** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** THE CHRONIC INFLAMMATORY EFFECTS OF SUBACUTE ACIDOSIS ARE THE GREATEST IMPEDIMENT TO ACHIEVING OPTIMAL BEEF PRODUCTIVITY IN MODERN WELL-MANAGED BEEF PRODUCTION SYSTEMS. WHILE RUMINAL HEALTH HAS RECEIVED MUCH ATTENTION, IT IS INCREASINGLY EVIDENT THAT THE POST-RUMINAL GASTROINTESTINAL TRACT (GIT) PLAYS A SIGNIFICANT ROLE IN THE PROGRESSION OFDISEASE.THESE ILL EFFECTS MAY BE COMPOUNDEDBY RESTRICTIONS PLACED ON CERTAIN DIETARY ANTIBIOTICS. AS ALTERNATIVES TO ANTIBIOTICS ARE SOUGHT, THERE IS A SURPRISING LACK OF KNOWLEDGE ABOUT HOW THEY INTERACT WITH COMMENSALBACTERIA AND PATHOGENS TO ALTER INTESTINAL FUNCTION AND INTEGRITY. MICROBIALLY MODIFIED BILE ACIDS ARE A COMPELLING MECHANISTIC TARGET FOR ENHANCED GUT BARRIER FUNCTION. TO ADDRESS THIS GAP, THESPECIFIC OBJECTIVESOF THIS PROPOSAL ARE TO FEED TYLOSIN + MONENSIN TO GRAIN-FINISHED FEEDLOT CATTLE AND: 1) CHARACTERIZE CHANGES IN THE RUMINAL, INTESTINAL, AND CECAL MICROBIOME, 2) IDENTIFY ANTIBIOTIC-RESPONSIVE METABOLITES IN DIGESTA 3) DETERMINE HOST RESPONSE TO MICROBIAL SIGNALS, AND 4) INTEGRATE METAGENOME-METABOLOME-TRANSCRIPTOME DATA FOR A COMPREHENSIVE MODEL OF THE SYSTEM. OURCENTRAL HYPOTHESIS, IS THATANTIMICROBIAL DRUGS IMPROVE HOST INTESTINALFUNCTION AND INTEGRITYBY INHIBITING BILE SALT HYDROLYZING BACTERIAL SPECIES IN THE LOWER GIT, RESULTING IN LESS MICROBIAL MODIFICATION OF BILE ACIDS AND A PRIMARY CONJUGATED BILE ACID PROFILE THAT DAMPENS PHYSIOLOGICAL INFLAMMATION. IN TURN, GUT BARRIER FUNCTION WILL IMPROVE AND THE CATABOLIC COST OF MAINTAINING AN IMMUNE RESPONSE WILL DECREASE. BY USING MULTIPLE-OMICS TECHNIQUES, OUR AIM IS TO REVEAL ELEMENTS OF THE SYSTEM TO TARGET FOR DEVELOPMENT OF ALTERNATIVES THAT IMPROVE EFFICIENCY, HEALTH, AND WELFARE OF FEEDLOT CATTLE MANAGEDUNDER VARIOUS CONDITIONS.