Identification of Cross-feeding Metabolism Reveals Oral-Microbiome Modulated Host Behavior

The oral epithelial cell barrier allows the host to interact with commensals and protects from pathogenic organisms. Metabolites from commensal bacteria regulate host immune responses and promote host health under mutually beneficial conditions. However, during infection, commensals regulate inflammatory responses of the potentially opportunistic pathogens, escaping the host defense protocols and increasing the risk of diseases. Therefore, it is critical to identify the factor(s) responsible for the ecosystem shift from commensal to opportunistic flora. We used a genome-based in-silico model to overcome existing challenges and elucidate the host adaptation through immunomodulatory activity mediated by bacterial molecules. We analyzed the gene expression data from GEO (GSE6927) to identify the differentially expressed genes (DEGs) of gingival epithelial cells infected by co-culture with the oral commensal Streptococcus gordonii (Sgo) and the opportunistic Fusobacterium nucleatum (Fnu). We propose a systems-based approach for identifying bacteria-host reaction pairs where the bacterial metabolites were consumed as substrates by the host reactions (potential cross-feeding agent). We identified 170 host DEGs associated with 162 metabolic/signaling/disease pathways modulated by the studied oral microbiome. Our results indicate that the commensal S. gordonii, modulates more metabolic/signaling pathways in the host than the opportunistic commensals F. nucleatum. The cross-feeding metabolic analysis allowed us to identify 61 and 32 different biochemical (metabolic/signaling) pathways for S. gordonii and F. nucleatum infections, respectively. Differentially expressed host genes like MYC, FOS, BCAM, MAT2A, and FGF21 have been identified as potential biomarkers useful in clinical settings to develop novel therapeutic strategies. The S. gordonii genes PDHB, PDHA, PGAM, G6PD, LDH, PYK, IDHI, and PFKA have been seen to alter host behaviors. S. gordonii metabolite GlcCer has been identified as a novel bio-effector molecule regulating the synthesis of LacCer. Additionally, our findings elucidate the role of S. gordonii as an important probiotic consisting of critical bacterial molecules capable of affecting human genes that are instrumental in treating dental caries and periodontal diseases.