Host genetic regulation of human gut microbial structural variation

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 microbes. Here we conducted a meta-analysis of 
associations between human genetic variation and gut microbial structural variations 
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