Host Transmission of <i>Salmonella enterica</i> Serovar Typhimurium Is Controlled by Virulence Factors and Indigenous Intestinal Microbiota

<jats:title>ABSTRACT</jats:title> <jats:p> Transmission is an essential stage of a pathogen's life cycle and remains poorly understood. We describe here a model in which persistently infected 129X1/SvJ mice provide a natural model of <jats:italic>Salmonella enterica</jats:italic> serovar Typhimurium transmission. In this model only a subset of the infected mice, termed supershedders, shed high levels (>10 <jats:sup>8</jats:sup> CFU/g) of <jats:italic>Salmonella</jats:italic> serovar Typhimurium in their feces and, as a result, rapidly transmit infection. While most <jats:italic>Salmonella</jats:italic> serovar Typhimurium-infected mice show signs of intestinal inflammation, only supershedder mice develop colitis. Development of the supershedder phenotype depends on the virulence determinants <jats:italic>Salmonella</jats:italic> pathogenicity islands 1 and 2, and it is characterized by mucosal invasion and, importantly, high luminal abundance of <jats:italic>Salmonella</jats:italic> serovar Typhimurium within the colon. Immunosuppression of infected mice does not induce the supershedder phenotype, demonstrating that the immune response is not the main determinant of <jats:italic>Salmonella</jats:italic> serovar Typhimurium levels within the colon. In contrast, treatment of mice with antibiotics that alter the health-associated indigenous intestinal microbiota rapidly induces the supershedder phenotype in infected mice and predisposes uninfected mice to the supershedder phenotype for several days. These results demonstrate that the intestinal microbiota plays a critical role in controlling <jats:italic>Salmonella</jats:italic> serovar Typhimurium infection, disease, and transmissibility. This novel model should facilitate the study of host, pathogen, and intestinal microbiota factors that contribute to infectious disease transmission. </jats:p>