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 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. Rutten, Mihai G. Netea, Serena Sanna, Cisca Wijmenga, Rinse K. Weersma, Alexandra Zhernakova, Hermie J. M. Harmsen () and Jingyuan Fu ()
Additional contact information
Daria V. Zhernakova: University of Groningen, University Medical Center Groningen, Department of Genetics
Daoming Wang: University of Groningen, University Medical Center Groningen, Department of Genetics
Lei Liu: University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention
Sergio Andreu-Sánchez: University of Groningen, University Medical Center Groningen, Department of Genetics
Yue Zhang: University of Groningen, University Medical Center Groningen, Department of Genetics
Angel J. Ruiz-Moreno: University of Groningen, University Medical Center Groningen, Department of Genetics
Haoran Peng: University of Groningen, University Medical Center Groningen, Department of Genetics
Niels Plomp: University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention
Ángela Castillo-Izquierdo: University of Groningen, University Medical Center Groningen, Department of Genetics
Ranko Gacesa: University of Groningen, University Medical Center Groningen, Department of Genetics
Esteban A. Lopera-Maya: University of Groningen, University Medical Center Groningen, Department of Genetics
Godfrey S. Temba: Radboud University Medical Center
Vesla I. Kullaya: Kilimanjaro Christian Medical University College
Sander S. van Leeuwen: University of Groningen, University Medical Center Groningen, Department of Laboratory Medicine
Ramnik J. Xavier: Broad Institute of MIT and Harvard
Quirijn de Mast: Radboud University Medical Center
Leo A. B. Joosten: Radboud University Medical Center
Niels P. Riksen: Radboud University Medical Center
Joost H. W. Rutten: Radboud University Medical Center
Mihai G. Netea: Radboud University Medical Center
Serena Sanna: University of Groningen, University Medical Center Groningen, Department of Genetics
Cisca Wijmenga: University of Groningen, University Medical Center Groningen, Department of Genetics
Rinse K. Weersma: University of Groningen, University Medical Center Groningen, Department of Gastroenterology and Hepatology
Alexandra Zhernakova: University of Groningen, University Medical Center Groningen, Department of Genetics
Hermie J. M. Harmsen: University of Groningen, University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention
Jingyuan Fu: University of Groningen, University Medical Center Groningen, Department of Genetics

Nature, 2024, vol. 625, issue 7996, 813-821

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-023-06893-w

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