HLA-DQ2/8 genotype imprints strain-level gut microbiome and constrains pantothenate availability in healthy adults

Objective To determine whether HLA-DQ2/8 genotype shapes the human microbiome at strain and functional levels, and whether such effects relate to systemic metabolism and clinical phenotypes in healthy adults. Design We analyzed 60 young adults stratified by HLA-DQ2/8 status (28 carriers, 32 non-carriers). Over 8 weeks, we collected fecal and salivary metagenomes, serum metabolomes, dietary records, and clinical phenotypes. We combined species-level and strain-level analyses of microbiome composition and function, HLA class II binding predictions of microbial gene products, and structural modeling of HLA-DQ-microbial peptide complexes. Results HLA-DQ2/8 carriers showed higher gut microbial α-diversity, elevated Gut Microbiome Health Index, and fewer virulence genes. Gut species composition differed significantly by genotype (PERMANOVA p<0.01), and species-level profiles predicted genotype with high accuracy (LASSO AUC=0.90). Strain-level divergence was identified in 15 gut species, with functional specialization in peptidoglycan, indole, and coenzyme A (CoA) biosynthesis pathways; Blautia obeum was the principal contributor to CoA-related differences. At the gene level, GO enrichment highlighted membrane-associated processes across gut and saliva, suggesting adaptation at the host-microbe interface. Microbial genes with predicted HLA-DQ binding occurred at lower prevalence than non-binders, and AlphaFold3 modeling confirmed haplotype-specific microbial peptide-HLA interactions. Serum metabolomics revealed lower pantothenate in carriers, with reduced HDL-cholesterol, heart rate, neutrophil and basophil counts; HDL-cholesterol correlated positively with pantothenate. Conclusions HLA-DQ2/8 genotype is associated with the adult microbiome at strain and functional levels through antigen-presentation-mediated selection, with systemic signatures in vitamin B5/CoA metabolism and HDL-cholesterol. These findings reveal a genotype-microbiome-host axis in health and motivate larger, multi-ethnic cohorts.