Two complementary genome-wide association studies provide new insights into how host genetics influence the human gut microbiome, identifying multiple reproducible genetic loci associated with microbial composition and function.
Both studies, published simultaneously in the journal Nature Genetics, aimed to define host genetic determinants of variation in the gut microbiota using high-resolution metagenomic sequencing for over 28,000 individuals.
The first, based on the Norwegian Trøndelag Health Study (HUNT), analysed 12,652 individuals, with replication in Nordic cohorts (n=16,017–21,976).
The second analysed 16,017 adults from four Swedish population-based cohorts, with replication in the HUNT study (n=12,652).
Participants were primarily adults of European descent. Stool samples were analysed to determine microbial composition at the species level, and in the HUNT study, functional pathways were also examined. Across all studies, hundreds of microbial taxa were evaluated, including 546 species in HUNT and 921 species in the Swedish cohorts.
Key genetic drivers of gut microbiome identified
In the HUNT study, 13 single-nucleotide polymorphism (SNP)-species associations were identified, of which 12 replicated across cohorts, spanning six genomic loci, including known regions (LCT and ABO) and novel loci (HLA-DQB1, MUC12, SLC37A2, FUT2). Associations reached study-wide significance with strong replication.
The Swedish-led analysis identified 15 study-wide significant SNP-species associations across eight loci, with 11 replicated in HUNT. Newly implicated loci included MUC12, CORO7–HMOX2, SLC5A11 and FOXP1.
Both studies confirmed robust associations at LCT and ABO, expanding the number of reproducible microbiome-associated loci beyond these previously known signals.
The HUNT study further identified six replicated genetic associations with microbial functional modules from the Kyoto Encyclopedia of Genes and Genomes, marking the first replicated genetic signals linked to microbiome functionality.
Immunity and disease risk
Several loci showed links to disease. For example, variants at HLA-DQB1 were associated with both microbial abundance and reduced risk of autoimmune diseases, including type 1 diabetes and coeliac disease.
At the MUC12 locus, genetic variation influencing Coprobacillus cateniformis abundance was strongly associated with haemorrhoidal disease (P=1.3×10⁻²²).
Mendelian randomisation analyses suggested a causal effect of body mass index on microbiota composition, supporting a role for host metabolic state in shaping the microbiome.
The Swedish study identified the novel OR51E1–OR51E2 locus, which was associated with microbial richness, implicating enteroendocrine fatty acid-sensing pathways. Genetic variation in bile acid metabolism and mucosal glycan pathways – for example, FUT2 and ABO – was also linked to microbiome composition.
Both studies, however, were limited to populations of primarily European ancestry, which may limit generalisability. Despite large sample sizes, heritability estimates for microbial traits remained modest (mean ~6.8–7.2% in HUNT), reflecting the strong influence of environmental factors. Differences in microbiome measurement and cohort characteristics also remain potential sources of variability.
Together, the findings highlight a complex interplay among host genetics, metabolism and the gut microbiota.
Understanding the gut microbiome’s role in human health
Tove Fall, professor of molecular epidemiology at Uppsala University, who led the Swedish cohort study, said: ‘We have learnt a lot about the role played by genetics in the gut microbiome. Several of the genetic connections that we found have to do with very specific biological mechanisms.
‘These concern, for instance, which molecules are present on the surface of gut cells and are thereby available as food for bacteria. They also relate to the way in which the gut reacts to molecules produced by bacteria.’
Overall, these studies mark a significant step towards understanding the genetic architecture of the gut microbiome and its role in human health. Commenting further on the findings, Claes Ohlsson, professor at the University of Gothenburg, who led the HUNT study, said: ‘We saw that some of these genetic variants were linked to the risk of gluten intolerance, haemorrhoids and cardiovascular diseases.
‘This suggests that changes in the composition of intestinal bacteria could provide a way to better understand how genetic risks affect health.’
References
Moksnes M et al. The HUNT study identifies host genetic factors reproducibly associated with human gut microbiota composition. Nat Genet 2026;58(3):530–9.
Dekkers K et al. Genome-wide association analyses highlight the role of the intestinal molecular environment in human gut microbiota variation. Nat Genet 2026; 58(3):540–9.