Animal ecology and evolution have long been known to shape host physiology, but more recently, the gut microbiome has been identified as a mediator between animal ecology and evolution and health. Sitting at the interface between the environment, host evolution, and host biology, the gut microbiome is increasingly considered a potential tool to improve animal health. To succeed, however, any microbial manipulations must recognize the evolutionary and ecological drivers of gut microbiome variation and its resulting impact on host functioning. These dual forces are both prominent in the context of domestication, where the gut microbiome is thought to play a role in promoting host adaptation and health. During domestication, animals underwent artificial and natural selection for morphological and behavioral traits (e.g., smaller brain and tooth size, lighter skin color, tameness), which allowed them to live near humans and cope with human settlements’ dietary and ecological conditions. The gut microbiome of domestic animals is compositionally distinct from those of their wild progenitors, but it is unknown if such changes are due to the effects of host lineage (wild vs. domestic) or ascribed to differences in ecological conditions in which domestic animals are kept. Further, it is unclear if compositional differences translate to functional differences between wild and domestic lineages and supercede host phylogeny. Because domestic animals live across a diverse breadth of environmental settings, variation in ecology within domestic animals is expected to shape the gut microbiome, both compositionally and functionally. Resulting changes in the gut microbiome may then impact the functions microbiomes provide for their hosts. There is mounting evidence that the gut microbiome is a pathway linking the environment and animal immunity. Importantly, the gut microbiome directly contributes to colonization resistance, a phenomenon limiting microbial invasion. Identifying the unique evolutionary and ecological impact from domestication on interactions between microbial communities and potential invaders (pathogenic or commensal) is critical to develop microbially-mediated health interventions. In this dissertation, I first propose that domesticated animals can model microbiome variation across human populations due to their diverse environmental and lifestyle settings. I then use an observational approach to compare gut microbiomes and immune states from wild and domestic pigs living across different ecological contexts. I then consider the implications of the resulting microbial differences across these contexts for microbially-mediated resistance against invading microbes. Collectively, my findings underscore the significance of ecological variation in shaping gut microbiome dynamics and its implications for host health. Finally, I broaden the scale to investigate whether evolutionary pressures during domestication have led to convergent shaping of the gut microbiome. Altogether, my dissertation sets the stage to generate findings that could inform gut microbial manipulations designed to improve animal performance and resilience.