Gut microbial structural variation improves disease discrimination and reveals a strain-level regulatory mechanism in rheumatoid arthritis

Gut microbial structural variation captures strain-level genomic diversity beyond species abundance, yet its contribution to rheumatoid arthritis (RA) remains unclear. Integrating gut metagenomic datasets from four independent cohorts (n = 491), we identified reproducible RA-associated structural variants (SVs), most of which occurred in species without differential abundance. Incorporating SVs into machine learning models consistently improved disease discrimination across independent validation cohorts. Functional analyses identified a core deletion SV in Agathobacter rectalis that removes an XRE-family transcriptional regulator. Motif discovery and 3D structural modeling demonstrated sequence-specific binding of the regulator to the promoter of a short-chain fatty acid biosynthetic gene, supporting a strain-level regulatory mechanism. Together, these findings establish microbial structural variation as a complementary functional layer beyond taxonomy for RA discrimination and mechanistic interpretation.