Gnotobiotic zebrafish reveal evolutionarily conserved responses to the gut microbiota. Researchers developed methods to produce and rear germ-free (GF) zebrafish through late juvenile stages. DNA microarray analysis of 6-day post-fertilization GF, conventionalized (CONV), and conventionally raised (CONR) zebrafish showed 212 genes regulated by the microbiota, with 59 responses conserved in mice, including epithelial proliferation, nutrient metabolism, and innate immune responses. Sequencing of 16S rDNA amplicons revealed the microbiota's bacterial species specificity. These studies establish gnotobiotic zebrafish as a useful model for studying host-microbial interactions in the vertebrate digestive tract. The zebrafish gut microbiota was characterized, and monoassociation experiments showed bacterial species specificity in host responses. The zebrafish gut has a structure similar to mammals, with epithelial renewal and a proliferative compartment. The study highlights the importance of the microbiota in host development and physiology, and the zebrafish's potential as a model organism for understanding host-microbial interactions. The findings suggest that the absence of a microbiota in zebrafish leads to a fasting-like metabolic state, affecting nutrient metabolism and immune responses. The study also reveals conserved transcriptional responses to the microbiota, including genes involved in nutrient metabolism, immune responses, and xenobiotic metabolism. The zebrafish microbiota contains bacteria similar to those in the mammalian gut, and the study shows that some host responses are specific to certain bacterial species. The results indicate that the zebrafish is a valuable model for studying the molecular mechanisms of host-microbial interactions in the digestive tract. The study also highlights the importance of considering the microbiota when designing genetic and chemical screens for factors that modulate zebrafish development. The findings suggest that the zebrafish could be used as a model for studying symbiotic or pathogenic relationships between microorganisms and their vertebrate hosts. The study was supported by the Ellison Medical Foundation and the National Institutes of Health.Gnotobiotic zebrafish reveal evolutionarily conserved responses to the gut microbiota. Researchers developed methods to produce and rear germ-free (GF) zebrafish through late juvenile stages. DNA microarray analysis of 6-day post-fertilization GF, conventionalized (CONV), and conventionally raised (CONR) zebrafish showed 212 genes regulated by the microbiota, with 59 responses conserved in mice, including epithelial proliferation, nutrient metabolism, and innate immune responses. Sequencing of 16S rDNA amplicons revealed the microbiota's bacterial species specificity. These studies establish gnotobiotic zebrafish as a useful model for studying host-microbial interactions in the vertebrate digestive tract. The zebrafish gut microbiota was characterized, and monoassociation experiments showed bacterial species specificity in host responses. The zebrafish gut has a structure similar to mammals, with epithelial renewal and a proliferative compartment. The study highlights the importance of the microbiota in host development and physiology, and the zebrafish's potential as a model organism for understanding host-microbial interactions. The findings suggest that the absence of a microbiota in zebrafish leads to a fasting-like metabolic state, affecting nutrient metabolism and immune responses. The study also reveals conserved transcriptional responses to the microbiota, including genes involved in nutrient metabolism, immune responses, and xenobiotic metabolism. The zebrafish microbiota contains bacteria similar to those in the mammalian gut, and the study shows that some host responses are specific to certain bacterial species. The results indicate that the zebrafish is a valuable model for studying the molecular mechanisms of host-microbial interactions in the digestive tract. The study also highlights the importance of considering the microbiota when designing genetic and chemical screens for factors that modulate zebrafish development. The findings suggest that the zebrafish could be used as a model for studying symbiotic or pathogenic relationships between microorganisms and their vertebrate hosts. The study was supported by the Ellison Medical Foundation and the National Institutes of Health.