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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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Metabolic networks of the human gut microbiota
Selber‐Hnatiw, S., Sultana, T., Tse, W., Abdollahi, N., Abdullah, S., Rahbani, J. A., Alazar, D., Alrumhein, N. J., Aprikian, S., Arshad, R., et al. (2019) · Microbiology · doi:10.1099/mic.0.000853 · Cited by 38
Omics Integration for Mitochondria Systems Biology
Hu, X. Y., Go, Y., & Jones, D. P. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.8006 · Cited by 35
“butyrate impact mitochondrial energy metabolism (44), and pantothenic acid is essential for CoA biosynthesis, carbohydrate, fatty acid, and amino acid metabolism, but these are rarely examined as determinants in mitochondrial reprogramming.”
BackgroundParker, K. D., Maurya, A. K., Ibrahim, H., Rao, S., Hove, P. R., Kumar, D., Kant, R., Raina, B., Agarwal, R., Kuhn, K. A., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9020144 · Cited by 37
“This study highlights that nutritional intervention with rice bran modifies microbiota for prevention and control of CRC and has potential to reduce disease recurrence by improving metabolism by gut microbiota [31,32] alongside opportunities for fecal microbiota transplantation (FMT).”
BackgroundInfluentialMicrobial dysbiosis and epigenetics modulation in cancer development – A chemopreventive approach
Haque, S., Raina, R., Afroze, N., Hussain, A., Alsulimani, A., Singh, V., Mishra, B. N., Kaul, S., & Kharwar, R. N. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.06.024 · Cited by 35
Hallmarks of the human intestinal microbiome on liver maturation and function
Almeida, J. I., Tenreiro, M. F., Martínez‐Santamaría, L., Guerrero‐Aspizua, S., Gisbert, J. P., Alves, P. M., Serra, M., & Baptista, P. M. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.10.015 · Cited by 37
Enteroendocrine Cells: Metabolic Relays between Microbes and Their Host
Plovier, H., & Cani, P. D. (2017) · Endocrine Development · doi:10.1159/000475736 · Cited by 36
The associations of gut microbiota, endocrine system and bone metabolism
Tu, Y., Kuang, X., Zhang, L., & Xu, X. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1124945 · Cited by 34
Ding, J., Liu, J., Chen, J., Cheng, X., Cao, H., Guo, X., Hu, G., & Zhuang, Y. (2024) · Poultry Science · doi:10.1016/j.psj.2024.103482 · Cited by 38
Bacteroides and NAFLD: pathophysiology and therapy
Zhang, J., Zhou, J., He, Z., & Li, H. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1288856 · Cited by 37
Zachos, K. A., Gamboa, J. A., Dewji, A. S., Lee, J., Brijbassi, S., & Andreazza, A. C. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1428242 · Cited by 35
How bacterial pathogens use type III and type IV secretion systems to facilitate their transmission
Byndloss, M. X., Rivera-Chávez, F., Tsolis, R. M., & Bäumler, A. J. (2016) · Current Opinion in Microbiology · doi:10.1016/j.mib.2016.08.007 · Cited by 32
“Clostridia are the main producers of butyrate [20], a short-chain fatty acid that serves as the primary energy source for colonic epithelial cells (colonocytes) [21].”
BackgroundAnti-Inflammatory and Insulin-Sensitizing Effects of Free Fatty Acid Receptors
Miyamoto, J., Kasubuchi, M., Nakajima, A., & Kimura, I. (2016) · Handbook of experimental pharmacology · doi:10.1007/164_2016_47 · Cited by 34
From Colitis to Cancer: An Evolutionary Trajectory That Merges Maths and Biology
Bakir, I. A., Curtius, K., & Graham, T. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02368 · Cited by 33
“Butyrate in particular plays a key role in the maintenance of intestinal homeostasis, namely as the preferred energy source of colonic epithelial cells (29).”
BackgroundMucosal Microbiota and Metabolome along the Intestinal Tract Reveal a Location-Specific Relationship
Yuan, C., Graham, M. L., Staley, C. M., & Subramanian, S. (2020) · mSystems · doi:10.1128/msystems.00055-20 · Cited by 32
“Without a functional microbiota, the colon epithelia undergo autophagy and fail to maintain normal structure and function (11).”
BackgroundCaffaratti, C., Plazy, C., Méry, G., Tidjani, A.-R., Fiorini, F., Thiroux, S., Toussaint, B., Hannani, D., & Gouëllec, A. L. (2021) · Metabolites · doi:10.3390/metabo11060406 · Cited by 36
“Their primary role after absorption is to serve as an energy substrate for ATP generation in the tricarboxylic acid cycle (TCA), especially for the colonocytes [18].”
BackgroundThe role of fatty acids in Crohn's disease pathophysiology – An overview
Piotrowska, M., Binienda, A., & Fichna, J. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111448 · Cited by 37
Metabolic effects of portal vein sensing
Mithieux, G. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12338 · Cited by 34
“However, butyrate is a key energy substrate for both colonocytes and enterocytes [32], and it appears counterintuitive that an increase in energy harvest could be associated with a benefit on energy homeostasis.”
BackgroundEpigenetic Regulation of Enteric Neurotransmission by Gut Bacteria
Savidge, T. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00503 · Cited by 36
Li, X., Dong, L., Li, A., Yi, J., Brotto, M., & Zhou, J. (2022) · Biomolecules · doi:10.3390/biom12020333 · Cited by 33
“Butyrate, a short-chain fatty acid produced by bacterial fermentation of dietary fibers in the colon, is essential for gut homeostasis [35,36].”
