AVIAN PATHOGENIC ESCHERICHIA COLI (APEC) IS ONE OF THE MOST SIGNIFICANT HEALTH AND ECONOMIC THREATS TO THE MODERN POULTRY INDUSTRY. AS THERE EXISTS SEVERAL STRAINS OF E. COLI, MANY OF WHICH DO NOT OUTRIGHTLY CAUSE DISEASE AND CAN BE FOUND IN THE GUT AND RESPIRATORY TRACT OF HEALTHY POULTRY, THE MAJOR CHALLENGE IN DESIGNING STRATEGIES TO SUCCESSFULLY COMBAT AND PREVENT APEC INFECTION IN POULTRY IS TO IDENTIFY WHAT CONDITIONS IN THE CHICKEN GUT AND RESPIRATORY TRACT INFLUENCE E. COLI TO CAUSE DISEASE IN THE BIRD. THE IDENTIFICATION OF THESE ENVIRONMENTAL OR PHYSIOLOGICAL FACTORS WOULD BE OF IMMENSE VALUE IN CREATING SCIENTIFIC KNOWLEDGE THAT CAN BE USED TO DESIGN NOVEL HUSBANDRY AND THERAPEUTIC APPROACHES TO PREVENT COLIBACILLOSIS DUE TO APEC IN POULTRY.CHIEF AMONG PRODUCTION-RELATED ENVIRONMENTAL FACTORS THAT ARE WELL-RECOGNIZED TO ADVERSELY AFFECT BROILERS DURING THEIR PRODUCTION LIFETIMES IS HEAT STRESS.HEAT STRESS STANDS OUT AS PARTICULARLY IMPORTANT DUE TO THE SEVERITY BY WHICH IT AFFECTS CHICKEN MORBIDITY IN ADDITION TO GUT HEALTH AND THE COLLECTION OF BACTERIAL MICROORGANISMS IN THE GUT (TERMED THE 'MICROBIOME'). IN RESPONSE TO ENVIRONMENTAL STRESSORS SUCH AS HEAT, STRESS-RELATED "FIGHT-OR-FLIGHT" NEUROCHEMICALS ARE PRODUCED IN THE GUT AND RESPIRATORY TRACTS. A LARGE BODY OF RESEARCH IN NON-AVIAN SPECIES HAS DEMONSTRATED THAT CRITICAL DETERMINANTS OF ANIMAL (TERMED THE 'HOST') SUSCEPTIBILITY TO INFECTION INCLUDE THE PRODUCTION OF STRESS NEUROCHEMICALS, SUCH AS NOREPINEPHRINE AND EPINEPHRINE, WHICH OCCURS AT THE INTERFACE OF THE HOST-MICROBIOME ALONG THE MUCOSAL WALLS IN THE INTESTINAL AND RESPIRATORY TRACTS.THE CONNECTION BETWEEN THE GUT MICROBIOME AND LUNG HEALTH INCLUDING RESPIRATORY INFECTION HAS BEEN TERMED THE MICROBIOTA-GUT-LUNG AXIS. FECAL CONTAMINATION OF LITTER AND BROILER INHALATION OF CONTAMINATED AEROSOL PARTICLES REPRESENTS A NATURAL ROUTE OF TRANSMISSION DIRECTLY LINKING THE INTESTINAL AND RESPIRATORY TRACTS, CREATING REAL-WORLD RELEVANCE FOR THE MICROBIOTA-GUT-LUNG AXIS IN POULTRY AND SPECIFICALLY IN THE DESIGN OF NOVEL ANTIBIOTIC-ALTERNATIVE STRATEGIES AGAINST APEC.WE ANTICIPATE THAT OUR STUDIES WILL HAVE A LONG-TERM IMPACT ON THE SUSTAINABILITY OF THE POULTRY INDUSTRY IN U.S. AGRICULTURE BECAUSE WE WILL HAVE: 1) IDENTIFIED FUNCTIONAL, MECHANISTIC PATHWAYS TO UNDERSTAND HOW APEC INFECTION OCCURS IN BROILER CHICKENS, AND 2) PROVIDED MECHANISTIC EXPLANATIONS ENABLING THE DESIGN OF ANTIBIOTIC ALTERNATIVE APPROACHES FOR THE TREATMENT AND PREVENTION OF APEC INFECTION. THE IDENTIFICATION OF THE MICROBIAL MECHANISMS BY WHICH PRODUCTION-RELATED HEAT STRESS INITIATES E. COLI INFECTION IN BROILER CHICKENS IS EXPECTED TO SIGNIFICANTLY IMPROVE OUR ABILITY TO PREVENT E. COLI RESPIRATORY INFECTION AND COLIBACILLOSIS.