The objective of this research was to highlight the importance of the gastrointestinal tract (GIT) microbiota in modulating host health via bi-directional communication through microbiome-gut-organ axes. To test this objective, three experiments were conducted. The first experiment focused on the microbiome-gut-brain axis by evaluating the efficacy of a FMT as a point-of-injury therapeutic for traumatic brain injuries. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric porcine model. This project found for the first time in a highly translatable pediatric piglet TBI model, the potential of FMT treatment to significantly limit cellular and tissue damage leading to improved functional TBI outcomes. The second experiment, consisting of two studies, focused on the microbiome-gut-lung axis as a method of modulating calves’ GIT microbiotas preweaning to boost the host immune system and prevent colonization of Mannheimia haemolytica following experimental inoculation. The objective of the first study was to determine the effects of vaccination and creep-feeding on the immune systems of calves to aid in preventing colonization of Mannheimia haemolytica in the respiratory tract post weaning and found creep-feeding and vaccination modulate the immune system’s response following a M. haemolytica challenge. The objective of the second study was to determine how preweaning management strategies (e.g., creep-feeding and vaccination) stabilize the gastrointestinal tract microbiota preweaning thus reducing the risk of Mannheimia haemolytica colonization in the lungs via the microbiome-gut-lung axis. It provided the first evidence of how a M. haemolytica challenge impacts the GIT microbiota and demonstrated how creep-feeding and vaccination prior to weaning modulates the GIT microbiota by increasing many probiotic species that aid the immune system in preventing pathogenic colonization. Overall, the conclusions from this dissertation indicated modulating the GIT microbiota can have a therapeutic role on host health, and highlights target species that prevent dysbiosis and can recover from injury and prevent pathogen proliferation.