** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** NECROTIC ENTERITIS (NE), CAUSED BY CLOSTRIDIUM PERFRINGENS, RANKS AMONG THE MOST FINANCIALLY DEVASTATING DISEASES IN POULTRY. UNFORTUNATELY, THERE ARE CURRENTLY NO EFFECTIVE PREVENTIVE OR THERAPEUTIC MEASURES AVAILABLE. THE INTESTINAL BACTERIA PLAYS A CRITICAL ROLE IN MAINTAINING ANIMAL HEALTH AND PRODUCTIVITY BY RESISTING THE COLONIZATION AND INFECTION OF INVADING PATHOGENS. IN A RECENT SCREENING OF A LIBRARY OF CHICKEN INTESTINAL BACTERIA, WE IDENTIFIED SEVERAL BACTERIA WITH A STRONG ABILITY TO INHIBIT C. PERFRINGENS, WHILE ALSO ENHANCING INNATE IMMUNITY THROUGH THE INDUCTION OF HOST DEFENSE PEPTIDE (HDP) SYNTHESIS. NOTABLY, ORAL ADMINISTRATION OF A SELECTED COMMENSAL BACTERIUM MARKEDLY IMPROVED ANIMAL SURVIVAL AND ALLEVIATED INTESTINAL LESIONS IN A CHICKEN MODEL OF NE. THESE FINDINGS PROVIDE A TIMELY OPPORTUNITY TO EXPLORE THE POTENTIAL OF COMMENSAL BACTERIA IN RESISTING NE. IN THIS PROJECT, WE WILL SCREEN ADDITIONAL COMMENSAL BACTERIA FOR THEIR ABILITY TO INHIBIT C. PERFRINGENS GROWTH ANDINDUCE HDP SYNTHESIS. LEAD BACTERIAL CANDIDATES WILL BE FURTHER EVALUATED FOR THEIR PROTECTIVE EFFICACY IN NE-INFECTEDCHICKENS. MOREOVER, WE WILL STUDY THE MECHANISM OF ACTION OF THE MOST EFFECTIVE BACTERIUM. UPON COMPLETION, WE EXPECT TO IDENTIFY SEVERAL COMMENSAL BACTERIA THAT ARE HIGHLY EFFECTIVE IN MITIGATING NE AND FURTHER REVEAL THEIR MAJOR MECHANISM OF ACTION. THE OUTCOME WILL FACILITATE THE DEVELOPMENT OF AN INNOVATIVE ANTIBIOTIC-FREE APPROACH TO COMBAT NE AND POTENTIALLY OTHER ENTERIC DISEASES IN POULTRY.