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

By Dallas R. Donohoe, Nikhil R. Garge, Xinxin Zhang, Wei Sun, Thomas M. O'Connell, M. Bunger, S. Bultman. Cell Metabolism, 2011

1,783 citations recorded by the source corpus.

SUMMARY 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, 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.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/a3ca37efba59f6f2d0b9a177eb11cfe9dce819b5

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In Endocrinology, Diabetes and Metabolism

Jianbo Xiao

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In Physiology

Citations in the corpus

Dietary Gut Microbial Metabolites, Short-chain Fatty Acids, and Host Metabolic Regulation (2015, background): “in muscle and liver tissues, and the expression of PGC-1α and mitochondrial uncoupling protein-1 (UCP-1) in brown adipose tissues [21].”
Human breast milk: A review on its composition and bioactivity. (2015, background): “Short-chain fatty acids (SCFA) found in breast milk are also an important source of energy [22], as well as being essential for normal maturation of the gastrointestinal tract [23].”
Butyrate and Propionate Protect against Diet-Induced Obesity and Regulate Gut Hormones via Free Fatty Acid Receptor 3-Independent Mechanisms (2012, background): “Butyrate was also shown to regulate autophagy in colonocytes by acting as an energy source [28].”
Gut Microbiota in Cardiovascular Health and Disease (2017, background): “SCFAs, in particular butyrate, serve as energy substrates for epithelial cells of the gut.(95,96)”
Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease (2012, background): “Clostridium coccoides are major producers of short chain fatty acids, particularly butyrate, which is an energy source for colonocytes and has been shown to protect against damaging inflammatory responses [42].”
Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short chain fatty acid-producing intestinal microbiota in ESRD (2014, background): “The dependence of colonocytes on butyrate produced by bacteria was demonstrated in an elegant study by Donohoe et al. [37] who showed ATP depletion and autophagy in colonocytes of the germ-free mice and their reversal by addition of butyrate.”
Exercise Alters Gut Microbiota Composition and Function in Lean and Obese Humans (2017, background): “Butyrate is a primary fuel source for colonocytes (39), is required for maintaining gut barrier function (40), and is a critical metabolite regulating the antiinflammatory/regulatory phenotypes of gut-resident immune cells (41).”
Microbiota-activated PPAR-γ-signaling inhibits dysbiotic Enterobacteriaceae expansion (2017, neutral): “We exposed the model epithelia to butyrate, a fermentation product of the gut microbiota that serves as the main carbon source of colonic epithelial cells (colonocytes) (5).”