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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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“Thesemetabolites have established roles in host physiology (Donohoe et al., 2011) as energy sources for distinct cell types and tissues that account for up to 10% of daily caloric value, as precursors and regulators of important host molecules such as cholesterol, fatty acids, and glucose, and as…”
BackgroundAkkermansia muciniphila : is it the Holy Grail for ameliorating metabolic diseases?
Yan, J., Sheng, L., & Li, H. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1984104 · Cited by 143
Cheng, H., Liu, J., Tan, Y., Feng, W., & Peng, C. Y. (2021) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2021.10.003 · Cited by 140
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“Butyrate is a major energy source for colonic health (105) and also stimulates gut peptide PYY production (106).”
BackgroundChen, J., Li, Y., Tian, Y., Huang, C., Li, D., Zhong, Q., & Ma, X. (2015) · Current Protein and Peptide Science · doi:10.2174/1389203716666150630135720 · Cited by 135
Cleophas, M. C. P., Ratter, J. M., Bekkering, S., Quintin, J., Schraa, K., Stroes, E. S. G., Netea, M. G., & Joosten, L. A. B. (2019) · Scientific Reports · doi:10.1038/s41598-018-37246-7 · Cited by 141
The microbiome and its potential as a cancer preventive intervention
Bultman, S. J. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2015.09.001 · Cited by 134
“Unlike most cell types in the body, which utilize glucose as their primary energy source, normal colonocytes rely on butyrate for 60%–70% of their energy [53–55] (Fig.”
BackgroundSelf-citationBell, K. J., Saad, S., Tillett, B. J., McGuire, H. M., Bordbar, S., Yap, Y. A., Nguyen, L. T., Wilkins, M. R., Corley, S., Brodie, S., et al. (2022) · Microbiome · doi:10.1186/s40168-021-01193-9 · Cited by 138
Short chain fatty acids: the messengers from down below
Mansuy‐Aubert, V., & Ravussin, Y. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1197759 · Cited by 144
“Estimates suggest they are responsible for 5–15% of total caloric requirements while providing 60–70% of colonic epithelial energy in humans (Bergman, 1990; Donohoe et al., 2011).”
BackgroundThe path towards microbiome-based metabolite treatment
Suez, J., & Elinav, E. (2017) · Nature Microbiology · doi:10.1038/nmicrobiol.2017.75 · Cited by 134
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Paneth cell defects in Crohn’s disease patients promote dysbiosis
Liu, T., Gurram, B., Baldridge, M. T., Head, R. D., Lam, V., Luo, C., Cao, Y., Simpson, P. M., Hayward, M., Holtz, M. L., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.86907 · Cited by 134
“microbiota has been proposed to play an important role in regulating host energy homeostasis through oxidative phosphorylation (49).”
BackgroundRole of the intestinal microbiome and its therapeutic intervention in cardiovascular disorder
Luqman, A., Hassan, A., Ullah, M., Naseem, S., Ullah, M., Zhang, L., Din, A. U., Ullah, K., Ahmad, W., & Wang, G. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1321395 · Cited by 145
Notting, F., Pirovano, W., Sybesma, W., & Kort, R. (2023) · Gut Microbiome · doi:10.1017/gmb.2023.14 · Cited by 135
“SCFAs are taken up by colonic cells of the host as a high-energy source (Donohoe et al., 2011) and induce anti-inflammatory effects (Parada Venegas et al., 2019).”
BackgroundMicrobial Metabolites and Gut Immunology
Takeuchi, T., Nakanishi, Y., & Ohno, H. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-102035 · Cited by 143
Microbiota Effects on Carcinogenesis: Initiation, Promotion, and Progression
Lopez, L. R., Bleich, R. M., & Arthur, J. C. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-080719-091604 · Cited by 136
Prenatal and postnatal contributions of the maternal microbiome on offspring programming
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Recognition of Histone Crotonylation by Taf14 Links Metabolic State to Gene Expression
Gowans, G. J., Bridgers, J. B., Zhang, J., Dronamraju, R., Burnetti, A., King, D. A., Thiengmany, A., Shinsky, S. A., Bhanu, N. V., Garcia, B. A., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.029 · Cited by 126
“For example, shortchain fatty acid metabolism occurs in gut microbiota and influences epigenetic profiles in multiple tissues (Donohoe et al., 2011; Krautkramer et al., 2016), including histone crotonylation in the colon that is dynamically regulated by the cell cycle (Fellows et al.”
