The Microbiome and Butyrate Regulate Energy Metabolism and Autophagy in the Mammalian Colon

SummaryThe 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, p27kip1 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.

► The microbiome is required to maintain energy homeostasis in colonocytes
► Germfree colonocytes are energy deprived and survive via autophagy
► Butyrate rescues the energetic perturbation and inhibits autophagy
► Butyrate rescues as energy source rather than HDAC inhibitor