title: The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon.
abstract: The microbiome is being characterized by large-scale sequencing efforts, yet it is not known whether it regulates host metabolism in a general versus tissue-specific manner or which bacterial metabolites are important. Here, we demonstrate that microbiota have a strong effect on energy homeostasis in the colon compared to other tissues. This tissue specificity is due to colonocytes utilizing bacterially produced butyrate as their primary energy source. Colonocytes from germfree mice are in an energy-deprived state and exhibit decreased expression of enzymes that catalyze key steps in intermediary metabolism including the TCA cycle. Consequently, there is a marked decrease in NADH/NAD(+), oxidative phosphorylation, and ATP levels, which results in AMPK activation, p27(kip1) phosphorylation, and autophagy. When butyrate is added to germfree colonocytes, it rescues their deficit in mitochondrial respiration and prevents them from undergoing autophagy. The mechanism is due to butyrate acting as an energy source rather than as an HDAC inhibitor.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, 27599-7264, USA.
authors.forename: Dallas R
authors.initials: DR
authors.lastname: Donohoe
authors.forename: Nikhil
authors.initials: N
authors.lastname: Garge
authors.forename: Xinxin
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Thomas M
authors.initials: TM
authors.lastname: O'Connell
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Bunger
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D002478:Cells, Cultured; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D005856:Germ-Free Life; D005947:Glucose / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D002087:Butyrates; D009243:NAD; D050760:Cyclin-Dependent Kinase Inhibitor p27; D055372:AMP-Activated Protein Kinases; D005947:Glucose