Foodborne diseases take a toll of around 420000 lives with 600 million cases worldwide annually as per who estimates. 30% of the foodborne deaths occur among children under 5 years of age. the major causative agents of bacterial foodborne diseases are salmonella, listeria, e. coli or campylobacter. invasive non-typhoidal salmonella (ints) are the major cause of health concern in the low-income, under-developed nations in africa and asia that lack proper sanitation facilities. around 5% of the nts cases give rise to invasive, extraintestinal diseases leading to focal infections and bacteremia like osteomyelitis, meningitis, osteoarthiritis, endocarditis, and neonatal sepsis. similarly, invasive listeriosis invading beyond the gut barrier to the blood and brain cause deadly meningitis, and other fatal complications. in pregnant women, listeria can lead to miscarriage and stillbirths. the rampant usage of antibiotics leading to the emergence of multi-drug-resistant strains poses a great challenge in disease management. therefore, designing novel alternative therapeutic strategies to thwart foodborne illnesses is of prime importance. here, we have identified a gut-commensal species, odoribacter splanchnicus (os)-secreted antimicrobial proteins bacteriocins that are responsible for mitigating salmonella and listeria pathogenesis. our finding depicted the mechanism by which os counters salmonella and listeria infection in mice, that is, by inhibiting gut vascular barrier disruption, acute inflammatory infection signs, in vivo biofilm formation and by preserving tight junction protein functions upon pre-colonization. os pre-colonized mice showed decreased susceptibility to salmonella infection in comparison to the non-colonized mice cohort which succumbed to death by day 9 post-infection. contrastingly, 100% of the os colonized mice were alive even at day 11 post salmonella infection. the increased salmonella fecal, organ loads, and bacterial dissemination were reduced upon os pre-colonization. os non-colonized mice exhibited increased weight loss percentage upon salmonella infection and os pre-colonization led to diminished weight reduction percentage. further, our in vitro studies revealed that not only live o. splanchnicus 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. os-colonized mice exhibited increased survival rates upon listeria monocytogenes challenge compared to the non-colonized mice cohort. in line with the survival data, increased bacterial burden was observed in blood, feces, intestine, mln, spleen and liver alongside enhanced percent loss in mice body weight in the case of listeria infection in non-colonized mice group with respect to os-precolonized- mice group. further, os promoted intestinal tight junction functions during listeria infection with reduced expression of gvb damage marker, pv-1 and angiogenesis marker, vegf expression. moreover, os colonization could restrict the in vivo salmonella and listeria biofilm within the spleens of the infected mice cohorts as opposed to the non-colonized mice cohorts. in vitro listeria and salmonella co-culture with os or its culture supernatant led to a loss in flagella as evidenced via the tem imaging. 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.