Regulation of olfactomedin 4 by Porphyromonas gingivalis in a community context

Abstract

At mucosal barriers, the virulence of microbial communities reflects the outcome of both dysbiotic and eubiotic interactions with the host, with commensal species mitigating or potentiating the action of pathogens. We examined epithelial responses to the oral pathogen Porphyromonas gingivalis as a monoinfection and in association with a community partner, Streptococcus gordonii. RNA-Seq of oral epithelial cells showed that the Notch signaling pathway, including the downstream effector olfactomedin 4 (OLFM4), was differentially regulated by P. gingivalis alone; however, regulation was overridden by S. gordonii. OLFM4 was required for epithelial cell migratory, proliferative and inflammatory responses to P. gingivalis. Activation of Notch signaling was induced through increased expression of the Notch1 receptor and the Jagged1 (Jag1) agonist. In addition, Jag1 was released in response to P. gingivalis, leading to paracrine activation. Following Jag1-Notch1 engagement, the Notch1 extracellular domain was cleaved by P. gingivalis gingipain proteases. Antagonism by S. gordonii involved inhibition of gingipain activity by secreted hydrogen peroxide. The results establish a novel mechanism by which P. gingivalis modulates epithelial cell function which is dependent on community context. These interrelationships have relevance for innate inflammatory responses and epithelial cell fate decisions in oral health and disease.

Role of Porphyromonas gingivalis in oral and orodigestive squamous cell carcinoma

“…Indeed, coinfection of gingival epithelial cells with S. gordonii overrides much of the transcriptional program differentially regulated by P. gingivalis and returns the cells closer to the homeostatic state. 130,131 One of the major pathways transcriptionally induced by P. gingivalis, but suppressed in a dualspecies context with S. gordonii, is the Notch signaling pathway. 131 Activation of Notch signaling proceeds through increased expression of the Notch1 receptor and the Jagged1 agonist.…”

“…Mechanistically, S. gordonii activates the TAK1‐NLK pathway, which negatively regulates Forkhead Box O1–dependent regulation of Zinc Finger E‐box Binding Homeobox 2. Indeed, coinfection of gingival epithelial cells with S. gordonii overrides much of the transcriptional program differentially regulated by P. gingivalis and returns the cells closer to the homeostatic state 130,131 . One of the major pathways transcriptionally induced by P. gingivalis , but suppressed in a dual‐species context with S. gordonii , is the Notch signaling pathway 131 .…”

“…130,131 One of the major pathways transcriptionally induced by P. gingivalis, but suppressed in a dualspecies context with S. gordonii, is the Notch signaling pathway. 131 Activation of Notch signaling proceeds through increased expression of the Notch1 receptor and the Jagged1 agonist. Following Jagged1-Notch1 engagement, the Notch1 extracellular domain is cleaved by P. gingivalis gingipain proteases to activate signaling.…”

Cross Talk between Synthetic Food Colors (Azo Dyes), Oral Flora, and Cardiovascular Disorders

“…Biofilm is formed by the accumulation of bacterial pathogens, which move into blood vessels through cell-cell junction and cause the formation of plaque in major arteries. This would lead to different cardiovascular disorders through dental plaque formation, which produces a dental biofilm, a thick layer of bacteria [53]. The oral microbiomes such as P. gingivalis, T. denticola, T. forsythia, and Strep.…”

Porphyromonas gingivalis Induces Increases in Branched-Chain Amino Acid Levels and Exacerbates Liver Injury Through livh/livk

“…It has also been suggested that Porphyromonas gingivalis , a gram-negative anaerobe, is the most important pathogenic bacterium in periodontitis ( Lamont et al., 2018 ; Liu et al., 2021 ). Furthermore, P. gingivalis possesses a plurality of virulence factors that invade periodontal tissues and subsequently enter blood circulation and disseminate into the whole body, increasing the risk of several systemic diseases, notably diabetes, cardiovascular diseases, rheumatoid arthritis, Alzheimer’s disease, and NAFLD ( Potempa et al., 2017 ; Nakahara et al., 2018 ; Mei et al., 2020 ; Fitzsimonds et al., 2021 ). Previous studies have shown that P. gingivalis infection aggravates liver inflammation and fibrosis in NASH mouse model induced by high-fat diet (HFD) ( Furusho et al., 2013 ; Nagasaki et al., 2020 ).…”