Transcriptional Integration of Distinct Microbial and Nutritional Signals by the Small Intestinal Epithelium.

Autor:	Lickwar CR; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Davison JM; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Kelly C; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Mercado GP; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Wen J; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Davis BR; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Tillman MC; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina., Semova I; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Andres SF; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Vale G; Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas., McDonald JG; Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas., Rawls JF; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, North Carolina; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: john.rawls@duke.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2022; Vol. 14 (2), pp. 465-493. Date of Electronic Publication: 2022 May 06.
DOI:	10.1016/j.jcmgh.2022.04.013
Abstrakt:	Background & Aims: The intestine constantly interprets and adapts to complex combinations of dietary and microbial stimuli. However, the transcriptional strategies by which the intestinal epithelium integrates these coincident sources of information remain unresolved. We recently found that microbiota colonization suppresses epithelial activity of hepatocyte nuclear factor 4 nuclear receptor transcription factors, but their integrative regulation was unknown. Methods: We compared adult mice reared germ-free or conventionalized with a microbiota either fed normally or after a single high-fat meal. Preparations of unsorted jejunal intestinal epithelial cells were queried using lipidomics and genome-wide assays for RNA sequencing and ChIP sequencing for the activating histone mark H3K27ac and hepatocyte nuclear factor 4 alpha. Results: Analysis of lipid classes, genes, and regulatory regions identified distinct nutritional and microbial responses but also simultaneous influence of both stimuli. H3K27ac sites preferentially increased by high-fat meal in the presence of microbes neighbor lipid anabolism and proliferation genes, were previously identified intestinal stem cell regulatory regions, and were not hepatocyte nuclear factor 4 alpha targets. In contrast, H3K27ac sites preferentially increased by high-fat meal in the absence of microbes neighbor targets of the energy homeostasis regulator peroxisome proliferator activated receptor alpha, neighbored fatty acid oxidation genes, were previously identified enterocyte regulatory regions, and were hepatocyte factor 4 alpha bound. Conclusions: Hepatocyte factor 4 alpha supports a differentiated enterocyte and fatty acid oxidation program in germ-free mice, and that suppression of hepatocyte factor 4 alpha by the combination of microbes and high-fat meal may result in preferential activation of intestinal epithelial cell proliferation programs. This identifies potential transcriptional mechanisms for intestinal adaptation to multiple signals and how microbiota may modulate intestinal lipid absorption, epithelial cell renewal, and systemic energy balance. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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