ALBERT

Description: Fecal microbiome variation in the average, healthy population has remained under-investigated. Here, we analyzed two independent, extensively phenotyped cohorts: the Belgian Flemish Gut Flora Project (FGFP; discovery cohort; N = 1106) and the Dutch LifeLines-DEEP study (LLDeep; replication; N = 1135). Integration with global data sets (N combined = 3948) revealed a 14-genera core microbiota, but the 664 identified genera still underexplore total gut diversity. Sixty-nine clinical and questionnaire-based covariates were found associated to microbiota compositional variation with a 92% replication rate. Stool consistency showed the largest effect size, whereas medication explained largest total variance and interacted with other covariate-microbiota associations. Early-life events such as birth mode were not reflected in adult microbiota composition. Finally, we found that proposed disease marker genera associated to host covariates, urging inclusion of the latter in study design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Falony, Gwen -- Joossens, Marie -- Vieira-Silva, Sara -- Wang, Jun -- Darzi, Youssef -- Faust, Karoline -- Kurilshikov, Alexander -- Bonder, Marc Jan -- Valles-Colomer, Mireia -- Vandeputte, Doris -- Tito, Raul Y -- Chaffron, Samuel -- Rymenans, Leen -- Verspecht, Chloe -- De Sutter, Lise -- Lima-Mendez, Gipsi -- D'hoe, Kevin -- Jonckheere, Karl -- Homola, Daniel -- Garcia, Roberto -- Tigchelaar, Ettje F -- Eeckhaudt, Linda -- Fu, Jingyuan -- Henckaerts, Liesbet -- Zhernakova, Alexandra -- Wijmenga, Cisca -- Raes, Jeroen -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):560-4. doi: 10.1126/science.aad3503. Epub 2016 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉KU Leuven-University of Leuven, Department of Microbiology and Immunology, Leuven, Belgium. VIB, Center for the Biology of Disease, Leuven, Belgium. ; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Leuven, Belgium. VIB, Center for the Biology of Disease, Leuven, Belgium. Vrije Universiteit Brussel, Faculty of Sciences and Bioengineering Sciences, Microbiology Unit, Brussels, Belgium. ; Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. Novosibirsk State University, Novosibirsk, Russia. ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, Netherlands. ; VIB, Center for the Biology of Disease, Leuven, Belgium. Vrije Universiteit Brussel, Faculty of Sciences and Bioengineering Sciences, Microbiology Unit, Brussels, Belgium. ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, Netherlands. Top Institute Food and Nutrition, Wageningen, Netherlands. ; University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, Netherlands. University of Groningen, University Medical Center Groningen, Department of Pediatrics, 9700 RB Groningen, Netherlands. ; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Leuven, Belgium. KU Leuven-University Hospitals Leuven, Department of General Internal Medicine, Leuven, Belgium. ; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Leuven, Belgium. VIB, Center for the Biology of Disease, Leuven, Belgium. Vrije Universiteit Brussel, Faculty of Sciences and Bioengineering Sciences, Microbiology Unit, Brussels, Belgium. jeroen.raes@kuleuven.be.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27126039" target="_blank"〉PubMed〈/a〉

