Biology subjects

Riksen, N. P.

Publications and source records attributed to Riksen, N. P..

5 recordsLinked to original sources

bioRxiv2026

Genetic, intrinsic, and environmental determinants of innate immune cytokine responses in healthy four-year-old children

Abstract/SummaryInnate immune responses are crucial for host defence but vary markedly between individuals. Although determinants of this variation are well characterised in adults, data from healthy children remain scarce. We therefore profiled whole-blood cytokine responses to innate immune stimulation in 286 children aged approximately four years and examined genetic, host-intrinsic, and environmental correlates of response. Cytokine responses showed marked inter-individual heterogeneity and stimulus-specific patterns. The top 50 genetic variants explained a substantial proportion ([~]20-45%) of this variance across many stimulus conditions, including a biologically coherent association of the STING locus with cGAMP-induced cytokine production. In contrast, sex, age, adiposity, and perinatal variables showed limited or modest associations. Systemic inflammatory biomarkers of systemic inflammation (hsCRP, glycoprotein acetyls, granulocyte-to-lymphocyte ratio) were strongly positively associated with cytokine responses. Finally, seasonal population-level viral infection burden was positively associated with antiviral and inflammatory cytokine responses. Collectively, these findings advance our understanding of variation in early-life whole-blood cytokine responses, underscoring this developmental period as a critical window for understanding immune development trajectories relevant to long-term health.

immunology↗

bioRxiv2025

HDL-associated phosphatidylserine blunts myeloid activation and protects from atherosclerosis

Background and aimsLipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, in vitro assays and in vivo experiments in Apoe-/- mice. MethodsHuman lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In vitro assays were carried out using human monocytes and macrophages, and in vivo experiments included histopathological, immunophenotyping and single-cell transcriptomic analyses. ResultsIn humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. In vitro, this formulation potently inhibited inflammatory cytokine production on human myeloid cells. Our in-depth in vivo experiments provided evidence of the formulations potent plaque-stabilizing and anti-inflammatory actions. These effects were mediated by a shift in the monocyte/macrophage compartment toward homeostatic/repairing phenotypes. ConclusionsCollectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies.

immunology↗

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

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↗