Desulfovibrio spp. are associated with inflammatory diseases and human health, yet limited representative genomes and isolates hinder our understanding of their role in disease. Here, we assembled a comprehensive database of 2,658 Desulfovibrio genomes across 90 diseases and 32 countries, including 24 human isolates. Genomic analyses showed extensive species diversity and revealed disease-associated functional traits, including flagellin and virulence genes (i.e. ureases). Flagellin-mediated Toll-like receptor 5 activation was species-specific and D. desulfuricans flagellin downregulated TGF-beta signalling in murine small intestinal organoids, suggesting impaired immune tolerance. Additionally, we investigated genomic capacity for hydrogen sulfide (H2S) production, a main Desulfovibrio metabolite. While health- and disease-associated Desulfovibrio spp. mainly encoded dissimilatory sulfate reduction, tetrathionate metabolism-encoding bacteria were exclusively detected in inflammatory bowel diseases, including Proteus mirabilis and Morganella morganii. Overall, our study provides a comprehensive genomic Desulfovibrio resource and identifies new links associating strain variation, functional traits and H2S-production with inflammatory diseases.Competing Interest StatementR.K.W. acted as consultant for Takeda Pharmaceuticals, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico and Ferring and received speakers fees from MSD, Abbvie and Janssen Pharmaceuticals.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project number 395357507 (SFB 1371, Microbiome Signatures)BMBF, 16LW0432DFG, TRR353-471011418NWO Vidi grant, VI.Vidi. 233.079