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

Salmonellais one of the most common foodborne pathogens, resulting in inflammatory gastroenteritis and frequently accompanied by dysbiosis. Gut commensals, such asLactobacillusspecies, have been proven to exhibit broad anti-bacterial activities and protect hosts against pathogenic infections. Here,Lacticaseibacillus rhamnosusstrain P118, with great probiotic properties, was screened from 290 isolates recovered from fermented yoghurts and piglet intestines using traditional andC. elegans-infection screening strategies. Notably, P118 and its supernatant exhibited great antibacterial activities and attenuatedC. eleganssusceptibility toSalmonellainfection. We found that P118 protected mice againstSalmonellalethal infections by enhancing colonization resistance, reducing pathogen invasion, alleviating intestinal pro-inflammatory response, and improving microbial dysbiosis and metabolic disorders. Microbiota and fecal metabolome analyses suggested P118 administration significantly decreased the relative abundances of harmful microbes (e.g.,Salmonella,Anaeroplasma,Klebsiella) 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 toSalmonellainfection 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 thatL. rhamnosusP118 could enhance host tolerance toSalmonellainfections via various pathways, including direct antibacterial actions, inhibitingSalmonellacolonization and invasion, attenuating pro-inflammatory responses of intestinal macrophages, and modulating gut microbiota mediated by microbe-derived indole metabolites.