ABSTRACTBacterial diseases of the gastrointestinal (GI) tract continue to be a major worldwide cause of human morbidityand mortality. Among various enteric pathogens, Shigella spp. are some of the most common and deadlybacterial pathogens. They are responsible for ~125 million worldwide cases of shigellosis and ~14,000 deathsannually, the majority in children under the age of 5 and occurring in developing countries [1-3]. Preventing andtreating shigellosis with conventional tools (e.g., vaccines and antibiotics) has proven to be very difficult, andthe increasing prevalence of multi-antibiotic-resistant Shigella strains [4-7] creates the alarming possibility thatthese already staggering morbidity and mortality rates may further increase. The CDC  and WHO  haverecently emphasized the threat of antibiotic resistant Shigella, and is underscored further by the increasingprevalence of antibiotic resistant Shigella in food , occurrence through sexual transmission  and unusuallylarge outbreaks . Therefore, alternative approaches for reducing the incidence and severity of Shigellainfections are urgently needed. Ideally, these approaches will be affordable, so that they can be widelydistributed in developing countries where resources are scarce and Shigella infections are a significant publichealth concern. They also should be non-antibiotic-based, so their continued use will not promote theemergence of antibiotic-resistant strains of Shigella or other enteric pathogens. We believe thatbacteriophages offer one such approach. Lytic bacteriophages present a platform technology which can beused to develop a series of products for the treatment of various infectious diseases of bacterial etiology. Indeveloping this platform technology for human clinical applications and integrating it into modern medicalpractices, we focus here on evaluating the safety and efficacy of our Shigella phage preparation (ShigActive?)in Phase 1/2a human clinical trials. The aims of this proposal are to: 1) manufacture the ShigActive? clinicaltrial material; 2) set the regulatory framework for concurrence and approval by regulatory entities; and 3)perform an FDA-approved proof-of-concept Phase 1 safety and Phase 2a efficacy trial using a controlledhuman infection model of shigellosis. This study will also generate novel, preliminary microbiome data ofbacteriophage interaction with normal gut microbiota. This will be the first clinical trial of a bacteriophagepreparation for managing Shigella infections conducted under FDA guidelines. If successful, our studies herewill provide an innovative, safe, and effective approach for managing Shigella infections. Moreover, they alsowill provide critical groundwork for developing additional phage preparations against other bacterial pathogensof concern, including Vibrio cholerae, diarrheagenic Escherichia coli, and other important bacterial agents of GItract disease.