Host Genetics Affect Makeup of Gut Microbiome, With Influence From Diet, Studies Find

Previous analyses have suggested that the gut microbiome is in part heritable. By combining genetic and gut microbiome data from thousands of people, two research groups have identified hundreds of SNPs associated with the presence of certain gut microbes. Both groups in particular found strong links between variants near the lactase, or LCT, and ABO genes and the levels of certain bacterial groups, though diet and other factors could modulate these associations.

Their findings further hinted that there are causal relationships between the gut microbiome and complex traits, but that even larger samples sizes are needed for better insights into those interactions.

"[W]e believe that identifying additional host genetic factors that influence the gut microbiome, even those with small effects, will provide important insights into complex host-microbiome interactions and could inform therapies and personalized treatments," researchers led by the University of Groningen's Alexandra Zhernakova wrote in a commentary accompanying the new Nature Genetics studies.

Both research groups conducted genome-wide association studies of bacterial taxa and human genetic variation. In particular, researchers led by Groningen's Serena Sanna and Zhernakova conducted a GWAS of 207 taxa and 7,738 participants from the Dutch Microbiome Project, as they reported in Nature Genetics. At the same time, a team led by Guillaume Méric from the Baker Heart and Diabetes Institute in Melbourne conducted a GWAS of 2,801 microbial taxa and 5,959 individuals from the FINRISK 2002 study of Finnish individuals, as they reported in their own study.

Both analyses homed in on robust signals near the LCT and ABO genes.

LCT encodes the lactase enzyme that breaks lactose into glucose and galactose and, in both studies, the variant associated with lactase non-persistence — the inability to breakdown lactose into adulthood — was linked to a higher level of Bifidobacterium in the gut microbiome. This increase in Bifidobacterium was particularly increased among lactose-intolerant people who reported the regular consumption of dairy products. The Dutch team further traced this effect largely to B. longum, B. adolescentis, B. catenulatum, and B. bifidum.

The ABO gene, meanwhile, encodes proteins related to blood groups, and the Dutch team found links between a locus there and levels of Bifidobacterium bifidum and Collinsella aerofaciens, while the study of Finnish individuals found links between a variant there and levels of Faecalicatena lactaris and between a second signal and members of the Collinsella genus.

Both teams additionally reported that the associations they observed at ABO were dependent on FUT2 secretor status — non-secretors do not express the A or B antigens of ABO on their mucosa. In their study of Finnish individuals, that team of researchers noted that levels of F. lactaris — a likely mucin-degrading commensal bacterium — was similar in A/B/AB secretors as non-secretors no matter their fiber intake, while F. lactaris levels were increased among non-secretors with a high-fiber diet, as compared to a low-fiber diet.

The study of Finnish individuals additionally found that variants in the MED13L loci were linked to Enterococcus faecalis levels. MED13L, they noted, has previously been tied to colorectal cancer risk, suggesting that E. faecalis could be linked to colorectal cancer risk through MED13L.

By drawing on additional data from their two cohorts, the research groups also conducted Mendelian randomization studies to home on possible causal effects between certain microbes and complex traits. The study of Finnish individuals uncovered a possible causal effect of Morganella on major depressive disorder, while the Dutch study noted a possible causal relationship between microbiome variation and salt intake and triglyceride levels.

These and other studies have highlighted the need for even larger and more diverse cohorts to home in on additional loci that may influence the makeup of the gut microbiome, Zhernakova and her colleagues wrote in their commentary.

"Data sharing and collaboration to combine GWAS in meta-analysis were major factors that contributed to advances in human genetic studies of complex traits," they added. "We therefore encourage researchers working in the field of microbiome genetics to embrace these scientific practices."