biostudies-literatureDavis BRHoward Hughes Medical InstituteNational Institutes of HealthNIH HHSe0226725https://www.ebi.ac.uk/biostudies/studies/S-EPMC12691682biostudies-literatureUnknown16(12)Animals defend against infections and other diseases by adaptively responding to the microbiota they encounter. These adaptations are driven by changes in gene expression programs; however, our understanding of the transcription factors regulating host responses to microbiota remains limited. By leveraging gene expression and chromatin accessibility data from zebrafish and mice, we identified the epithelial-specific E74-like ETS transcription factor 3 (<i>Elf3</i>) as a conserved microbially responsive transcription factor. Transcriptomic analysis of gnotobiotic <i>elf3</i> mutant zebrafish larvae revealed that <i>elf3</i> is required for a normal host response to microbiota, including induction of immune response genes. Mutation of <i>elf3</i> led to immune-related pathologies such as infmBioEpithelial transcription factor Elf3 mediates host immune responses to microbiota and protects against aerocystitis in zebrafish.PMC12691682F30-DK135357P01-DK0947GT13485Morash MWen JLickwar CRTobin DMLohr CVMoore PJDavis BRSweeney MIReich ELRawls JFfalseEpithelial transcription factor Elf3 mediates host immune responses to microbiota and protects against aerocystitis in zebrafish.Animals defend against infections and other diseases by adaptively responding to the microbiota they encounter. These adaptations are driven by changes in gene expression programs; however, our understanding of the transcription factors regulating host responses to microbiota remains limited. By leveraging gene expression and chromatin accessibility data from zebrafish and mice, we identified the epithelial-specific E74-like ETS transcription factor 3 (<i>Elf3</i>) as a conserved microbially responsive transcription factor. Transcriptomic analysis of gnotobiotic <i>elf3</i> mutant zebrafish larvae revealed that <i>elf3</i> is required for a normal host response to microbiota, including induction of immune response genes. Mutation of <i>elf3</i> led to immune-related pathologies such as inf2025-01-01T00:00:00Z2025 Dec2026-06-06T00:19:40.135Z2026-05-23T03:14:09.705ZS-EPMC126916824114774110.1128/mbio.02267-25