Hajra, D.; Mukherjee, D.; Vij, R.; Rajmani, R. S.; Dadireddy, V.; Das, D.; Hussain, T.; Ganji, M.; Tatu, U.; Chakravortty, D.

Foodborne pathogens continue to be a leading concern of health hazards worldwide claiming the lives of millions. The emergence of drug-resistant strains poses a great threat to global world health management. Therefore, designing novel therapeutic strategies aiming to overcome pathogen burden is of utmost importance. Here, we identified the crucial role of a gut-commensal species, Odoribacter splanchnicus in mitigating Salmonella pathogenesis in mice by inhibiting gut vascular barrier disruption, acute inflammatory infection signs, in vivo biofilm formation and by preserving tight junction protein functions upon pre-colonization. Further, our in vitro studies revealed that not only live O. splanchnicus (OS) but also its culture supernatant inhibit Salmonella biofilm formation, intracellular proliferation in human intestinal cells, and its virulence gene expression. In addition, OS\'s inhibitory effect on Salmonella is specific as Enterococcus faecalis fails to exert an inhibitory effect on Salmonella. Further, our results depicted that the specific protective role of OS acts over a broad spectrum as it confers protection against flagellated Gram-positive, Listeria monocytogenes and Gram-negative, Salmonella Typhimurium foodborne pathogens, as opposed to non-flagellated Shigella flexneri. Moreover, OS conferred protection even after its administration to mice post-establishment of infection highlighting its therapeutic potential. Using several biochemical and proteomics approaches, we characterized the key active molecule secreted by OS to limit intracellular Salmonella and Listeria replication in human intestinal epithelial cells by regulating key virulence effectors and flagella. Collectively, our study highlights the broad-spectrum protective role of OS in mitigating Salmonella and Listeria pathogenesis and implicates its therapeutic potential.