NEW YORK – An international team led by researchers from the Netherlands has started teasing out structural variation in gut microbe genome sequences that is influenced by human host genetic factors.
While there is known to be "huge variation" in the composition and content of the microbiome, host genetic influences uncovered so far explained only "a limited part of this variation," University of Groningen researchers Jingyuan Fu and Hermie Harmsen, the study's co-senior and co-corresponding authors, said in an email.
Their team's new research, published in Nature on Wednesday, suggests "some strains of specific species have a gene or pathway that enables them to grow in the gut in a niche that is determined by the host," they explained.
For their study, Fu, Harmsen, and their colleagues used metagenomic sequencing and array-based genotyping to profile gut microbiome and host SNP patterns in more than 9,000 participants from four Netherlands-based cohorts, including the Dutch Microbiome Project, the Lifelines-DEEP study, the 500 Functional Genomics Project, and the 300-Obesity study.
With the help of bioinformatic tools, the team performed a meta-analysis aimed at picking out associations between host gene variants and structural variation in the gut microbiome, which they subsequently verified through experimental analyses and data from another 279 participants from the 300-Tanzanian cohort. Through this, they identified reproducible relationships between microbial carbon source utilization capabilities and host genetic factors.
"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," the authors wrote in their paper.
In particular, the investigators' analyses suggested that host variants involving the ABO blood group locus were linked to variability in nearly 10,500 genome sequences for microbial species in the Faecalibacterium, Collinsella, and Bifidobacterium genera.
For example, the investigators flagged relationships between host production of a so-called "A-antigen" that includes N-acetylgalactosamine (GalNAc) — a type A oligosaccharide antigen influenced by ABO and FUT2 genotypes — and GalNAc gene clusters found in the F. prausnitzii microbial species.
"[W]e find that some strains of Faecalibacterium have a pathway to utilize the blood type A sugars and in particular GalNAc that is coating the human mucin in the gut," Fu and Harmsen explained. "This mucin is only coated with this sugar when the host also expresses the FUT2 gene."
In follow-up growth rate experiments on a dozen F. prausnitzii strains, the team found that strains of the bug that can metabolize GalNAc were able to survive on the galactose-derived amino acid as a sole carbohydrate source.
Conversely, the authors in their study pointed to ties between the presence of genes involved in GalNAc utilization and "the host's cardiometabolic health, particularly in individuals with mucosal A-antigen."
In participants with the A blood type, for example, the results suggested that the presence of GalNAc-utilizing microbial genes in the gut corresponded to favorable heart and metabolic health measures, Fu and Harmsen explained, noting that "it seems to be important that we have a microbiome that is adapted to our genetic makeup."
Given such findings, the team speculated that there may eventually be a benefit to boosting GalNAc and, in turn, broader microbial diversity in blood type A individuals, particularly since ABO blood group features have been implicated in conditions ranging from cardiometabolic conditions to infectious disease susceptibility.
Fu and Harmsen further called for additional research to try to understand the processes by which genetically influenced microbial communities take hold in the gut — from parental microbiome influences to diet, hygiene habits, antibiotic use, and other environmental factors early in life.
Moreover, they and their coauthors said that future research is needed to "assess host genetic and microbial associations in more diverse populations to build a better understanding of host-microbiome co-adaptation and co-divergence, as well as to aid fine-mapping of causal genes."