21Oral microbiome influences human health, specifically pre-and type 2 diabetes (Pre-DM/DM) and 22 periodontal diseases (PD), through complex microbial interactions. To explore these relations, we 23 performed 16S rDNA sequencing, metabolomics, lipidomics, and proteomics analyses on 24 supragingival dental plaque collected from individuals with Pre-DM/DM (n=39), Pre-DM/DM and 25 PD (n=37), PD alone (n=11), or neither (n=10). We identified on average 2,790 operational 26 taxonomic units and 2,025 microbial and host proteins per sample and quantified 110 metabolites 27 and 415 lipids. Plaque samples from Pre-DM/DM patients contained higher abundance of 28 Fusobacterium and Tannerella vs. plaques from metabolically healthy. Phosphatidylcholines, 29 plasmenyl-phosphatidylcholines, ceramides containing non-OH fatty acids, and host proteins 30 related to actin filament rearrangement were elevated in plaques from PD vs. non-PD. Cross-31 omic correlation analysis enabled the detection of a strong association between Lautropia and 32 mono-methyl phophospotidlyethanolamine (PE-NMe), striking because synthesis of PE-NMe is 33 uncommon in oral bacteria. Lipidomics analysis of in vitro cultures of Lautropia mirabilis confirmed 34 the bacteria's synthesis of PE-NMe. This comprehensive analysis revealed a novel microbial 35 metabolic pathway and significant associations of host-derived proteins with PD. 36 42 contribute to the progression of PD are also correlated with systemic diseases, including diabetes, 43arthritis, and heart disease 5-7 , suggesting that oral microbial ecologies have a broad impact on 44 human health, and a better understanding of pathogenesis and host-microbe interactions will be 45 essential for mitigating negative effects of pathogenic microbiota. 46With poor oral hygiene, bacterial populations accumulate, become increasingly diverse, and 47