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Verhaar, B. J. H.

Publications and source records attributed to Verhaar, B. J. H..

3 recordsLinked to original sources

Ethnic differences in gut microbiota composition and functional capacity persist over six years in the HELIUS multi-ethnic longitudinal cohort

Background: Ethnic minority groups in Western Europe carry a disproportionate cardiometabolic disease burden not fully explained by conventional risk factors, and their gut microbiomes differ markedly from those of European-origin populations. Whether these differences persist over time has not been examined prospectively. Results: We followed 1,903 participants from six ethnic groups in the HELIUS cohort over 6 years, using faecal 16S rRNA sequencing across all groups and shotgun metagenomics in a matched Dutch and South-Asian Surinamese subset (N = 238 per group). The extent of microbiota compositional change over time differed between ethnic groups: Moroccan participants showed the largest change, while the Dutch and South-Asian Surinamese participants were most stable. Diabetes mellitus and medication use at baseline were associated with greater compositional drift. However, ethnic differences in composition were largely preserved across all six groups (16S: ethnicity R2 0.044 to 0.037; all 15 pairwise contrasts significant at follow-up) and in the shotgun subset (R2 0.047 to 0.037). At the species level, 61 of 78 ethnicity-associated species remained differentially abundant at follow-up. Alistipes putredinis, the species converging most strongly, was absent at baseline in 43% of South-Asian Surinamese participants, and the convergence was consistent with acquisition of this species by this group. At strain level, within-person strain sharing declined with follow-up duration but was similar between ethnic groups. Within hosts, 90% of A. putredinis populations were retained as the same or a closely related lineage, and within the retained subset, microdiversity increased in both groups. Ethnic differences in functional profiles persisted to a similar extent as those in composition, with limited convergence in fibre-degrading enzyme families (GH5_37, GH26). The total antibiotic resistance gene (ARG) burden in the gut microbiome declined similarly in both groups over time. Dutch participants showed higher baseline ARG diversity that converged toward South-Asian Surinamese levels, while class-level differences were predominantly stable. Conclusions: Six years of follow-up in a shared urban environment narrowed ethnic differences in the gut microbiome only modestly; assuming exponential decline, the observed change corresponds to a half-life of roughly two decades.

microbiology↗

Gut microbial metabolite imidazole propionate impairs endothelial cell function and promotes the development of atherosclerosis

BackgroundThe microbially generated amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effect of ImP on endothelial cell physiology and its role in atherosclerotic coronary artery disease (CAD) is unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis. MethodsPlasma levels of ImP were measured in patients undergoing elective cardiac angiography (n = 831) by means of ultra high-performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios (ORs) and corresponding 95% confidence intervals for CAD were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. Atheroprone apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet were additionally treated with ImP (800 {micro}g) or vehicle and aortic atherosclerotic lesion area was evaluated after 12 weeks. In a mouse model of carotid artery injury, the effect of ImP on vascular regeneration was examined. Using human aortic endothelial cells (HAECs) the effect of ImP on functional properties of endothelial cells were assessed. Next-generation sequencing, western blot analysis, siRNA-based gene knockdown and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms. ResultsPlasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk for prevalent CAD. In atheroprone Apoe-/- mice ImP increased atherosclerotic lesion size. We found that ImP dose-dependently impaired migratory and angiogenic properties of human endothelial cells, and promoted an increased inflammatory response. Long-term exposure to ImP impaired the repair potential of the endothelium after an arterial insult. Mechanistically, ImP attenuated insulin receptor signaling by suppressing PI3K/AKT pathway leading to the sustained activation of the forkhead box protein O1 (FOXO1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of endothelial cells after carotid injury. ConclusionsOur findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.

systems biology↗

Pneumonia induced rise in glucagon promotes endothelial damage and vascular thrombogenicity

BackgroundRecent studies have demonstrated a link between respiratory infections and increased short-term risk of cardiovascular disease (CVD). However, the molecular mechanisms underlying the increased cardiovascular risk after respiratory infections are only poorly understood. Here, we aimed to decipher pathophysiological circuits of pneumonia associated CVD in experimental models of bacterial pneumonia and vascular injury. MethodsC57BL/6J mice were exposed to intranasal inoculation with either Streptococcus pneumoniae (S. pneumoniae) serotype 4 (pneumonia group) or phosphate buffered saline (PBS) (control group). 24 hours post infectionem (p.i.) mice were treated with antibiotics until the end of the study. On day 7 p.i. carotid artery injury (CI) was induced by electric stimulation and vascular repair was analyzed 3 days after injury. Plasma proteomic analyses were performed by Olink Bioscience. Primary human aortic endothelial cells (HAECs) were used to study alterations of the endothelial functional properties, bioenergetic state and thrombogenic potential in vitro. Intravital fluorescence microscopy equipped with video recording was applied to measure thrombus formation in real-time. ResultsBacterial pneumonia impaired repair capacity of the endothelium after vascular injury. Proteomic analyses revealed significantly higher plasma levels of glucagon in mice after recovery from pneumonia relative to controls, which was further confirmed by ELISA detecting glucagon. Mechanistically, we found that glucagon impaired mitochondrial bioenergetics and migratory potential in HAECs and induced an inflammatory response. Moreover, glucagon fostered vascular thrombogenicity as demonstrated by increased thrombocyte adhesion to HAECs and accelerated carotid artery thrombus formation in vivo. Acute application of the glucagon-like peptide-1 receptor (GLP1-R) agonist liraglutide to lower blood glucagon levels, restored vascular repair potential and attenuated vascular thrombogenicity in mice with pneumonia. ConclusionsOur findings reveal a novel mechanism that associates elevated circulatory glucagon levels to dysfunctional endothelium and increased vascular thrombogenicity, suggesting glucagon signaling as a potential therapeutic target to prevent pneumonia-induced cardiovascular events. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/592488v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1dab59eorg.highwire.dtl.DTLVardef@1c9a033org.highwire.dtl.DTLVardef@34a566org.highwire.dtl.DTLVardef@56e33d_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