BackgroundDisruption of intestinal oxygen balance in acute colitis alters the gut microbiome
Zong, W., Friedman, E. S., Allu, S., Firrman, J., Tu, V., Daniel, S. G., Bittinger, K. L., Liu, L., Vinogradov, S. A., & Wu, G. D. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2361493 · Cited by 33
“This revealed decreases in buty-ric acid, an important source of energy for the colonic epithelium 21,22 under oxygenated conditions (Figure 5d).”
BackgroundHypothesis: solid tumours behave as systemic metabolic dictators
Lee, Y., Chang, W., & Ma, W. (2016) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12794 · Cited by 35
“Short-chain fatty acids not only can serve as an energy source for the epithelium and liver but also as mediators of the immune response [114].”
BackgroundThe intestinal microbiome and surgical disease
Krezalek, M. A., Skowron, K. B., Guyton, K. L., Shakhsheer, B. A., Hyoju, S. K., & Alverdy, J. C. (2016) · Current Problems in Surgery · doi:10.1067/j.cpsurg.2016.06.001 · Cited by 35
Implication of the intestinal microbiome in complications of cirrhosis
Bhat, M., Arendt, B. M., Bhat, V., Renner, E. L., Humar, A., & Allard, J. P. (2016) · World Journal of Hepatology · doi:10.4254/wjh.v8.i27.1128 · Cited by 36
Use of sodium butyrate in the feeding of Arapaima gigas (Schinz, 1822) juvenile
Luz, J. R., Ramos, A. P. D. S., Melo, J. F. B., & Braga, L. G. T. (2019) · Aquaculture · doi:10.1016/j.aquaculture.2019.05.065 · Cited by 33
Holtan, S. G., Shabaneh, A., Betts, B. C., Rashidi, A., MacMillan, M. L., Ustun, C., Amin, K., Vaughn, B. P., Howard, J. R., Khoruts, A., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.129762 · Cited by 31
Lupien‐Meilleur, J., Andrich, D. E., Quinn, S., Micaelli-Baret, C., St-Amand, R., Roy, D., & St-Pierre, D. H. (2019) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2019.10.006 · Cited by 34
The Inhibitory Effect of Gut Microbiota and Its Metabolites on Colorectal Cancer
Chen, C., & Li, H. (2020) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.2002.02032 · Cited by 34
“Butyrate provides energy for colonic cell proliferation, but it does not have the same effect on CRC cell, because the energy of CRC cells is from glucose utilization and aerobic glycolysis due to Warburg effect [14].”
BackgroundKong, D., Schipper, L., & van Dijk, G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.755845 · Cited by 31
“microbiota derived from conventionally raised mice, or with a butyrate-producing bacterial strain, supporting the notion that butyrate is preferentially used by colonocytes as energy source (Donohoe et al., 2011).”
BackgroundThe Role of Gut Microbiota in the Etiopathogenesis of Multiple Chronic Diseases
Pires, L., Gonzaléz‐Paramás, A. M., Heleno, S. A., & Calhelha, R. C. (2024) · Antibiotics · doi:10.3390/antibiotics13050392 · Cited by 33
“The reduction in butyrate levels in CKD diminishes mucin production and tight junction proteins, which have anti-inflammatory properties [133].”
BackgroundSaha, B., Rithi, A. T., Adhikary, S., Banerjee, A., Radhakrishnan, A., Duttaroy, A. K., & Pathak, S. (2024) · Nutrition and Cancer · doi:10.1080/01635581.2024.2367266 · Cited by 39
“The colon tissue’s energy equilibrium depends heavily on butyrate, a primary energy source for colonocytes (76).”
Systems Biology Approaches for Inflammatory Bowel Disease
Moco, S., Candela, M., Chuang, E., Draper, C. F., Cominetti, O., Montoliu, I., Barron, D., Kussmann, M., Brigidi, P., Gionchetti, P., et al. (2014) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000116 · Cited by 34
“Butyrate is transported into colonocytes, enters the mitochondria, and undergoes beta oxidation to acetyl-CoA, resulting in the reduction of NAD+ to NADH, ATP production and CO2 release, through the Krebs cycle.(51) Propionate is removed by the liver but is largely converted to glucose by gluconeogenesis.”
BackgroundRole of the microbiome in the normal and aberrant glycemic response
Suez, J., Shapiro, H., & Elinav, E. (2016) · Clinical Nutrition Experimental · doi:10.1016/j.yclnex.2016.01.001 · Cited by 31
“The cells in the colonic epithelium utilize the SCFA produced by the bacteria as an energy source, while GF mice have low SCFAs and are energy deprived with deficit in mitochondrial oxidative phosphorylation and ATP levels leading to autophagy [65].”
BackgroundIn Vivo Wireless Sensors for Gut Microbiome Redox Monitoring
Baltsavias, S., Treuren, W. V., Weber, M. J., Charthad, J., Baker, S. W., Sonnenburg, J. L., & Arbabian, A. (2019) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2019.2948575 · Cited by 32
“The mechanisms are complex, but oxidant balance plays a key role: without colonic butyrate, colonocytes reduce beta-oxidation, leading to increased aerobicity in the gut [15], [16].”
Background
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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