Publications by authors named "Jingyuan Fu"

107 Publications

Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota.

Nat Med 2021 Jul 19. Epub 2021 Jul 19.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

Serum antibodies can recognize both pathogens and commensal gut microbiota. However, our current understanding of antibody repertoires is largely based on DNA sequencing of the corresponding B-cell receptor genes, and actual bacterial antigen targets remain incompletely characterized. Here we have profiled the serum antibody responses of 997 healthy individuals against 244,000 rationally selected peptide antigens derived from gut microbiota and pathogenic and probiotic bacteria. Leveraging phage immunoprecipitation sequencing (PhIP-Seq) based on phage-displayed synthetic oligo libraries, we detect a wide breadth of individual-specific as well as shared antibody responses against microbiota that associate with age and gender. We also demonstrate that these antibody epitope repertoires are more longitudinally stable than gut microbiome species abundances. Serum samples of more than 200 individuals collected five years apart could be accurately matched and could serve as an immunologic fingerprint. Overall, our results suggest that systemic antibody responses provide a non-redundant layer of information about microbiota beyond gut microbial species composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-021-01409-3DOI Listing
July 2021

Strategies for Interfering With Bacterial Early Stage Biofilms.

Front Microbiol 2021 8;12:675843. Epub 2021 Jun 8.

Innovative Engineering Research Center of Veterinary Pharmaceutics, Department of Pharmacy, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.

Biofilm-related bacteria show high resistance to antimicrobial treatments, posing a remarkable challenge to human health. Given bacterial dormancy and high expression of efflux pumps, persistent infections caused by mature biofilms are not easy to treat, thereby driving researchers toward the discovery of many anti-biofilm molecules that can intervene in early stage biofilms formation to inhibit further development and maturity. Compared with mature biofilms, early stage biofilms have fragile structures, vigorous metabolisms, and early attached bacteria are higher susceptibility to antimicrobials. Thus, removing biofilms at the early stage has evident advantages. Many reviews on anti-biofilm compounds that prevent biofilms formation have already been done, but most of them are based on compound classifications to introduce anti-biofilm effects. This review discusses the inhibitory effects of anti-biofilm compounds on early stage biofilms formation from the perspective of the mechanisms of action, including hindering reversible adhesion, reducing extracellular polymeric substances production, interfering in the quorum sensing, and modifying cyclic di-GMP. This information can be exploited further to help researchers in designing new molecules with anti-biofilm activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmicb.2021.675843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217469PMC
June 2021

Oral Microbiome in Relation to Periodontitis Severity and Systemic Inflammation.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Internal Medicine and Radboud Institute for Molecular Life Science (RIMLS), Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The "red complex" and "cluster B" abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22115876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199296PMC
May 2021

A Benchmark of Genetic Variant Calling Pipelines Using Metagenomic Short-Read Sequencing.

Front Genet 2021 10;12:648229. Epub 2021 May 10.

Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands.

Microbes live in complex communities that are of major importance for environmental ecology, public health, and animal physiology and pathology. Short-read metagenomic shotgun sequencing is currently the state-of-the-art technique for exploring these communities. With the aid of metagenomics, our understanding of the microbiome is moving from composition toward functionality, even down to the genetic variant level. While the exploration of single-nucleotide variation in a genome is a standard procedure in genomics, and many sophisticated tools exist to perform this task, identification of genetic variation in metagenomes remains challenging. Major factors that hamper the widespread application of variant-calling analysis include low-depth sequencing of individual genomes (which is especially significant for the microorganisms present in low abundance), the existence of large genomic variation even within the same species, the absence of comprehensive reference genomes, and the noise introduced by next-generation sequencing errors. Some bioinformatics tools, such as metaSNV or InStrain, have been created to identify genetic variants in metagenomes, but the performance of these tools has not been systematically assessed or compared with the variant callers commonly used on single or pooled genomes. In this study, we benchmark seven bioinformatic tools for genetic variant calling in metagenomics data and assess their performance. To do so, we simulated metagenomic reads to mimic human microbial composition, sequencing errors, and genetic variability. We also simulated different conditions, including low and high depth of coverage and unique or multiple strains per species. Our analysis of the simulated data shows that probabilistic method-based tools such as HaplotypeCaller and Mutect2 from the GATK toolset show the best performance. By applying these tools to longitudinal gut microbiome data from the Human Microbiome Project, we show that the genetic similarity between longitudinal samples from the same individuals is significantly greater than the similarity between samples from different individuals. Our benchmark shows that probabilistic tools can be used to call metagenomes, and we recommend the use of GATK's tools as reliable variant callers for metagenomic samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.648229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141913PMC
May 2021

