The bacteria that reside within and upon us have a key role in maintaining our health. The intestinal microbiota provides a number of important functions for the host including processing and acquisition of nutrients, development of the immune system, modulation of bioavailable lipids, and serves as a barrier against pathogens. How the microbiota carries out these functions and how they can be manipulated in a diseased state to restore health is pooriy understood. The vast complexity of the gut microbial community has only recently begun to be addressed with the emergence of high-throughput sequencing technologies. However, most of the initial studies of the human microbiota have focused on identifying which organisms are present and not on functional aspects of microbial communities. In this project we will address a function of microbial communities of fundamental importance to the host: the ability to keep pathogens from colonizing and/or causing disease. Using bioreactor models and mice with a humanized intestinal microbiota we will begin to uncover the underiying ecological principles of how pathogen resistance is maintained within a community. We will also attempt to understand what types of disruption are sufficient to allow pathogens to invade the community and cause disease. To achieve these goals the following specific aims are proposed; Specific Aim 1. Investigate how microbial community diversity affects the ability of diarrheal pathogens to become established within the community. Specific Aim 2. Assess the effects of microbial community alterations on the ability of pathogens to cause disease in mice carrying a humanized micriobiota. The work proposed in these specific aims will address a key function of the intestinal microbiota using a combination of in vitro and in vivo approaches.