Project Summary/AbstractWe intend to leverage a unique model system developed in our laboratories to reproduce diverse ecosystemsrepresenting the human distal colon (DC) and use them to identify the role of the vast communities of virusesthat inhabit the DC. Many of these viruses are bacteriophages that are postulated to play major roles in alteringhuman bacterial communities, but until now there has been no available technology to assess their roles.Because bacteriophages kill their hosts or provide them with potentially beneficial gene functions, wehypothesize that they have a significant capacity to shape the human microbiome and potentially play a role inthe maintenance of health and the development of disease. Our laboratories have pioneered technologies tocharacterize these viral communities, and have shown that viral communities are highly personal, persistent,host sex consistent, harbor genes involved in antibiotic resistance, and are readily transmissible between closecontacts. We believe that the unique model ecosystems we have developed will allow us to reproduce thediverse and complex microbial ecology of the DC, and will play a critical role in helping to decipher the role ofthe viral communities that inhabit the human DC.We now know that bacteria in the gut play significant roles in human health and disease, yet the forces thatshape the gut microbiome are still being uncovered. Much of the diversity in the DC can be grouped intodistinct enterotypes; these groups are driven by the relative abundances of microbes such as Bacteroides indifferent individuals. Our model system simulates the diverse DC microbiota, and is the first model capable ofrecapitulating the enormous microbial diversity of the DC. The system incorporates bile salts, mucins, andstarches to create an environment suitable for DC bacteria. Another major benefit of this system is its accuratereproduction of viral communities from the DC. We hypothesize that the use of this model system willallow us to directly test the impacts of virus-mediated perturbations on different enterotypes.The proposed studies will help decipher the impacts of viruses on the diversity and taxonomy of gutenterotypes, and determine whether virus-mediated perturbations result in enterotype switching. Our aims areas follows: Aim 1) Establish model systems representing different distal colon enterotypes, andAim 2) Characterize the responses of cultured communities to virus-mediated perturbations.We believe that through the development of our model DC ecosystem, we can address fundamental questionsabout the roles of viruses in the human microbiome, including: 1) how do viral communities impact our DCmicrobiomes?, 2) are viruses important determinants of DC microbial ecology?, and 3) how do viruses fromindividuals with different enterotypes affect one another? We believe the proposed research is a critical firststep in understanding how viral communities may be used to manipulate the human microbiome.