Molar–Incisor and Generalized Grade C Periodontitis: Distinct Microbiome–Immune Interactions Suggest Divergent Pathogenesis

Aim: Molar-Incisor (PerioC-MIP) and Generalized (PerioC-G) Grade C Periodontitis could have distinctive etiopathogenesis behind their unique clinical patterns. Thus, this study aimed to distinguish these two phenotypes by analyzing the subgingival metagenomic profile and the inflammatory markers levels. Methods: In this cross-sectional comparative study, Gingival Crevicular Fluid (GCF) and Subgingival Biofilm (SB) were collected from 18 PerioC-MIP North Americans and 14 periodontally healthy controls (HC) from the same location (HC-MIP) and 20 PerioC-G Brazilians and 20 controls (HC-G). From GCF, immunoenzymatic analysis was performed. SB functional and taxonomic bacterial content was determined using shotgun metagenomics sequencing. Results: Taxonomic results showed significantly different alpha- and beta-diversity profiles between disease groups (p < 0.05). Aggregatibacter actinomycetemcomitans and Streptococcus sanguinis were associated with PerioC-MIP; levels of Tannerella forsythia, Filifactor alocis, Porphyromonas gingivalis, Fretibacterium fastidiosum, and Treponema denticola were significantly enriched at PerioC-G (p < 0.05). PerioC-G had the function for flagellar assembly enriched, while PerioC-MIP SB was associated with biofilm formation of Escherichia coli. Different GCF inflammatory marker levels for each pattern resulted in PerioC-G presenting higher levels of IL-1β, IL-6, and IL-10 than PerioC-MIP (p < 0.05). Conclusion: PerioC-G and PerioC-MIP presented different taxonomical profiles and GCF cytokine levels, raising the hypothesis that they may represent two different stages/susceptibility patterns of Periodontitis Grade C.