Tannerella forsythia-Porphyromonas gingivalis polymicrobial biofilm synergy boosts host inflammation and remodels the T. forsythia transcriptome

Abstract Periodontitis is a complex polymicrobial biofilm disease for which no targeted pharmacological therapies currently exist. Although Porphyromonas gingivalis is considered the keystone pathogen of periodontitis, how its synergistic interaction with the pathobiont Tannerella forsythia shapes biofilm community dynamics, host inflammatory responses, and bacterial gene expression remains largely unexplored. Using a five-species commensal biofilm model, we show that co-introduction of P. gingivalis triggers a greater than 10-fold increase in T. forsythia cell numbers, fundamentally restructuring the microbial community composition. Combined biofilm challenge induced upregulation of 47 genes in human periodontal ligament mesenchymal stromal cells, predominantly within the TNF and NF-κB signaling pathways, far exceeding inflammatory responses elicited by either pathogen alone. Strikingly, T. forsythia underwent sweeping transcriptomic remodeling in dual-species biofilms—upregulating nutrient acquisition systems, virulence factors, and lanthipeptide biosynthetic gene clusters—whereas P. gingivalis exhibited only minor transcriptomic changes. This asymmetric transcriptional response identifies T. forsythia as the primary responder to polymicrobial interaction and suggests that inter-species signaling drives a transition towards a more virulent T. forsythia phenotype. Collectively, these findings provide mechanistic support for the polymicrobial dysbiosis model of periodontitis pathogenesis and open new avenues for precision therapeutic intervention targeting inter-species synergy.