The objective of this study was to evaluate the inclusion of the autolyzed yeast (AY) Saccharomyces cerevisiae with or without an immunomodulator (1,3/1,6 β-glucans) as a total/partial substitute for blood plasma (BP) in the diet of post-weaning piglets; zootechnical performance, intestinal health and microbiota, immune responses and energy metabolism were assessed. A total of 240 castrated male and female piglets, with a mean age of 22 days and mean initial weight of 5.24 ± 0.82 kg, were randomly divided into blocks of four treatments with 12 replicates. The dietary inclusions were blood plasma (BP), autolyzed yeast (AY), autolyzed yeast + immunomodulator (AYI) and 50% BP and 50% AY (BPAY). In pre-initial phase II (29–35 days), piglets fed AY showed better feed conversion (FCR = 1.358) than the piglets in the BP (1.484), AYI (1.379) and BPAY (1.442) groups, i.e., 8.49% (0.126), 1.52% (0.021) and 4.50% (0.084), respectively (p = 0.0293). In the total period (21–42 days), better FCR was observed in the AYI (1.458) group, i.e., 4.64% (0.071), 1.15% (0.017) and 4.58% (0.070), than in the BP (1.529), AY (1.475) and BPAY (1.528) groups, respectively (p = 0.0150). In piglets fed AY (n = 3) and BPAY (n = 2), there was a reduction in the number of medications, i.e., 82.35% (−14n) and 88.23% (−15n), respectively (p = 0.0001), compared with that in the BP group (n = 17). In the AY group (73.83 mg/dL), AYI group (69.92 mg/dL), and BPAY group (69.58 mg/dL), piglets exhibited increases in triglyceride levels of 79.32%, 69.83%, and 69.00%, respectively, in comparison to those in the BP group, which had triglyceride levels of 41.17 mg/dL (p = 0.0400). The beta-hydroxybutyrate concentration in the AY group (79.96 ng/μL) was lower by 31.95%, 22.64%, and 5.89% compared to the BP group (117.50 ng/μL), AYI group (103.36 ng/μL), and BPAY group (84.67 ng/μL), respectively (p = 0.0072). In the AYI group, there was modulation of the microbiota, with an increase in the relative abundance of bacteria of the genera Lactobacillus, Collinsella and Bulleidia. AY, associated or not associated with an immunomodulator, is a potential substitute for BP in diets for piglets in the nursery phase, with positive effects on immune, metabolic, and intestinal microbial performance.

Background/Objectives: Trained innate immunity refers to the enhanced responsiveness of innate immune cells, particularly macrophages, following exposure to stimuli such as β-glucan or zymosan, enabling improved defense against unrelated pathogens. This phenomenon has been widely investigated to better understand host–pathogen interactions and to support the development of improved infection control strategies. This study evaluated whether these training stimuli could enhance the protective efficacy of attenuated or inactivated vaccine models against Brucella ovis and Listeria monocytogenes infection. Methods: Trained innate immunity was induced in vivo using β-glucan or zymosan, and seven days later mice were vaccinated with attenuated or gamma-irradiated formulations and subsequently challenged with B. ovis or L. monocytogenes. Vaccine-induced protection and immune responses were assessed through multiple experimental approaches. Results: β-glucan significantly reduced bacterial infection in vitro in bone-marrow-derived macrophages and in vivo in target organs compared with zymosan. Although β-glucan did not enhance the efficacy of the attenuated B. ovis ΔabcBA vaccine, it markedly reduced bacterial colonization in mice vaccinated with gamma-irradiated B. ovis. β-glucan also did not improve the efficacy of the gamma-irradiated L. monocytogenes vaccine; however, 50% of the trained and vaccinated mice showed no detectable bacterial recovery. Increasing the number of β-glucan doses negatively affected infection control, suggesting that overstimulation may impair trained immunity. Conclusion: Trained innate immunity enhances the protective effect of inactivated experimental vaccines against B. ovis and L. monocytogenes, while exerting a detrimental influence on the efficacy of a live attenuated B. ovis vaccine model.