<p class="MsoNormal" style="margin-bottom: 12.0pt; text-align: left; mso-line-height-alt: 12.0pt; layout-grid-mode: char; mso-layout-grid-align: none;" align="left">Oral Microbiome Driving Chemical Carcinogenesis Dampening Therapeutic Outcomes

Background: This narrative review evaluates bacterial pathogen dysbiosis support of host risk for oral squamous cel carcinoma (OSCC) mediating environmental exposomes. Objective: Review provides metabolic, enzymatic, and immunologic mechanisms of oral dysbiosis amplifying chemical carcinogenesis and suppressing therapies for cancer. Narrative: Oral dysbiosis engages with endogenous synthesis of tobacco specific N-Nitrosamines (TSNA) and degradation of tobacco leaf’s poly-aromatic hydrocarbons (PAHs), and pollutants creating a reservoir of carcinogenic agent. Bacteria metabolism of essential amino acid tryptophan-tryptamine, PAHs and TSNAs amplifies chemical carcinogenesis risk for OSCC synthesizing ligands for aryl-hydrocarbon receptor (AHR) transcriptional environmental sensing. Lipophilic chemical affinities between bacteria and carcinogen facilitate intercellular aggregations and accumulations in oral epithelium. Gram negative bacteria’s lipopolysaccharide (LPS) and endopeptidases enhance lipophilic peroxidation (e.g., trimethylamine oxide (TMAO), exciting pathogen pattern recognition responses (e.g., DAMP, PAMP) with toll-like receptor expression eliciting NF-KB transcription of cytokines, and pathogen’s epoxide hydrolases of diol epoxides producing DNA adducts, mutations and oxidative stresses. LPS+PAH+TSNA causes lipophilic membrane disruption driving ubiquitination-proteosome and Golgi-trans network’s inappropriate host protein degradation, sorting, and transporting of epithelial proteins. Pathogens adhere to epithelium and release bacterial virulence factors, (cysteine-serine) proteases, and endopeptidases. degrading immunoglobulins, complement, cytokines, and extracellular matrix increasing intracellular transcriptional complex expressions of proto-oncogene/oncogenes. Influence of arginine-polyamine-epigenetics-methylation, and nonessential (cysteine) amino acid, sulphuration suppresses oncology therapies. AHR derived E3 ubiquitin ligase enhances DNA instability, with biomolecular condensates supporting tumor microenvironment (TME). Conclusion: Oral bacterial oncogenesis results in evasion from immune recognition, depressed mucosal tumor immune surveillance, cytotoxicity and therapies.