HLA-B27 modulates the composition of the gut microbiota and drives a proinflammatory intestinal microecology

The pathogenesis of autoimmune diseases such as spondyloarthritis (SpA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) involves genetic factors and gut microbiota dysbiosis, which have been widely reported in patients and animal models. Although genetic factors are known to reshape the gut microbiota, the mechanistic role of the host gene-reshaped gut microbiota in mediating inflammatory diseases remains poorly characterized. This study focused on HLA-B27 to investigate its impact on the gut microbial composition and its association with HLA-B27 related autoimmune inflammatory diseases. The expression of HLA-B27/β2M significantly altered the diversity of the gut microbiota in mice, leading to changes in bacterial species and their functions. Concurrently, HLA-B27/β2M profoundly modified the gut metabolic profile, resulting in increased levels of multiple prostaglandins and decreased levels of anti-inflammatory metabolites. Multi-omics integrated analysis demonstrated that HLA-B27/β2M promoted the synthesis of Gram-negative bacteria while suppressing Gram-positive bacteria, findings validated in both omics datasets. Further validation confirmed that these HLA-B27/β2M-driven alterations in the gut microbial composition caused a shift toward a proinflammatory microbial community. These findings first revealed that genetic factors significantly reshaped the gut microbiota composition and further drove the microbial ecosystem toward a proinflammatory state. This study provides a foundation for identifying gut microbial signature targets in HLA-B27 associated diseases.