Stability of the human gut virome and effect of gluten-free diet.

Cell Rep 2021 May;35(7):109132

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands. Electronic address:

The human gut microbiome consists of bacteria, archaea, eukaryotes, and viruses. The gut viruses are relatively underexplored. Here, we longitudinally analyzed the gut virome composition in 11 healthy adults: its stability, variation, and the effect of a gluten-free diet. Using viral enrichment and a de novo assembly-based approach, we demonstrate the quantitative dynamics of the gut virome, including dsDNA, ssDNA, dsRNA, and ssRNA viruses. We observe highly divergent individual viral communities, carrying on an average 2,143 viral genomes, 13.1% of which were present at all 3 time points. In contrast to previous reports, the Siphoviridae family dominates over Microviridae in studied individual viromes. We also show individual viromes to be stable at the family level but to vary substantially at the genera and species levels. Finally, we demonstrate that lower initial diversity of the human gut virome leads to a more pronounced effect of the dietary intervention on its composition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109132DOI Listing
May 2021

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.

medRxiv 2021 Apr 7. Epub 2021 Apr 7.

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.04.01.21254789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043484PMC
April 2021

The long-term genetic stability and individual specificity of the human gut microbiome.

Cell 2021 Apr 9;184(9):2302-2315.e12. Epub 2021 Apr 9.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713GZ, the Netherlands. Electronic address:

By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart. We further observe temporal changes in the abundance of multiple bacterial species, metabolic pathways, and structural variation, as well as strain replacement. We report 190 longitudinal microbial associations with host phenotypes and 519 associations with plasma metabolites. These associations are enriched for cardiometabolic traits, vitamin B, and uremic toxins. Finally, mediation analysis suggests that the gut microbiome may influence cardiometabolic health through its metabolites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2021.03.024DOI Listing
April 2021

Patient attitudes towards faecal sampling for gut microbiome studies and clinical care reveal positive engagement and room for improvement.

PLoS One 2021 8;16(4):e0249405. Epub 2021 Apr 8.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Faecal sample collection is crucial for gut microbiome research and its clinical applications. However, while patients and healthy volunteers are routinely asked to provide stool samples, their attitudes towards sampling remain largely unknown. Here, we investigate the attitudes of 780 Dutch patients, including participants in a large Inflammatory Bowel Disease (IBD) gut microbiome cohort and population controls, in order to identify barriers to sample collection and provide recommendations for gut microbiome researchers and clinicians. We sent questionnaires to 660 IBD patients and 112 patients with other disorders who had previously been approached to participate in gut microbiome studies. We also conducted 478 brief interviews with participants in our general population cohort who had collected stool samples. Statistical analysis of the data was performed using R. 97.4% of respondents reported that they had willingly participated in stool sample collection for gut microbiome research, and most respondents (82.9%) and interviewees (95.6%) indicated willingness to participate again, with their motivations for participating being mainly altruistic (57.0%). Responses indicated that storing stool samples in the home freezer for a prolonged time was the main barrier to participation (52.6%), but clear explanations of the sampling procedures and their purpose increased participant willingness to collect and freeze samples (P = 0.046, P = 0.003). To account for participant concerns, gut microbiome researchers establishing cohorts and clinicians trying new faecal tests should provide clear instructions, explain the rationale behind their protocol, consider providing a small freezer and inform patients about study outcomes. By assessing the attitudes, motives and barriers surrounding participation in faecal sample collection, we provide important information that will contribute to the success of gut microbiome research and its near-future clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249405PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031379PMC
April 2021

Long-term dietary patterns are associated with pro-inflammatory and anti-inflammatory features of the gut microbiome.

