Metabolite mimicry identifies butyrate analogs with select protective functions in the intestinal mucosa
Abstract
Microbial-derived short-chain fatty acids regulate a variety of pathways in the healthy colonic mucosa. In particular, butyrate serves as the primary energy source for colonocytes and regulates gene transcription by stabilizing the transcription factor hypoxia-inducible-factors (HIF) and functioning as a histone deacetylase (HDAC) inhibitor. A limitation of butyrate as a therapeutic is its rapid metabolism in differentiated colonocytes. Furthermore, intestinal stem cells (ISCs) respond differently to butyrate, preferentially using glucose for energy procurement. To address these limitations, we explored metabolite mimicry to identify compounds with potent or selective biological responses within the butyrate pathway(s). We found an analog, 3-chlorobutyrate (3-Cl BA), that significantly enhances epithelial barrier formation and wound healing in vitro. Mechanistically, we revealed that 3-Cl BA is a potent HDAC inhibitor. Furthermore, unlike butyrate, 3-Cl BA does not stabilize HIF and it is not used as metabolic fuel. In vivo studies in a dextran sulfate sodium-colitis model revealed that contrary to butyrate, 3-Cl BA is protective. Studies in stem-like colonoids demonstrated that only butyrate inhibits ISC proliferation and differentiation. Furthermore, it was recently reported that HIF stabilization inhibits ISCs activity. Given the fact that butyrate but not 3-Cl BA stabilizes HIF, we surmised that 3-Cl BA would circumvent these detrimental functional consequences. We demonstrate here that pharmacologic HIF stabilization inhibits colonoid differentiation and that genetic loss of HIF significantly promotes ISC differentiation. This study reveals a promising butyrate analog protective in colitis and demonstrates the advantages of metabolite mimicry to dissect selective biological functions from major metabolites in the gut.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Alfredo Ornelas
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Jacob A. Countess
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Ji Yeon Kim
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Rachel H. Cohen
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Brittany D. Gomez
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus
Rebecca L. Roer
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Faiz Minhajuddin
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Kiranmayee Yenugudhati Vijaya Sai
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Liheng Zhou
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Julia L. M. Dunn
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus
Caleb Chandler
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
Philip Reigan
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
Ian M. Cartwright
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Caroline H. T. Hall
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus
Geetha Bhagavatula
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Colorado Anschutz Medical Campus
Joseph C. Onyiah
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Alexander S. Dowdell
Mucosal Inflammation Program and Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus
Sean P. Colgan
Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus