ABSTRACTThe gut microbiota confers resistance to pathogens of the intestinal ecosystem, yet the dynamics of pathogen-microbiome interactions and the metabolites involved in this process remain largely unknown. Here, we use gnotobiotic mice infected with the virulent pathogenSalmonella entericaserovar Typhimurium or the opportunistic pathogenCandida albicansin combination with metagenomics and discovery metabolomics to identify changes in the community and metabolome during infection. To isolate the role of the microbiota in response to pathogens, we compared mice monocolonized with the pathogen, uninfected mice “humanized” with a synthetic human microbiome, or infected humanized mice. InSalmonella-infected mice, by 3 days into infection, microbiome community structure and function changed substantially, with a rise inEnterobacteriaceaestrains and a reduction in biosynthetic gene cluster potential. In contrast,Candida-infected mice had few microbiome changes. The LC-MS metabolomic fingerprint of the cecum differed between mice monocolonized with either pathogen and humanized infected mice. Specifically, we identified an increase in glutathione disulfide, glutathione cysteine disulfide, inosine 5’-monophosphate, and hydroxybutyrylcarnitine in mice infected withSalmonellain contrast to uninfected mice and mice monocolonized withSalmonella. These metabolites potentially play a role in pathogen-induced oxidative stress. These results provide insight into how the microbiota community members interact with each other and with pathogens on a metabolic level.IMPORTANCEThe gut microbiota is increasingly recognized for playing a critical role in human health and disease, especially in conferring resistance to both virulent pathogens such asSalmonella, which infects 1.2 million people in the United States every year (E. Scallan, R. M. Hoekstra, F. J. Angulo, R. V. Tauxe, et al., Emerg Infect Dis 17:7–15, 2011,https://doi.org/10.3201/eid1701.P11101), and opportunistic pathogens likeCandida, which causes an estimated 46,000 cases of invasive candidiasis each year in the United States (Centers for Disease Control and Prevention,Antibiotic Resistance Threats in the United States,2013, 2013). Using a gnotobiotic mouse model, we investigate potential changes in gut microbial community structure and function during infection using metagenomics and metabolomics. We observe that changes in the community and in biosynthetic gene cluster potential occur within 3 days for the virulentSalmonella entericaserovar Typhimurium, but there are minimal changes with a poorly colonizingCandida albicans. In addition, the metabolome shifts depending on infection status, including changes in glutathione metabolites in response toSalmonella infection, potentially in response to host oxidative stress.
Gut Microbial and Metabolic Responses toSalmonella entericaSerovar Typhimurium andCandida albicans
