Host genetic regulation of human gut microbial structural variation

• 成果类型: Article
• 署名作者: Zhernakova, Daria V.; Wang, Daoming; Liu, Lei; Andreu-Sanchez, Sergio; Zhang, Yue; Ruiz-Moreno, Angel J.; Peng, Haoran; Plomp, Niels; Del Castillo-Izquierdo, Angela; Gacesa, Ranko; Lopera-Maya, Esteban A.; Temba, Godfrey S.; Kullaya, Vesla I.; van Leeuwen, Sander S.; Xavier, Ramnik J.; de Mast, Quirijn; Joosten, Leo A. B.; Riksen, Niels P.; Rutten, Joost H. W.; Netea, Mihai G.; Sanna, Serena; Wijmenga, Cisca; Weersma, Rinse K.; Zhernakova, Alexandra; Harmsen, Hermie J. M.; Fu, Jingyuan
• 署名单位: University of Groningen; University of Groningen; University of Groningen; University of Groningen; Radboud University Nijmegen; Radboud University Nijmegen; Kilimanjaro Christian Medical Centre; University of Groningen; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Iuliu Hatieganu University of Medicine & Pharmacy; University of Bonn; University of Medicine & Pharmacy of Craiova; Consiglio Nazionale delle Ricerche (CNR); Istituto di Ricerca Genetica e Biomedica (IRGB-CNR)
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4873
• DOI: 10.1038/s41586-023-06893-w
• 发表日期: 2024-01-25
• 关键词: genome-wide association; chronic-pancreatitis; cytokine production; blood-group; tool; specificity; prediction; DYNAMICS; resource; RISK

摘要

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established1-6, little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship. A meta-analysis of associations between human genetic variation and gut microbial structural variations shows that ABO genotype differentially affects the presence of Faecalibacterium prausnitzii strains containing GalNAc utilization pathway in the gut.