Host genetic regulation of human gut microbial structural variation

Lifelines Cohort Study, 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 Gacesa, Esteban A Lopera-Maya, Godfrey S Temba, Vesla I Kullaya, Sander S van Leeuwen, Ramnik J Xavier, Quirijn de Mast, Leo A B Joosten, Niels P Riksen, Joost H W RuttenMihai G Netea, Serena Sanna, Cisca Wijmenga, Rinse K Weersma, Alexandra Zhernakova, Hermie J M Harmsen*, Jingyuan Fu*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established 1-6, 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.

Original languageEnglish
Publication statusE-pub ahead of print - 3-Jan-2024

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