Gut 2021 Jul 2;70(7):1287-1298. Epub 2021 Apr 2.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands

Objective: The microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. We aim to unravel interactions between diet, gut microbiota and their functional ability to induce intestinal inflammation.

Design: We investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn's disease, ulcerative colitis, irritable bowel syndrome and the general population. Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Associations between diet and microbial features were explored per cohort, followed by a meta-analysis and heterogeneity estimation.

Results: We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn's disease and UC (false discovery rate<0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, species of the genus and endotoxin synthesis pathways. The opposite was found for plant foods and fish, which were positively associated with short-chain fatty acid-producing commensals and pathways of nutrient metabolism.

Conclusion: We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2020-322670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223641PMC
July 2021

Gut microbiome and bile acids in obesity-related diseases.

Best Pract Res Clin Endocrinol Metab 2021 May 10;35(3):101493. Epub 2021 Feb 10.

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Dysbiosis has been implemented in the etiologies of obesity-related chronic diseases such as type 2 diabetes, NAFLD and cardiovascular diseases. Bile acids, a class of amphipathic steroids produced in the liver and extensively modified by the microbiome, are increasingly recognized as actors in onset and progression of these diseases. Indeed, human obesity is associated with altered bile acid metabolism. Bile acids facilitate intestinal fat absorption but also exert hormone-like functions through activation of nuclear and membrane-bound receptors and thereby modulate glucose, lipid and energy metabolism, intestinal integrity and immunity. Bile acid-signaling pathways have thus been identified as potential pharmacological targets for obesity-related diseases. Interfering with microbiome composition may also be considered, as liver- and microbiome-derived bile acid species have different signaling functions. This review summarizes recent developments in this rapidly expanding field of research and addresses potential clinical prospects of interference with bile acid signaling pathways in human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.beem.2021.101493DOI Listing
May 2021

The composition and metabolic potential of the human small intestinal microbiota within the context of inflammatory bowel disease.

J Crohns Colitis 2021 Jan 30. Epub 2021 Jan 30.

Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: The human gastrointestinal tract harbours distinct microbial communities essential for health. Little is known about small intestinal communities, despite the small intestine playing a fundamental role in nutrient absorption and host-microbe immune homeostasis. We aimed to explore the small intestine microbial composition and metabolic potential, in the context of inflammatory bowel disease (IBD).

Methods: Metagenomes derived from faecal samples and extensive phenotypes were collected from 57 individuals with an ileostomy or ileoanal pouch, and compared with 1178 general population and 478 IBD faecal metagenomes. Microbiome features were identified using MetaPhAn2 and HUMAnN2, and association analyses were performed using multivariate linear regression.

Results: Small intestinal samples had a significantly lower bacterial diversity, compared with the general population and, to a lesser extent, IBD samples. Comparing bacterial composition, small intestinal samples clustered furthest from general population samples and closest to IBD samples with intestinal resections. Veillonella atypica, Streptococcus salivarius and Actinomyces graevenitzii were among the species significantly enriched in the small intestine. Predicted metabolic pathways in the small intestine are predominantly involved in simple carbohydrate and energy metabolism, but also suggest a higher proinflammatory potential.

Conclusion: We described the bacterial composition and metabolic potential of the small intestinal microbiota. The colonic microbiome of IBD patients, particularly with intestinal resections, showed resemblance to that of the small intestine. Moreover, several features characterising the small intestinal microbiome have been previously associated with IBD. These results highlight the importance of studying the small intestinal microbiota to gain new insight into disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ecco-jcc/jjab020DOI Listing
January 2021

Healthy Cotwins Share Gut Microbiome Signatures With Their Inflammatory Bowel Disease Twins and Unrelated Patients.

