Nonliving biotherapeutics for veterinary enteric disease: Postbiotics, bacteriophage, and antivirulence strategies to reduce antibiotic dependence.

Enteric diseases in poultry and neonatal calves remain major drivers of productivity loss and therapeutic antimicrobial use, thereby contributing to antimicrobial resistance. Necrotic enteritis in poultry is estimated to cost the global industry US $5-6 billion annually, while neonatal calf diarrhea is reported as a leading cause of morbidity (∼20-40%) and mortality (up to 8%). Nonliving biotherapeutics have attracted increasing attention because they can reduce antibiotic dependence without requiring live microbial engraftment and can be formulated for stability and consistent delivery. This review synthesizes evidence for three nonliving biotherapeutic classes: postbiotics, bacteriophages, and antivirulence strategies. Postbiotics, preparations comprising inanimate microorganisms and/or their components, can strengthen epithelial barrier integrity, modulate mucosal immunity, suppress pathogen growth, and improve redox balance, though consistent efficacy depends on delivery kinetics (e.g., protected butyrate). Phage therapy enables pathogen-specific reduction with minimal nontarget effects; controlled and commercial-scale poultry studies report reductions that can reach multi-log levels in favorable deployments, but outcomes remain sensitive to host range, formulation, and resistance management. Antivirulence approaches (quorum sensing interference, toxin neutralization, and adhesion and biofilm disruption) aim to reduce disease severity by suppressing pathogenic behaviors, potentially lowering selection pressure compared with broad bactericidal exposure. However, these interventions are not intrinsically free of antibacterial selection or implementation risks. Bacteriocins and other microbial antimicrobial peptides exert direct antibacterial activity, whereas successful phage therapy requires timely identification of the causal bacterium, confirmation of phage-host compatibility, reliable delivery, and surveillance for resistance. Product heterogeneity, variable field exposure, incomplete standardization, and regulatory and diagnostic constraints continue to limit routine adoption. We propose a syndrome-specific, stage-based selection framework for poultry necrotic enteritis and dysbiosis-associated diarrhea and calf diarrhea complex and highlight minimum characterization and trial endpoint standards required for field translation.