The past 20 years have witnessed a paradigm shift in the interplay between humans and their gut microbiota. Numerous studies have explored the association between the gut microbiota, and particularly dysbiosis, and human physiology and health, e.g. neurological conditions, cancer, cardiovascular disease, and immunity. However, far fewer studies have investigated the effect of genetic variations in the human host on the gut microbiota.
Twin studies have pointed at the heritability of the gut microbiota and several small studies (< 100 participants) have shown that a genetic variant near the lactase gene, which leads to lactase persistence, is associated with Bifidobacterium level (1). Nonetheless, such associations are difficult to find because the gut microbiota is strongly influenced by diet and medication, and moreover, it shows functional redundancies across numerous species. Two recent studies (2,3) using large populations (5,959 and 7,738 participants) carried out host genotyping and detailed phenotyping along with whole-genome metagenomic sequencing to identify genetic variants that are associated with gut microbial abundances on a taxa level.
These studies reported several genetic loci to be strongly associated with gut microbial variation. In particular, they both replicated associations at the LCT and ABO loci. LCT is the gene that encodes for lactase, the enzyme allowing the cleavage of lactose into glucose and galactose. Participants who did not express lactase in adulthood, i.e. lactase non-persistent, and who had regular dairy intake, were characterized by higher levels of bifidobacteria. Since bifidobacteria have the ability to degrade lactose, they could exert a probiotic effect that could modulate the relationship between lactase non-persistence and lactose intolerance. ABO encodes an enzyme that modifies the oligosaccharides on cell-surface glycoproteins and determines the ABO blood group of an individual. Interestingly, both studies identified an interaction between a variant in ABO and a variant in FUT2 on the abundance of several bacterial taxa. FUT2 affects the secretor-status of ABO antigens on mucosal cells: individuals’ homozygotes for the G allele at rs601338, which is a nonsense SNP, do not secrete A, B, or AB antigens of ABO on their mucosa. These individuals exhibited lower bacterial abundance for Faecalicatena lactaris and, upon a fiber-rich diet, they also exhibited lower bacterial abundance for Collinsella sp. rs601338 in FUT2 is a SNP that is also known to influence vitamin B12 circulating concentrations, with non-secretors exhibiting higher circulating vitamin B12 concentrations (4). Since several infectious and chronic diseases, where a dysbiosis is often seen, are associated with host blood type, the authors suggest the gut microbiota could interact with host blood type to modify disease risk.
Such large well-conducted studies pave the way for future microbiome genome-wide association studies aiming at better understanding the complex interactions between a host and its gut microbiota and could help the development of personalized therapeutics, including dietary recommendations.
References:
- Sanna, S., Kurilshikov, A., van der Graaf, A., Fu, J., Zhernakova, A., Challenges and future directions for studying effects of host genetics on the gut microbiome. Nat Genet 2022, 54, 100-106.
- Lopera-Maya, E. A., Kurilshikov, A., van der Graaf, A., Hu, S., et al., Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project. Nature Genetics 2022, 54, 143-151.
- Qin, Y., Havulinna, A. S., Liu, Y., Jousilahti, P., et al., Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort. Nat Genet 2022, 54, 134-142.
- Velkova, A., Diaz, J. E. L., Pangilinan, F., Molloy, A. M., et al., The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation. Hum Mol Genet 2017, 26, 4975-4988.