Gastroenterology 2021 May 19;160(6):1970-1985. Epub 2021 Jan 19.

Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Background & Aims: It is currently unclear whether reported changes in the gut microbiome are cause or consequence of inflammatory bowel disease (IBD). Therefore, we studied the gut microbiome of IBD-discordant and -concordant twin pairs, which offers the unique opportunity to assess individuals at increased risk of developing IBD, namely healthy cotwins from IBD-discordant twin pairs.

Methods: Fecal samples were obtained from 99 twins (belonging to 51 twin pairs), 495 healthy age-, sex-, and body mass index-matched controls, and 99 unrelated patients with IBD. Whole-genome metagenomic shotgun sequencing was performed. Taxonomic and functional (pathways) composition was compared among healthy cotwins, IBD-twins, unrelated patients with IBD, and healthy controls with multivariable (ie, adjusted for potential confounding) generalized linear models.

Results: No significant differences were observed in the relative abundance of species and pathways between healthy cotwins and their IBD-twins (false discovery rate <0.10). Compared with healthy controls, 13, 19, and 18 species, and 78, 105, and 153 pathways were found to be differentially abundant in healthy cotwins, IBD-twins, and unrelated patients with IBD, respectively (false discovery rate <0.10). Of these, 8 (42.1%) of 19 and 1 (5.6%) of 18 species, and 37 (35.2%) of 105 and 30 (19.6%) of 153 pathways overlapped between healthy cotwins and IBD-twins, and healthy cotwins and unrelated patients with IBD, respectively. Many of the shared species and pathways have previously been associated with IBD. The shared pathways include potentially inflammation-related pathways, for example, an increase in propionate degradation and L-arginine degradation pathways.

Conclusions: The gut microbiome of healthy cotwins from IBD-discordant twin pairs displays IBD-like signatures. These IBD-like microbiome signatures might precede the onset of IBD. However, longitudinal follow-up studies are needed to infer a causal relationship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2021.01.030DOI Listing
May 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

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 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) 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 might have causal effects in ulcerative colitis and rheumatoid arthritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Cholangiopathy and Biliary Fibrosis in Cyp2c70-Deficient Mice Are Fully Reversed by Ursodeoxycholic Acid.

Cell Mol Gastroenterol Hepatol 2021 10;11(4):1045-1069. Epub 2020 Dec 10.

Department of Pediatrics, University of Groningen, University Medical Center Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: Bile acids (BAs) aid intestinal fat absorption and exert systemic actions by receptor-mediated signaling. BA receptors have been identified as drug targets for liver diseases. Yet, differences in BA metabolism between humans and mice hamper translation of pre-clinical outcomes. Cyp2c70-ablation in mice prevents synthesis of mouse/rat-specific muricholic acids (MCAs), but potential (patho)physiological consequences of their absence are unknown. We therefore assessed age- and gender-dependent effects of Cyp2c70-deficiency in mice.

Methods: The consequences of Cyp2c70-deficiency were assessed in male and female mice at different ages.

Results: Cyp2c70 mice were devoid of MCAs and showed high abundances of chenodeoxycholic and lithocholic acids. Cyp2c70-deficiency profoundly impacted microbiome composition. Bile flow and biliary BA secretion were normal in Cyp2c70 mice of both sexes. Yet, the pathophysiological consequences of Cyp2c70-deficiency differed considerably between sexes. Three-week old male Cyp2c70 mice showed high plasma BAs and transaminases, which spontaneously decreased thereafter to near-normal levels. Only mild ductular reactions were observed in male Cyp2c70 mice up to 8 months of age. In female Cyp2c70 mice, plasma BAs and transaminases remained substantially elevated with age, gut barrier function was impaired and bridging fibrosis was observed at advanced age. Addition of 0.1% ursodeoxycholic acid to the diet fully normalized hepatic and intestinal functions in female Cyp2c70 mice.

