Transcriptional integration of distinct microbial and nutritional signals by the small intestinal epithelium

To preserve its physiologic functions, the intestine must interpret and adapt to complex combinations of stimuli from dietary and microbial sources. However, the transcriptional strategies by which the intestinal epithelium integrates and adapts to dietary and microbial information remains unresolved. We compared adult mice reared germ free (GF) or conventionalized with a microbiota (CV) either fed normally or after a single high-fat meal (HFM). Jejunal epithelium preparations were queried using genomewide assays for RNA-seq, the activating histone mark H3K27ac ChIP-seq, and ChIP-seq of the microbially-responsive transcription factor HNF4A. We identified distinct nutritional and microbial responses at certain genes, but also apparent simultaneous influence of both stimuli at many other loci and regulatory regions. Increased expression levels and H3K27ac enrichment following HFM at a subset of these sites was dependent on microbial status. H3K27ac sites that were preferentially increased by HFM in the presence of microbes neighbor lipid anabolism and proliferation genes as well as intestinal stem cell (ISC) markers, were usually active only in ISCs, and were not HNF4A targets. In contrast, H3K27ac sites that were preferentially increased by HFM in the absence of microbes neighbored targets of the nuclear receptor and energy homeostasis regulator PPARA, were frequently accessible only in enterocytes, and were HNF4A bound. These results reveal that HNF4A supports a differentiated enterocyte and FAO program in GF, and that suppression of HNF4A by the combination of microbes and HFM may result in preferential activation of IEC proliferation programs. Microbial and nutritional responses are therefore integrated with some of the same transcriptional programs that regulate intestinal proliferation and differentiation.