Bismuth drugs tackle Porphyromonas gingivalis and attune cytokine response in human cells
Periodontitis is the leading cause of severe tooth loss and edentulism in adults worldwide, and yet links closely to systemic conditions like diabetes and cardiovascular disease. Porphyromonas gingivalis is the keystone pathogen of periodontitis. Herein, we provided the first evidence that bismuth drugs suppressed P. gingivalis in its planktonic, biofilm and intracellular states. Totally, 42 bismuth-associated proteins were identified including its major virulence factors (e.g. gingipains, hemagglutinin HagA and fimbriae). Bismuth perturbed its iron acquisition, disturbed energy metabolism and virulence, and inactivated multiple key enzymes (e.g., superoxide dismutase and thioredoxins). Moreover, bismuth inhibited its biofilm formation and disrupted the 3-day matured biofilms. Notably, the internalized P. gingivalis in various human cells (e.g., gingival epithelium progenitors, HGEPs) was oppressed by bismuth, but not the commonly used antibiotics metronidazole. Importantly, bismuth drugs enabled to counteract immuno-inflammatory responses in different host cells perturbed by P. gingivalis. The production of IL-6 and IL-8 attenuated by P. gingivalis in both native and IL-1β-stimulated HGEPs was restored, while the bacterium-enhanced expression of IL-6, IL-1β and TNFα in THP-1 macrophages was alleviated. This proof-of-concept study brings prospects to potential reposition of the routinely used anti-Helicobacter pylori bismuth drugs to better manage inflammatory diseases like periodontitis and P. gingivalis-related complex systemic disorders.