Domestic animals represent important resources for understanding shared mechanisms underlying complex natural diseases that arise due to both genetic and environmental factors. Intestinal inflammation, particularly inflammatory bowel disease (IBD), is a significant health challenge in humans and domestic animals. While the etiology of IBD is multifactorial, imbalance of symbiotic gut microbiota has been hypothesized to play a central role in disease pathophysiology. Advances in genomic sequencing and analytical pipelines have enabled researchers to decipher the composition of the intestinal microbiota during health and in the context of naturally occurring diseases. This review compiles microbiome genomic data across domestic species and highlights a common occurrence of gut microbiome dysbiosis during idiopathic intestinal inflammation in multiple species, including dogs, cats, horses, cows, and pigs. Current microbiome data obtained from animals with intestinal inflammation are mostly limited to taxonomical analyses in association with broad clinical phenotype. In general, a pathogen or pathosymbiont were not detected. Rather, functional potential of the altered microbiota has been suggested to be one of the key etiologic factors. Among the domestic species studied, canine analyses are currently the most advanced with incorporation of functional profiling of microbiota. Canine IBD parallels features of the disease in humans, thus canines represent a strong natural model for human IBD. While deeper analyses of metagenomic data, coupled with host molecular analyses are needed, comparative studies across domestic species can reveal shared microbial alterations and regulatory mechanisms that will improve our understanding of intestinal inflammation in both animals and humans.