61. Enriching Early Life to Promote the Co-development of Microbiome and Immune System in Neonatal Calves.

Abstract Early life is a period of heightened developmental plasticity during which biological systems are particularly responsive to environmental, nutritional, and microbial inputs. In neonatal calves, the pre-weaning period represents a critical window for the establishment of the gastrointestinal microbiome and the development of mucosal immune system. These processes are tightly interconnected, as pioneer microbiota provides essential signals that guide the gut-associated immune system development. Evidence from human and rodent studies has demonstrated that microbial exposures during early life can exert long-lasting effects on immune competence and disease susceptibility, suggesting that this developmental window may profoundly influence lifelong health and productivity. The neonatal calf gut microbiome develops rapidly following birth through exposure to the dam, diet, environment, and management practices. Importantly, microbial colonization occurs in a region-specific manner along the gastrointestinal tract, with distinct microbial communities performing specialized functions that support host development. For example, microbes colonizing the rumen contribute to epithelial development and metabolic maturation, whereas microbial communities in the small intestine play key roles in priming mucosal immune responses. In the small intestine, differences in dominant bacterial taxa are associated with enrichment of distinct immune pathways, indicating that the composition of early-life microbial communities can influence the trajectory of immune maturation. Consequently, perturbations to microbial colonization during this critical developmental period may disrupt microbiome-immune system co-development and contribute to variation in disease susceptibility, health, and resilience. However, the high plasticity that characterizes early life provides an opportunity to actively shape microbial colonization and potentially correct perturbations before long-term consequences become established. This concept has stimulated considerable interest in microbiome-targeted interventions in calves, including probiotics, prebiotics, postbiotics such as yeast-derived products, and fecal microbiota transplantation. Although these approaches have shown promise, their effectiveness has been inconsistent across studies and production systems. One potential explanation is that many interventions fail to account for the natural dynamics of microbial succession that are necessary for appropriate immune education and the establishment of long-term immunological memory. Future efforts should therefore move beyond simply altering microbial composition and instead focus on promoting the coordinated development of microbial communities and host immunity. Complementary strategies, including management practices that support healthy colonization dynamics and maternal interventions that enhance the transfer of beneficial microbes to offspring, may further strengthen this developmental programming approach. Together, these strategies offer an opportunity to improve calf health, resilience, and lifetime productivity by harnessing the microbiome-immune axis during this critical window of development.