Lacticaseibacillus rhamnosus P118 enhances host tolerance to Salmonella infection by promoting microbe-derived indole metabolites

<i>Salmonella</i> is one of the most common foodborne pathogens, resulting in inflammatory gastroenteritis and frequently accompanied by dysbiosis. Gut commensals, such as <i>Lactobacillus</i> species, have been proven to exhibit broad antibacterial activities and protect hosts against pathogenic infections. Here, <i>Lacticaseibacillus rhamnosus</i> strain P118, screened from 290 isolates recovered from fermented yogurts and healthy piglet intestines using traditional and <i>Caenorhabditis elegans</i>-infection screening strategies, exerts great probiotic properties. Notably, P118 and its supernatant exhibited great antibacterial activities and attenuated <i>C. elegans</i> susceptibility to <i>Salmonella</i> infection. We found that P118 protected mice against <i>Salmonella</i> lethal infections by enhancing colonization resistance, reducing pathogen invasion, alleviating intestinal pro-inflammatory response, and improving microbial dysbiosis and fecal metabolite changes. Microbiota and fecal metabolome analyses suggested P118 administration significantly decreased the relative abundances of potentially harmful microbes (e.g., <i>Salmonella</i>, <i>Anaeroplasma</i>, <i>Klebsiella</i>) and increased the fecal levels of tryptophan and its derivatives (indole, indole-3-acrylic acid, 5-hydroxytryptophan, 5-methoxyindoleacetate). Deterministic processes determined the gut microbial community assembly of P118-pretreated mice. Integrated omics further demonstrated that P118 probiotic activities in enhancing host tolerance to <i>Salmonella</i> infection were mediated by microbe-derived tryptophan/indole metabolites (e.g., indole-3-acrylic acid, indole, tryptophan, 5-methoxyindoleacetic acid, and 5-hydroxytryptophan). Collective results demonstrate that <i>L. rhamnosus</i> P118 could enhance host tolerance to <i>Salmonella</i> infections via various pathways, including direct antibacterial actions, inhibiting <i>Salmonella</i> colonization and invasion, attenuating pro-inflammatory responses of intestinal macrophages, and modulating gut microbiota mediated by microbe-derived indole metabolites.