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The Microbiome and Butyrate Regulate Energy Metabolism and Autophagy in the Mammalian Colon
Open accessAbstract
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.
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“The pathophysiological consequences of this condition are predictable (epithelial cell death and dysregulated inflammation), but the clinical consequences are unknown.”
From The microbiome and critical illness (2016) · cites this paper as [75]
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Probiotic strains and mechanistic insights for the treatment of type 2 diabetes
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Genes and Gut Bacteria Involved in Luminal Butyrate Reduction Caused by Diet and Loperamide
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Gut microbiota modify risk for dietary glycemia-induced age-related macular degeneration
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“short-chain fatty acids).(17,20) Other cometabolites reflect bacterial-”
Gut microbiota: a new angle for traditional herbal medicine research
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“Butyrate also plays an important role as major energy source for colonocytes [45,46].”
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“Since butyrate serve several functions such as being an energy substrate for cells (Donohoe et al., 2011; Maslowski, 2019); signaling via interaction with G-protein-coupled receptors and the inhibition of histone deacetylases stimulating gene expression (Tan et al., 2014), the current results…”
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“Fermentation of these substrates provides SCFA, mainly butyrate [17], which is beneficial to the health of the colon as energy source [18] and for the maintenance of gut barrier function through the increase in occludins [19,20].”
BackgroundShort chain fatty acids: Postbiotics/metabolites and graft versus host disease colitis
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The Gut Microbiota: How Does It Influence the Development and Progression of Liver Diseases
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“The butyrate-producing microbiota regulates energy metabolism, ATP synthesis, and autophagy in the colon [18].”
BackgroundTargeting the gut microbiome: An emerging trend in hematopoietic stem cell transplantation
Čierniková, S., Kasperová, B. J., Drgoňa, Ľ., Smolková, B., Števurková, V., & Mego, M. (2020) · Blood Reviews · doi:10.1016/j.blre.2020.100790 · Cited by 43
Emerging roles of non-histone protein crotonylation in biomedicine
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“Short-chain fatty acid metabolism occurs in intestinal microflora and affects the epigenetic characteristics of multiple proteins [107], including colonic histone Kcr which is dynamically regulated by the cell cycle [104].”
BackgroundIntestinal function and transit associate with gut microbiota dysbiosis in cystic fibrosis
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Chrono-exercise: Time-of-day-dependent physiological responses to exercise
Kim, H., Radak, Z. O., Takahashi, M., Inami, T., & Shibata, S. (2022) · Sports Medicine and Health Science · doi:10.1016/j.smhs.2022.11.003 · Cited by 46
Fecal transplant from myostatin deletion pigs positively impacts the gut-muscle axis
Luo, Z., Han, S., Yin, X., Liu, H., Wang, J., Xuan, M., Hao, C., Wang, D., Liu, Y., Chang, S.-Y., et al. (2023) · eLife · doi:10.7554/elife.81858 · Cited by 45
“SCFAs are the principal metabolites generated by the intestinal microbiota and are involved in multiple physiological processes in the host ( Donohoe et al., 2011 ; Canfora et al., 2015 ).”
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Dietary and metabolic effects on intestinal stem cells in health and disease
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“…rates of oxidative phosphorylation compared with conventional mice, and the addition of butyrate can largely rescue this defect through β-oxidation as use of the CPT1A inhibitor etomoxir prevented a butyrate-associated increase in oxidative phosphorylation in colonocytes from germ-free mice 212 .”
A fishy gut feeling – current knowledge on gut microbiota in teleosts
Tolås, I., Zhou, Z., Zhang, Z., Teame, T., Olsen, R. E., Ringø, E., & Rønnestad, I. (2025) · Frontiers in Marine Science · doi:10.3389/fmars.2024.1495373 · Cited by 52
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“Simultaneously, they modulate host immunity by promoting regulatory T-cell differentiation and mucosal tolerance through mechanisms that include GPR43-mediated signaling and epigenetic regulation via histone deacetylase inhibition (59).”
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Microbiota-Nourishing Immunity: A Guide to Understanding Our Microbial Self
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Therapeutic advances in non-alcoholic fatty liver disease: A microbiota-centered view
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The vitamin B5/coenzyme A axis: A target for immunomodulation?
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“VNN1 overexpression also induced a dysbiosis, leading to an enrichment in bacterial species associated with increased butyrate production, the predominant short chain fatty acid required for CoA-dependent colonocyte energetics [60].”
BackgroundA synbiotic of Anaerostipes caccae and lactulose prevents and treats food allergy in mice
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“Butyrate produced by gut microbiota primarily provides energy for colonic cells [53] and is primarily produced by Clostridium clusters IV and XIVa species of the genera Eubacterium and Butyrivibrio in the phylum Firmicutes [26].”
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Dietary Proteins Regulate Serotonin Biosynthesis and Catabolism by Specific Gut Microbes
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Production and Sensing of Butyrate in a Probiotic E. coli Strain
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Review of the Relationships Between Human Gut Microbiome, Diet, and Obesity
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“%) for colonocytes [49]. the possible consequence of stimulating the apoptosis and therefore SCFAs stimulate secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) and, as such, participate in the regulation of appetite [50] and reduction of body weight [51]. decreasing risk Due to the…”
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Metadata
- Authors
- Donohoe, D. R., Garge, N., Zhang, X., Sun, W., O'Connell, T. M., Bunger, M. K., & Bultman, S. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- RTI International (US)
- Corresponding author
- Bultman, Scott J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 13
- Issue
- 5
- Pages
- 517-526
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3099420
- OpenAlex
- W2082578477
- Cited by
- 2,003
- References
- 47
- Citations by year
- 2026: 203 · 2025: 192 · 2024: 170 · 2023: 171 · 2022: 190 · 2021: 228 · 2020: 182 · 2019: 148 · 2018: 115 · 2017: 104 · 2016: 96 · 2015: 68 · 2014: 56 · 2013: 44 · 2012: 23
- FWCI
- 17.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 844 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (CA125237)
- Prevent Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Nutrition and Physiology
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- gut microbiota, butyrate, colonic epithelial cells, energy metabolism, autophagy, germ-free mice, TCA cycle, oxidative phosphorylation, AMPK, p27, mitochondrial respiration, bacterial metabolites, energy homeostasis
- MeSH terms
- Animals, Autophagy, Butyrates, Cells, Cultured, Colon, Energy Metabolism, Germ-Free Life, Glucose, Male, Mice, Inbred C57BL, Mitochondria, NAD, Magnetic Resonance Spectroscopy, Oxidative Phosphorylation, Phosphorylation, Blotting, Western, Signal Transduction, Biomarkers, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cyclin-Dependent Kinase Inhibitor p27, Mice, Metagenome, AMP-Activated Protein Kinases, Metabolomics
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