the maternal gut viromes. The infant gut virome composition was also influenced by infant feeding mode and place of delivery. Lastly, we provide evidence of viral-bacterial strains co-transmission from mothers to infants, demonstrating that infants acquire some of their virome from their mothers gut. Highlights- Longitudinal characterisation of the gut microbiome and virome in 30 mothers during pregnancy, at birth and 3 months after birth and in 32 infants from birth across the first year of life. - The maternal gut bacteriome changes from the first to the second trimester and then remains stable through birth and the first 3 months after birth. - The maternal gut virome remains stable during late pregnancy, birth and the first 3 months after birth. - The infant gut virome is highly dynamic during the first year of life and is shaped by infant feeding mode and place of delivery. - The infant gut harbours more temperate bacteriophages than the maternal gut, but their relative abundance decreases with increasing infant age. - Gut viral strains and their bacterial host strains are co-transmitted from mothers to their infants. - Gut viral strains are transferred from mother to infant around birth directly or via transfer of their bacterial hosts followed by the induction of prophages.

microbiology↗

bioRxiv2022

Diversity and ecology of Caudoviricetes phages with genome terminal repeats in fecal metagenomes from four Dutch cohorts

The human gut harbors numerous viruses infecting the human host, microbes and other inhabitants of the gastrointestinal tract. Most of these viruses remain undiscovered, and their influence on human health is unknown. Here we characterize viral genomes in gut metagenomic data from 1,950 individuals from four population and patient cohorts. We focus on a subset of viruses that is highly abundant in the gut, remains largely uncharacterized, and allows confident complete genome identification - phages that belong to the class Caudoviricetes and possess genome terminal repeats. We detect 1,899 species-level units belonging to this subset, 19% of which do not have complete representative genomes in major public gut virome databases. These units display diverse genomic features, are predicted to infect a wide range of microbial hosts, and on average account for < 1% of metagenomic reads. Analysis of longitudinal data from 338 individuals shows that the composition of this fraction of the virome remained relatively stable over a period of 4 years. We also demonstrate that 54 species-level units are highly prevalent (detected in > 5% of individuals in a cohort). Finally, we find 34 associations between highly prevalent phages and human phenotypes, 24 of which can be explained by the relative abundance of potential hosts.

microbiology↗

bioRxiv2021

Genetic, parental and lifestyle factors influence telomere length

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1,046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Coupling these measurements to single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.

cell biology↗

bioRxiv2021

In-depth characterization of the serum antibody epitope repertoire in inflammatory bowel disease using phage-displayed immunoprecipitation sequencing

Inflammatory bowel diseases (IBD), e.g. Crohns disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases. A comprehensive overview of an IBD-specific antibody epitope repertoire is, however, lacking. We leveraged a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow to identify antibodies against 344,000 antimicrobial, immune and food antigens in 497 IBD patients as compared to 1,326 controls. IBD was characterized by 373 differentially abundant antibodies (202 overrepresented and 171 underrepresented), with 17% shared by both IBDs, 55% unique to CD and 28% unique to UC. Antibodies against bacterial flagellins dominated in CD and were associated with ileal involvement, fibrostenotic disease and anti-Saccharomyces cerevisiae antibody positivity, but not with fecal microbiome composition. Antibody epitope repertoires accurately discriminated CD from controls (AUC=0.89), and similar discrimination was achieved when using only ten antibodies (AUC=0.87). IBD patients thus show a distinct antibody repertoire against selected peptides, allowing patient stratification and discovery of immunological targets.

immunology↗

bioRxiv2021

Genetic, environmental and intrinsic determinants of the human antibody epitope repertoire

Phage-displayed immunoprecipitation sequencing (PhIP-Seq) has successfully enabled high-throughput profiling of human antibody profiles. However, a comprehensive overview of environmental and genetic determinants shaping human adaptive immunity is currently lacking. In this study, we aimed to investigate the effects of genetic, environmental and intrinsic factors on the variation in human antibody repertoires. We characterized serological antibody repertoires against 344,000 peptides using PhIP-Seq libraries from a wide range of microbial and environmental antigens in 1,443 participants from a population cohort. We demonstrate individual-specificity, temporal consistency and co-housing similarities in antibody repertoire. Genetic analyses showed involvement of the HLA, IGHV and FUT2 regions. Furthermore, we uncovered associations between 48 phenotypic factors and 544 antibody-bound peptides, including age, cell counts, sex, smoking behavior and allergies, among others. Overall, our results indicate that human antibody epitope repertoires are shaped by both host genetics and environmental exposures and highlight unique signatures of distinct phenotypes and genotypes.

immunology↗

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↗

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↗

bioRxiv2020

Genetics of human gut microbiome composition

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 out of 410 genera were detected in more than 95% samples. A genome-wide association study (GWAS) of host genetic variation in relation to microbial taxa identified 31 loci affecting microbiome at a genome-wide significant (P<5x10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (GWAS signal P=1.28x10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95x10-10<P<5x10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome has causal effects in ulcerative colitis and rheumatoid arthritis.

genetics↗

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↗