Microbial regulation of intestinal epithelial gene transcription

The microbiome influences a growing spectrum of diseases, yet the transcriptional networks through which intestinal epithelial cells (IECs) interpret microbial signals have remained incompletely defined. Because cell-specific gene expression depends on coordinated interactions among transcription factors, cis-regulatory regions, and chromatin modifications, we set out to identify the conserved transcriptional regulatory mechanisms underlying host–microbiota communication. Using gnotobiotic zebrafish models we developed, we first defined microbiome-responsive transcriptional programs and showed that many are conserved in mice, revealing an ancient intestinal response program dating back ~420 million years. Focusing on the microbially suppressed gene angptl4, we identified a conserved cis-regulatory region controlled by HNF4 transcription factors and demonstrated partial redundancy between hnf4a and hnf4g in zebrafish, paralleling mice. In gnotobiotic mice, microbiota colonization reduced HNF4A activity – mirroring patterns seen in human inflammatory bowel disease – and IEC-specific loss of Hnf4a produced microbiota-dependent, episodic colitis. We further discovered that microbial regulation of IEC genes occurs primarily through histone modifications at enhancers rather than changes in chromatin accessibility, generating an atlas of microbiota-responsive enhancers and identifying additional conserved regulators, including NF-κB, FXR, and ELF3. Together, this work defines an evolutionarily-conserved transcriptional network that enables IECs to integrate microbial and nutritional cues in health and disease.