HLA-DQ2/8 genotype is associated with strain-level gut microbiome divergence and lower serum pantothenate in healthy adults

HLA-DQ2/8 haplotypes are established genetic risk factors for autoimmune diseases and are known to influence gut microbiota assembly in early life. However, their impact on the adult microbiome and functional consequences for host physiology remain unclear. Here, we performed a genotype-stratified multi-omics analysis of 60 healthy adults, including 28 HLA-DQ2/8 carriers and 32 non-carriers. We found that host HLA-DQ2/8 genotype was significantly associated with gut microbiome composition, with an effect size exceeding that of sex and BMI. HLA-DQ2/8 carriers exhibited higher gut microbial alpha-diversity, lower virulence factor abundance, and a distinct species profile enriched in butyrate-producing taxa. We identified pervasive intra-species phylogenetic and functional divergence linked to the DQ2/8 genotype. This diversification reflects predicted HLA-restricted microbial peptide-binding specificities, suggesting a possible role for antigen presentation-mediated immune selection, a mechanism further supported by AlphaFold3 structural modeling. We found an enrichment of microbial pathways for pantothenate and coenzyme A (CoA) biosynthesis in carriers, primarily driven by functionally divergent Blautia obeum strains. This functional shift paralleled lower levels of serum pantothenate and HDL-cholesterol in the host. Our findings suggest a potential genotype-microbiome-host axis where antigen presentation-mediated immune selection may modulate microbial adaptation, with possible implications for the host availability of essential cofactor precursors and lipid metabolism.