Conclusion: Cyp2c70 mice show transient neonatal cholestasis and develop cholangiopathic features that progress to bridging fibrosis in females only. These consequences of Cyp2c70-deficiency are restored by treatment with UDCA, indicating a role of BA hydrophobicity in disease development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898074PMC
December 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
October 2020

Genetic and Microbial Associations to Plasma and Fecal Bile Acids in Obesity Relate to Plasma Lipids and Liver Fat Content.

Cell Rep 2020 10;33(1):108212

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen 9713AV, the Netherlands. Electronic address:

Bile acids (BAs) are implicated in the etiology of obesity-related conditions such as non-alcoholic fatty liver disease. Differently structured BA species display variable signaling activities via farnesoid X receptor (FXR) and Takeda G protein-coupled BA receptor 1 (TGR5). This study profiles plasma and fecal BAs and plasma 7α-hydroxy-4-cholesten-3-one (C4) in 297 persons with obesity, identifies underlying genetic and microbial determinants, and establishes BA correlations with liver fat and plasma lipid parameters. We identify 27 genetic associations (p < 5 × 10) and 439 microbial correlations (FDR < 0.05) for 50 BA entities. Additionally, we report 111 correlations between BA and 88 lipid parameters (FDR < 0.05), mainly for C4 reflecting hepatic BA synthesis. Inter-individual variability in the plasma BA profile does not reflect hepatic BA synthetic pathways, but rather transport and metabolism within the enterohepatic circulation. Our study reveals genetic and microbial determinants of BAs in obesity and their relationship to disease-relevant lipid parameters that are important for the design of personalized therapies targeting BA-signaling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.108212DOI Listing
October 2020

The role of the gut microbiome in graft fibrosis after pediatric liver transplantation.

Hum Genet 2021 May 13;140(5):709-724. Epub 2020 Sep 13.

Pediatric Gastroenterology/Hepatology, Section of Nutrition and Metabolism, Research Laboratory of Pediatrics, Department of Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Liver transplantation (LT) is a life-saving option for children with end-stage liver disease. However, about 50% of patients develop graft fibrosis in 1 year after LT, with normal liver function. Graft fibrosis may progress to cirrhosis, resulting in graft dysfunction and ultimately the need for re-transplantation. Previous studies have identified various risk factors for the post-LT fibrogenesis, however, to date, neither of the factors seems to fully explain the cause of graft fibrosis. Recently, evidence has accumulated on the important role of the gut microbiome in outcomes after solid organ transplantation. As an altered microbiome is present in pediatric patients with end-stage liver diseases, we hypothesize that the persisting alterations in microbial composition or function contribute to the development of graft fibrosis, for example by bacteria translocation due to increased intestinal permeability, imbalanced bile acids metabolism, and/or decreased production of short-chain fatty acids (SCFAs). Subsequently, an immune response can be activated in the graft, together with the stimulation of fibrogenesis. Here we review current knowledge about the potential mechanisms by which alterations in microbial composition or function may lead to graft fibrosis in pediatric LT and we provide prospective views on the efficacy of gut microbiome manipulation as a therapeutic target to alleviate the graft fibrosis and to improve long-term survival after LT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02221-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052232PMC
May 2021

Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity.

Nat Commun 2020 08 11;11(1):4018. Epub 2020 Aug 11.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

The gut microbiome is an ecosystem that involves complex interactions. Currently, our knowledge about the role of the gut microbiome in health and disease relies mainly on differential microbial abundance, and little is known about the role of microbial interactions in the context of human disease. Here, we construct and compare microbial co-abundance networks using 2,379 metagenomes from four human cohorts: an inflammatory bowel disease (IBD) cohort, an obese cohort and two population-based cohorts. We find that the strengths of 38.6% of species co-abundances and 64.3% of pathway co-abundances vary significantly between cohorts, with 113 species and 1,050 pathway co-abundances showing IBD-specific effects and 281 pathway co-abundances showing obesity-specific effects. We can also replicate these IBD microbial co-abundances in longitudinal data from the IBD cohort of the integrative human microbiome (iHMP-IBD) project. Our study identifies several key species and pathways in IBD and obesity and provides evidence that altered microbial abundances in disease can influence their co-abundance relationship, which expands our current knowledge regarding microbial dysbiosis in disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-17840-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419557PMC
August 2020

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease.

