Host genetic regulation of human gut microbial structural variation
Daria V. Zhernakova, Daoming Wang, Lei Liu, Sergio Andreu‐Sánchez, Yue Zhang, Angel J. Ruiz‐Moreno, Haoran Peng, Niels Plomp, Ángela del Castillo-Izquierdo, Ranko Gaćeša, Esteban A. Lopera-Maya, Godfrey S. Temba, Vesla Kullaya, Sander S. van Leeuwen, Lifelines Cohort Study, Raul Aguirre-Gamboa, Patrick Deelen, Lude Franke, Jan A. Kuivenhoven, Ilja M. Nolte, Serena Sanna, Harold Snieder, Morris A. Swertz, Peter M. Visscher, Judith M. Vonk, Ramnik J. Xavier, Quirijn de Mast, Leo A. B. Joosten, Niels P. Riksen, Joost H.W. Rutten, Mihai G. Netea, Serena Sanna, Cisca Wijmenga, Rinse K. Weersma, Alexandra Zhernakova, Hermie J. M. Harmsen, Jingyuan Fu
Abstract
, 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.