From Gut to Shot: Microbiome-Guided Strategies to Improve Vaccine Responses in Food Animals.

Vaccine performance in livestock and poultry often varies under field conditions. Conventional explanations, such as handling errors, cold-chain failures, or antigen mismatch do not fully account for inconsistent immunogenicity and durability. Increasing evidence suggests that the gut microbiome acts as an upstream regulator of vaccine responses through microbial structural signals and metabolites that shape antigen presentation, B-cell metabolism, and inflammatory tone. Early life microbiome disruption can impair antibody responses to multiple vaccines, highlighting a plausible causal role for dysbiosis in suboptimal vaccine efficacy. Microbiota-derived metabolites, particularly short-chain fatty acids (SCFAs), can influence B-cell differentiation and antibody production through metabolic and epigenetic pathways. However, these effects are dose- and context-dependent, highlighting the need for controlled translation rather than generalized assumptions that higher SCFA levels are beneficial. This review synthesizes microbiome-immunometabolism pathways relevant to vaccine responses in food animals and assesses practical nutritional and microbiome-targeted strategies, such as amino acids, trace minerals, organic acids, phytogenics, and postbiotics, that may modulate these pathways to improve outcomes. We also propose field-deployable biomarker panels that combine immune readouts with inflammation- and microbiome-linked metabolite proxies to stratify likely responders, monitor intervention effects, and improve trial comparability. Finally, we outline translational study designs that connect microbiome shifts to protective immune endpoints and performance outcomes, enabling evidence-based integration of microbiome-informed strategies into vaccination programs for poultry, with broader conceptual relevance to other food animals.