NEW YORK — Host genetics, including genes affecting ABO histo-blood groups, may influence the composition of the human gut microbiome, a new analysis has found.
In a genome-wide association study, a team of researchers in Germany uncovered about three dozen genetic loci tied to the makeup of the human gut microbiome. As they reported in Nature Genetics on Monday, they particularly noted a link between ABO histo-blood groups or the FUT2 gene, which affects blood group secretor status, and the presence of Bacteroides or Faecalibacterium in the gut. They additionally found that the gut microbiome could influence conditions like inflammatory bowel disease and represent a therapeutic target.
"[Ultimately,] the aim is to identify candidate genes that are investigated in functional studies and that can at one time point be used in a framework of personalized treatment which considers multiple layers of host factors: life history, genetics, the microbiome, and the interaction of them all as target and modulator of treatment success," first author Malte Rühlemann, a postdoc at Kiel University, said in an email.
He and his colleagues conducted a large genome-wide association study of microbial traits that drew on five cohorts from different regions of Germany that encompassed a total of 8,965 individuals. Following a series of multivariate, univariate abundance, and presence-absence pattern analyses, they uncovered 38 genetic loci associated with the presence of particular bacteria and broad gut microbial community composition.
For instance, the researchers noted an association between variants in the lactase gene locus (LCT) and the genus Bifidobacterium. This association was nominal in four of the five cohorts and stronger in the fifth. As a link had previously been found between the LCT locus and Bifidobacterium, the researchers said this finding bolstered their approach.
They likewise noted an association between a Barnesiella bacterial species and variants in the biliverdin reductase A (BLVRA) gene, which encodes a protein that inhibits toll-like receptor 4 (TLR4) gene expression. The TLR-4 protein is a pattern recognition receptor of the ABO allele.
Further, the researchers added that variants at FUT2 and BACH2 that correlated with a Bacteroides species in this study were also previously linked to inflammatory bowel disease.
The researchers in particular investigated ABO histo-blood group associations, including FUT2 secretor status, with microbial features. They found a correlation between non-O blood group and positive secretor status and certain Bacteroides species in four of the five cohorts. Another Bacteroides species, they noted, was also associated with ABO blood status, bolstering the idea that there are histo-blood group-dependent effects on Bacteroides.
They further uncovered associations between Faecalibacterium and ABO and between Holdemanella and ABO, as well as an association between FUT2 secretor status and the abundance of Roseburia, independent of ABO type.
Through a Mendelian randomization analysis, the researchers found 19 suggestive microbial effects on host traits, nine of which were tied to IBD or Crohn's disease. One, for instance, suggests that a group of Bacteroides is associated with ABO histo-blood group status and a group of Prevotella appears to protect against Crohn's disease.
These findings, the researchers noted, support the notion that ABO histo-blood group and sector status influences the makeup of the gut microbiome and that they could potentially represent targets for modulating human health and disease.
"ABO/FUT2 have been candidates with potential disease-modulating effects, for example, in inflammatory bowel disease for some time and if this interaction with the microbiome can be harnessed to treat IBD will definitely be investigated further in future work," Rühlemann said.
He noted that the candidate genes they have identified in this and other studies first need to be investigated in functional studies.