Description: Deep sequencing of the gut microbiomes of 1135 participants from a Dutch population-based cohort shows relations between the microbiome and 126 exogenous and intrinsic host factors, including 31 intrinsic factors, 12 diseases, 19 drug groups, 4 smoking categories, and 60 dietary factors. These factors collectively explain 18.7% of the variation seen in the interindividual distance of microbial composition. We could associate 110 factors to 125 species and observed that fecal chromogranin A (CgA), a protein secreted by enteroendocrine cells, was exclusively associated with 61 microbial species whose abundance collectively accounted for 53% of microbial composition. Low CgA concentrations were seen in individuals with a more diverse microbiome. These results are an important step toward a better understanding of environment-diet-microbe-host interactions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhernakova, Alexandra -- Kurilshikov, Alexander -- Bonder, Marc Jan -- Tigchelaar, Ettje F -- Schirmer, Melanie -- Vatanen, Tommi -- Mujagic, Zlatan -- Vila, Arnau Vich -- Falony, Gwen -- Vieira-Silva, Sara -- Wang, Jun -- Imhann, Floris -- Brandsma, Eelke -- Jankipersadsing, Soesma A -- Joossens, Marie -- Cenit, Maria Carmen -- Deelen, Patrick -- Swertz, Morris A -- LifeLines cohort study -- Weersma, Rinse K -- Feskens, Edith J M -- Netea, Mihai G -- Gevers, Dirk -- Jonkers, Daisy -- Franke, Lude -- Aulchenko, Yurii S -- Huttenhower, Curtis -- Raes, Jeroen -- Hofker, Marten H -- Xavier, Ramnik J -- Wijmenga, Cisca -- Fu, Jingyuan -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):565-9. doi: 10.1126/science.aad3369. Epub 2016 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. Top Institute Food and Nutrition, Wageningen, Netherlands. a.zhernakova@umcg.nl c.wijmenga@umcg.nl j.fu@umcg.nl. ; Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia. Novosibirsk State University, Novosibirsk, Russia. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. Top Institute Food and Nutrition, Wageningen, Netherlands. ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA. ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Computer Science, Aalto University School of Science, Espoo, Finland. ; Top Institute Food and Nutrition, Wageningen, Netherlands. Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands. ; University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology, Groningen, Netherlands. ; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Leuven, Belgium. VIB, Center for the Biology of Disease, Leuven, Belgium. ; University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, Netherlands. ; KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, Leuven, Belgium. VIB, Center for the Biology of Disease, Leuven, Belgium. Vrije Universiteit Brussel, Faculty of Sciences and Bioengineering Sciences, Microbiology Unit, Brussels, Belgium. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. Microbial Ecology, Nutrition and Health Research Group, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain. Department of Pediatrics, Dr. Peset University Hospital, Valencia, Spain. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, Netherlands. ; Top Institute Food and Nutrition, Wageningen, Netherlands. Division of Human Nutrition, Wageningen University, Wageningen, Netherlands. ; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA. ; Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands. ; Novosibirsk State University, Novosibirsk, Russia. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. PolyOmica, Groningen, Netherlands. Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia. ; The Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA. Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. a.zhernakova@umcg.nl c.wijmenga@umcg.nl j.fu@umcg.nl. ; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, Netherlands. a.zhernakova@umcg.nl c.wijmenga@umcg.nl j.fu@umcg.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27126040" target="_blank"〉PubMed〈/a〉

Description: Although genome-wide association studies and fine mapping have identified 39 non-HLA loci associated with celiac disease (CD), it is difficult to pinpoint the functional variants and susceptibility genes in these loci. We applied integrative approaches to annotate and prioritize functional single nucleotide polymorphisms (SNPs), genes and pathways affected in CD. CD-associated SNPs were intersected with regulatory elements categorized by the ENCODE project to prioritize functional variants, while results from cis -expression quantitative trait loci (eQTL) mapping in 1469 blood samples were combined with co-expression analyses to prioritize causative genes. To identify the key cell types involved in CD, we performed pathway analysis on RNA-sequencing data from different immune cell populations and on publicly available expression data on non-immune tissues. We discovered that CD SNPs are significantly enriched in B-cell-specific enhancer regions, suggesting that, besides T-cell processes, B-cell responses play a major role in CD. By combining eQTL and co-expression analyses, we prioritized 43 susceptibility genes in 36 loci. Pathway and tissue-specific expression analyses on these genes suggested enrichment of CD genes in the Th1, Th2 and Th17 pathways, but also predicted a role for four genes in the intestinal barrier function. We also discovered an intricate transcriptional connectivity between CD susceptibility genes and interferon-, a key effector in CD, despite the absence of CD-associated SNPs in the IFNG locus. Using systems biology, we prioritized the CD-associated functional SNPs and genes. By highlighting a role for B cells in CD, which classically has been described as a T-cell-driven disease, we offer new insights into the mechanisms and pathways underlying CD.