BMC Pulm Med 2020 Jul 16;20(1):193. Epub 2020 Jul 16.

Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

Background: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis.

Methods: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach.

Results: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10 in the discovery and OR = 1.30, P = 1.8 × 10 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20).

Conclusions: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12890-020-01222-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364599PMC
July 2020

Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD.

Gut 2021 Feb 10;70(2):285-296. Epub 2020 Jul 10.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands

Objective: Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.

Design: To evaluate the impact of host genetics on the gut microbiota of patients with IBD, we combined whole exome sequencing of the host genome and whole genome shotgun sequencing of 1464 faecal samples from 525 patients with IBD and 939 population-based controls. We followed a four-step analysis: (1) exome-wide microbial quantitative trait loci (mbQTL) analyses, (2) a targeted approach focusing on IBD-associated genomic regions and protein truncating variants (PTVs, minor allele frequency (MAF) >5%), (3) gene-based burden tests on PTVs with MAF <5% and exome copy number variations (CNVs) with site frequency <1%, (4) joint analysis of both cohorts to identify the interactions between disease and host genetics.

Results: We identified 12 mbQTLs, including variants in the IBD-associated genes , , and . For example, the decrease of the pathway acetyl-coenzyme A biosynthesis, which is involved in short chain fatty acids production, was associated with variants in the gene (false discovery rate <0.05). Changes in functional pathways involved in the metabolic potential were also observed in participants carrying rare PTVs or CNVs in , and genes. These genes are known for their function in the immune system. Moreover, interaction analyses confirmed previously known IBD disease-specific mbQTLs in .

Conclusion: This study highlights that both common and rare genetic variants affecting the immune system are key factors in shaping the gut microbiota in the context of IBD and pinpoints towards potential mechanisms for disease treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-319706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815889PMC
February 2021

Lack of Association Between Genetic Variants at and Genes Involved in SARS-CoV-2 Infection and Human Quantitative Phenotypes.

Front Genet 2020 8;11:613. Epub 2020 Jun 8.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Coronavirus disease 2019 (COVID-19) shows a wide variation in expression and severity of symptoms, from very mild or no symptoms, to flu-like symptoms, and in more severe cases, to pneumonia, acute respiratory distress syndrome, and even death. Large differences in outcome have also been observed between males and females. The causes for this variability are likely to be multifactorial, and to include genetics. The SARS-CoV-2 virus responsible for the infection depends on two human genes: the human receptor angiotensin converting enzyme 2 () for cell invasion, and the serine protease for S protein priming. Genetic variation in these two genes may thus modulate an individual's genetic predisposition to infection and virus clearance. While genetic data on COVID-19 patients is being gathered, we carried out a phenome-wide association scan (PheWAS) to investigate the role of these genes in other human phenotypes in the general population. We examined 178 quantitative phenotypes including cytokines and cardio-metabolic biomarkers, as well as usage of 58 medications in 36,339 volunteers from the Lifelines population cohort, in relation to 1,273 genetic variants located in or near and . While none reached our threshold for significance, we observed several interesting suggestive associations. For example, single nucleotide polymorphisms (SNPs) near the genes were associated with thrombocytes count ( = 1.8 × 10). SNPs within the gene were associated with (1) the use of angiotensin II receptor blockers (ARBs) combination therapies ( = 5.7 × 10), an association that is significantly stronger in females ( = 0.01), and (2) with the use of non-steroid anti-inflammatory and antirheumatic products ( = 5.5 × 10). While these associations need to be confirmed in larger sample sizes, they suggest that these variants could play a role in diseases such as thrombocytopenia, hypertension, and chronic inflammation that are often observed in the more severe COVID-19 cases. Further investigation of these genetic variants in the context of COVID-19 is thus promising for better understanding of disease variability. Full results are available at https://covid19research.nl.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295011PMC
June 2020

Identification, Heritability, and Relation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure.

