SUMMARY/ABSTRACT Periodontal disease, a widespread global health issue, predominantly originates from dental plaque, which an intricate polymicrobial biofilm. Within this milieu, Veillonella, an anaerobic, Gram-negative bacterium, stands out for its unique ability to produce heme. Although this process seems non-essential for Veillonella itself, it’s critical for its bacterial associates. Despite its significance, the regulation of heme production in Veillonella and its impact on oral ecology remain enigmatic. This study zeroes in on the symbiotic dance between Veillonella and the periodontopathogen Porphyromonas gingivalis (Pg), which relies heavily on heme as its primary nutrient and is known to provoke inflammation via red blood cell breakdown. In the presence of Pg, heme production in Veillonella is significantly induced. Intriguingly, this heme production completely abolishes Pg’s hemolytic activity. This initial observation propels the hypothesis that Veillonella’s heme production might strategically temper Pg’s hemolytic behaviors, presenting a delicate balance with boarder implications for Pg-associated oral health. To rigorously dissect this interplay, we’ve delineated two central aims. 1) Explore Mechanisms by which Veillonella Inhibits Pg hemolysis. This will involve a comprehensive assay to discern the role of potential proteases produced by Veillonella in suppressing Pg’s hemolytic attributes, with RNA-seq analysis and transposon screening leading to a thorough insight. 2) Ascertain how the regulation of the heme biosynthesis in Veillonella by Pg and its role in Pg-host interaction. Given the significance of Veillonella’ heme production, understanding its regulation and impact on Pg’s interaction with the host immune system is pivotal. This objective will use transwell assays, luciferase reporter strains, Tn5 transposon library and in vitro tissue assays to provide a comprehensive view. In essence, this research aspires to shed light on the nuances of oral biofilm ecology, emphasizing the yet-to be-explored realm of Veillonella’s heme production. Unveiling the potential natural mechanism where one bacterium regulates another’s inflammatory actions, our study could pave the way for innovative periodontal treatments and a deeper grasp of dental biofilm interplay.