T Cell Responses to the Microbiota
Ivanov, I. I., Tuganbaev, T., Skelly, A. N., & Honda, K. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-011829 · Cited by 133
The Gut Microbiome as a Target for the Treatment of Type 2 Diabetes
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Probiotic treatment reduces appetite and glucose level in the zebrafish model
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“…gut microbiota fermentation activities stimulate the growth of intestinal epithelial cells, we speculate that the expansion of microvilli and enterocytes in the gut of probiotic treated larvae may be due to the increased presence of SFCAs in tandem with the elevated abundance of Firmicutes 43 .”
BackgroundInfluentialClavel, T., Neto, J. C. G., Lagkouvardos, I., & Ramer‐Tait, A. E. (2017) · Immunological Reviews · doi:10.1111/imr.12578 · Cited by 132
Rahim, M. B. H. A., Chilloux, J., Martínez-Gili, L., Neves, A. L., Myridakis, A., Gooderham, N. J., & Dumas, M. (2019) · Acta Diabetologica · doi:10.1007/s00592-019-01312-x · Cited by 127
Phylogenetic and ecological factors impact the gut microbiota of two Neotropical primate species
Amato, K. R., Martínez‐Mota, R., Righini, N., Raguet-Schofield, M., Corcione, F. P., Marini, E., Humphrey, G. C., Gogul, G., Gaffney, J., Lovelace, E., et al. (2015) · Oecologia · doi:10.1007/s00442-015-3507-z · Cited by 123
Fatty acids and their therapeutic potential in neurological disorders
Lei, E., Vacy, K., & Boon, W. C. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.02.014 · Cited by 128
van Zanten, G. C., Knudsen, A. S., Röytiö, H., Forssten, S. D., Lawther, M., Blennow, A., Lahtinen, S. J., Jakobsen, M., Svensson, B., & Jespersen, L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047212 · Cited by 125
“Metabolic activity of the gut microbiota results in production of short-chain fatty acids (SCFA), mainly acetic, propionic and butyric acids which serve as fuel for the intestinal epithelial cells and stimulate growth of colonic epithelial cells [36,37].”
Diet Versus Phylogeny: a Comparison of Gut Microbiota in Captive Colobine Monkey Species
Hale, V. L., Tan, C. L., Niu, K., Yang, Y., Knight, R. D., Zhang, Q., Cui, D., & Amato, K. R. (2017) · Microbial Ecology · doi:10.1007/s00248-017-1041-8 · Cited by 123
Kårlund, A., Gómez-Gallego, C., Turpeinen, A. M., Palo-oja, O.-M., El-Nezami, H. S., & Kolehmainen, M. (2019) · Nutrients · doi:10.3390/nu11040829 · Cited by 140
“All of them have well-reported health effects and microbiota-derived butyrate, for example, regulates the energy metabolism of colonocytes by acting as an energy source [94], while propionate participates in the hormonal downregulation of energy intake [95].”
BackgroundHolota, Y., Dovbynchuk, T., Kaji, I., Vareniuk, І., Dzyubenko, N., Chervinska, T., Zakordonets, L. V., Стецька, В. О., Остапченко, Л. І., Serhiichuk, T., et al. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220642 · Cited by 126
“Similarly, nutrient-deficient and energy-deficient colonocytes of germ-free mice experienced alterations in their redox state because of inadequate butyrate availability and decreased cellular oxidative phosphorylation with a resultant increase in oxidative stress [50, 67].”
BackgroundImpaired Intestinal Barrier and Tissue Bacteria: Pathomechanisms for Metabolic Diseases
Massier, L., Blüher, M., Kovacs, P. L., & Chakaroun, R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.616506 · Cited by 130
“Moreover, beneficial effects were reported for gut bacteria produced short chain fatty acids (60, 61), in particular butyrate (61, 62), which has been shown to act as an energy source for colonocytes (63), regulate hypoxia induced factor 1a (HIF-1a) dependent expression of many pro-barrier genes in intestinal epitheli…”
BackgroundTherapeutic Potential of Butyrate for Treatment of Type 2 Diabetes
Arora, T., & Tremaroli, V. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.761834 · Cited by 126
“In the GF mouse model, colonocytes are in a state of nutrient deficiency that causes cellular autophagy in the colonic epithelium (59) and slower intestinal transit (60).”
BackgroundEffects of food‐borne nanomaterials on gastrointestinal tissues and microbiota
Bouwmeester, H., van der Zande, M., & Jepson, M. A. (2017) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1481 · Cited by 122
Microbiota in cancer development and treatment
Raza, M. H., Gul, K., Arshad, A., Riaz, N., Waheed, U., Rauf, A., Aldakheel, F. M., Alduraywish, S. A., Rehman, M. U., Abdullah, M., et al. (2018) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-018-2816-0 · Cited by 122
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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