Hypertension 2020 07 10;76(1):195-205. Epub 2020 Jun 10.

Department of Endocrinology (B.H.R.W., J.V.v.V.-O.), University Medical Center Groningen, University of Groningen, The Netherlands.

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with <1×10. In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated (<1×10) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with <0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 () and cg00716257 () determined by environmental effects acting on both systolic BP and methylation levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295009PMC
July 2020

Interaction between drugs and the gut microbiome.

Gut 2020 08 14;69(8):1510-1519. Epub 2020 May 14.

Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

The human gut microbiome is a complex ecosystem that can mediate the interaction of the human host with their environment. The interaction between gut microbes and commonly used non-antibiotic drugs is complex and bidirectional: gut microbiome composition can be influenced by drugs, but, vice versa, the gut microbiome can also influence an individual's response to a drug by enzymatically transforming the drug's structure and altering its bioavailability, bioactivity or toxicity (pharmacomicrobiomics). The gut microbiome can also indirectly impact an individual's response to immunotherapy in cancer treatment. In this review we discuss the bidirectional interactions between microbes and drugs, describe the changes in gut microbiota induced by commonly used non-antibiotic drugs, and their potential clinical consequences and summarise how the microbiome impacts drug effectiveness and its role in immunotherapy. Understanding how the microbiome metabolises drugs and reduces treatment efficacy will unlock the possibility of modulating the gut microbiome to improve treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2019-320204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398478PMC
August 2020

Impact of commonly used drugs on the composition and metabolic function of the gut microbiota.

Nat Commun 2020 01 17;11(1):362. Epub 2020 Jan 17.

Dept. of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

The human gut microbiota has now been associated with drug responses and efficacy, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug-microbe interactions are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. Here, we report relations between commonly used drugs and the gut microbiome. We performed metagenomics sequencing of faecal samples from a population cohort and two gastrointestinal disease cohorts. Differences between users and non-users were analysed per cohort, followed by a meta-analysis. While 19 of 41 drugs are found to be associated with microbial features, when controlling for the use of multiple medications, proton-pump inhibitors, metformin, antibiotics and laxatives show the strongest associations with the microbiome. We here provide evidence for extensive changes in taxonomy, metabolic potential and resistome in relation to commonly used drugs. This paves the way for future studies and has implications for current microbiome studies by demonstrating the need to correct for multiple drug use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-14177-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969170PMC
January 2020

Integration of epidemiologic, pharmacologic, genetic and gut microbiome data in a drug-metabolite atlas.

Nat Med 2020 01 13;26(1):110-117. Epub 2020 Jan 13.

Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-019-0722-xDOI Listing
January 2020

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

Nat Commun 2019 12 20;10(1):5813. Epub 2019 Dec 20.

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

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. Recent development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13721-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925111PMC
December 2019

Studying the gut virome in the metagenomic era: challenges and perspectives.

BMC Biol 2019 10 28;17(1):84. Epub 2019 Oct 28.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

The human gut harbors a complex ecosystem of microorganisms, including bacteria and viruses. With the rise of next-generation sequencing technologies, we have seen a quantum leap in the study of human-gut-inhabiting bacteria, yet the viruses that infect these bacteria, known as bacteriophages, remain underexplored. In this review, we focus on what is known about the role of bacteriophages in human health and the technical challenges involved in studying the gut virome, of which they are a major component. Lastly, we discuss what can be learned from studies of bacteriophages in other ecosystems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12915-019-0704-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819614PMC
October 2019

Intestinal microbiome composition and its relation to joint pain and inflammation.

Nat Commun 2019 10 25;10(1):4881. Epub 2019 Oct 25.

Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12873-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814863PMC
October 2019

Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls.

Biol Psychiatry 2020 03 29;87(5):409-418. Epub 2019 Aug 29.

Department of Biological Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit, Amsterdam, The Netherlands.

Background: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.

Methods: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.

Results: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.

Conclusions: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2019.08.016DOI Listing
March 2020