ISSUE FOCUS FEED & ADDITIVE MAGAZINE February 2026 65 This review examines the hormetic principle and its application to modern poultry/swine feeding concepts, exploring how balanced nutrient design and controlled inclusion of bioactive compounds can strengthen cellular adaptation, improve stress tolerance, and enhance production efficiency. HOW DO AGPs ACTUALLY WORK? Despite AGP’s widespread historical use, the precise mechanisms by which subtherapeutic doses of antibiotics enhance animal productivity remained poorly understood. Recent advances in systems biology and mitochondrial research propose new answers, much needed to develop future advanced nutritional systems. The traditional explanations for AGP efficacy have focused primarily on antimicrobial effects: • reducing nutrient competition from microorganisms • decreasing harmful bacterial metabolites • improving gut wall morphology (thinner gut wall → better nutrient absorption) • preventing subclinical infections However, these mechanisms alone could not fully explain why different classes of antibiotics with diverse mechanisms of action produce similar growth-promoting effects (Gutierrez-Chavez et al., 2025). Niewold (2007) hypothesized that the primary mechanism of AGPs is non-antibiotic anti-inflammatory activity, reducing the energetic costs of chronic low-grade inflammation. Inflammation diverts nutrients from growth toward immune responses, with cytokine production (particularly IL-1β, IL-6, and TNF-α) suppressing anabolic pathways (Kogut et al., 2018). AGPs appear to selectively inhibit pro-inflammatory cytokine production without completely suppressing immune function. A paper published in 2024 by Fernandez Miyakawa et al. proposes that antibiotics at subtherapeutic levels act primarily through mitochondrial hormesis and adaptive stress responses, and not simply through antimicrobial activity. In this model, mitochondria act as bioenergetic hubs and signaling centers. Low-dose antibiotics trigger mild mitochondrial stress, which triggers the activation of adaptive protective pathways. This in turn induces mitokine release, leading to systemic adaptive responses improving growth, feed efficiency, and disease tolerance. MECHANISM OF ACTION IN THE HORMETIC MODEL OF AGP EFFICIENCY Hormesis is a biphasic mechanism whereby high doses are toxic, but low doses stimulate adaptive responses and are beneficial. In the case of AGPs, Fernandez Miyakawa et al. propose that low doses stimulate growth, stress resistance, and cellular repair. KEY SIGNALING PATHWAYS As Bottje et al. (2006, 2009) shows, efficient animals often have mitochondrial inner membranes that are less permeable to protons and other ions, allowing for more effective coupling between electron transport and ATP synthesis, which reduces energy loss through proton leak and maximizes the production of ATP per oxygen molecule consumed. Lower membrane permeability is influenced by factors like decreased membrane surface area per protein mass, specific membrane protein content (such as adenine nucleotide translocase), and fatty acid composition in the membrane phospholipids, all contributing to a tighter barrier that prevents unregulated electron or proton flow and supports higher energetic efficiency. Such features make mitochondria in efficient species more capable of maintaining membrane integrity and ATP generation, especially when facing environmental stress, as seen in freeze-tolerant animals whose mitochondria do not undergo damaging permeability transitions under extreme conditions. Nrf2 Many AGPs interfere with mitochondrial protein synthesis and electron transport chain. At subtherapeutic levels, they cause a mild ROS (Reactive Oxygen Species) increase, which triggers the activation of redox-sensitive transcription factor Nrf2. Since Nrf2 regulates over 250 antioxidant, detoxification, and anti-inflammatory genes, the result is improved cell survival, redox balance, and tolerance to stress (Petri et al., 2012).
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