Commensal-derived antigens may contribute to autoimmunity by coincidentally mimicking immune-targeted self-structures. Ruff et al. report that human autoreactive lymphocytes and autoantibodies cross-react with homologous regions expressed by the human gut commensal Roseburia intestinalis. Pathogenic APS-generated autoantibodies target bacterial DNA methyltransferase. Gavage of susceptible mice with R. intestinalis triggers autoimmune pathologies.