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Host Genetics Influence Composition of Human Gut Microbiome

NEW YORK (GenomeWeb) – Host genetics influence the makeup of the human gut microbiome, according to a new analysis appearing in Nature Genetics today.

An international team of researchers performed metagenomic sequencing on more than 1,500 people and looked for associations between host genetic loci and microbial taxonomies or microbial pathways. They found a number of genetic variants that are linked to the microbial gut composition, including an association with genes involved in innate immunity.

"Identifying associations between human genetics and the gut microbiome, and exploring their interactions, can provide insights into the role of the microbiome in complex diseases and drive the development of therapies to modulate the microbiome toward better health," wrote the University of Groningen's Alexandra Zhernakova and her colleagues in their paper.

The researchers performed a three-stage association analysis followed by a meta-analysis that drew upon three Dutch cohorts. They first conducted a genome-wide analysis to examine associations between common SNPs and microbial taxonomies and functional units that were present in at least a quarter of the individuals. Through this, they linked 58 SNPs at nine loci to microbial taxa and 33 loci with functional units.

The strongest taxonomical association the researchers uncovered was for the genus Blautia and the family Methanobacteriaceae and a region upstream of the LINGO2 gene, which is itself linked with body mass index, obesity, and motion sickness. Methanobacteriaceae, they noted, have been linked with BMI and lipid levels.

They also found a link between 2q37.3 and 10p12.1 and Diaslister invisus, and between a SNP in the VANGL1 gene and Sutterellacea abundance.

Zhernakova and her colleagues also uncovered 21 loci associated with MetaCyc pathways — the strongest association was between a pathway involved in the degradation of plant-derived sterols and loci in the SORCS2 gene and the SLIT3 gene, which are associated with insulin-like growth factors and obesity, respectively.

Likewise, they linked 12 loci to Gene Ontology terms. For instance, they noted an association between two loci near clusters of C-type lectin domain family 4 genes and the riboflavin biosynthetic process GO term.

In a more targeted analysis, Zhernakova and her colleagues examined associations between the gut microbiome and genes involved in immune response- and metabolism-related genes. For instance, they uncovered links between IBD-related genes and the gut microbiome, including a signal at the C11orf30-LRRC32 locus that was also associated with the GO term cell-cell signaling. This term was also correlated with the abundance of Coprococcus comes and Proteobacteria, which are bacteria that have been linked to IBD, the researchers noted.

At the same time, the investigators uncovered associations in the metabolism-linked PLTP, APOE, and PPARG genes. This suggested to them that the gut microbiome could mediate the link between host genetics and immunological and metabolic phenotypes.

Zhernakova and her colleagues also found 15 loci that encode innate immunity sensors that were associated with the composition of the gut microbiome. The NOD2 locus, which has been linked to Crohn's disease, was linked with enterobactin biosynthesis and the abundance of Escherichia coli. Enterobactin produced by E. coli inhibits the host bactericidal enzyme MPO, enabling E. coli to avoid the host innate immune response in inflammatory gut disease, the researchers said.

In addition, by examining SNPs in seven genes involved in food metabolism or preference, they also uncovered an association between the intake of dairy products and the abundance of Bifidobacterium. This, the researchers said, suggests that diet interacts with host genetics to regulate the composition of the gut microbiome.

"Our results demonstrate the importance of understanding host–microbe interactions to gain better insight into human health," the authors wrote.