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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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“Published estimates suggest that butyrate provides about 70% of colonic epithelial cell energy requirements (64), with a regular supply of butyrate required to maintain gut barrier function.”
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Thammayon, N., Wongdee, K., Teerapornpuntakit, J., Panmanee, J., Chanpaisaeng, K., Charoensetakul, N., Srimongkolpithak, N., Suntornsaratoon, P., & Charoenphandhu, N. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00330.2023 · Cited by 21
Understanding activity of butyrate at a cellular level
Chakraborty, P., & Laird, A. S. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-24-00468 · Cited by 21
“This energy production occurs through butyrate entering mitochondria, undergoing rapid oxidation to acetyl-CoA, which enters the Krebs cycle, resulting in NADH production, which enters the electron transport chain producing ATP and carbon dioxide (Donohoe et al., 2011).”
InfluentialStachelska, M. A., Karpiński, P., & Kruszewski, B. (2024) · Nutrients · doi:10.3390/nu17010009 · Cited by 26
“It includes protection against gastrointestinal infections, maturation of the immune system, regulation of host metabolic pathways, digestion of long-chain carbohydrates or dietary fiber, as well as the formation of short-chain fatty acids and vitamins [14,15].”
Sechovcová, H., Kulhavá, L., Fliegerova, K. O., Trundová, M., Morais, D., Mrázek, J., & Kopečný, J. (2019) · Proteome Science · doi:10.1186/s12953-019-0150-3 · Cited by 21
The effects of prebiotics on growth performance and in vitro immune biomarkers in weaned pigs1
Andres, J. V. S., Mastromano, G., Li, Y., Tran, H., Bundy, J. W., Miller, P. S., & Burkey, T. E. (2019) · Translational Animal Science · doi:10.1093/tas/txz129 · Cited by 21
Fujiwara, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.703298 · Cited by 22
“Particularly, butyrate serves as an energy source for IECs as demonstrated by reduced autophagy in SPF mice compared to germ-free mice (26).”
BackgroundInfluentialHenderson, B., Meurs, J., Lamers, C. R., Batista, G. L., Materić, D., Bertinetto, C. G., Bongers, C. C. W. G., Holzinger, R., Harren, F. J. M., Jansen, J. J., et al. (2022) · Metabolites · doi:10.3390/metabo12030224 · Cited by 21
Food as Treatment of Inflammatory Bowel Diseases
Maldonado‐Contreras, A. (2022) · Infection and Immunity · doi:10.1128/iai.00583-21 · Cited by 24
“For instance, the microbiome-derived SCFAs acetate, propionate, and butyrate represent the primary energy source for enterocytes (144), can act on genes involved in tight junction to seal the paracellular space (14, 145–147), increase oxygen consumption in the intestinal epithelium, which in turn stabilizes the hypoxi…”
BackgroundWei, W., Li, J., Liu, F., Wu, M., Xiong, K., He, Q., Zhang, B., Deng, Y., & Li, Y. (2022) · Molecular Immunology · doi:10.1016/j.molimm.2022.06.013 · Cited by 21
The interaction between obesity and visceral hypersensitivity
Wu, Y., Gao, X., Cheng, Y., Liu, M., Liao, S., Zhou, J., Hao, J., Jiang, G., Lu, Y., Qu, T., et al. (2022) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.16083 · Cited by 24
Immunometabolic regulation during the presence of microorganisms and parasitoids in insects
Li, S., Wang, J., Tian, X., Toufeeq, S., & Huang, W. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.905467 · Cited by 21
“Frontiers in Immunology 05 epithelial cells expressed fewer metabolic key enzymes than normal mice, and significantly down-regulated nicotinamide adenine dinucleotide (NADH)/NAD and ATP levels illustrating gut microbes affect epithelial metabolism (85).”
BackgroundZou, Y., Shi, Y., Liao, S., Li, E., Yang, Q., Chen, R., & Li, Q. (2024) · LWT · doi:10.1016/j.lwt.2024.115830 · Cited by 21
Mandić, M., Paunović, V., Vucicevic, L. M., Kosić, M., Mijatović, S., Trajković, V., & Harhaji-Trajkovic, L. M. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.31366 · Cited by 22
“A plethora of mutually nonexclusive/interconnected intracellular mechanisms including energy depletion (Donohoe et al., 2011; Sun et al., 2017; Zhang et al., 2020), activation of AMPK/mTOR signaling pathway (Cheng et al., 2020; Sun et al., 2017), induction of oxidative stress (Kumar et al., 2019),…”
Miyoshi, J., Nobutani, K., Musch, M. W., Ringus, D. L., Hubert, N. A., Yamamoto, M., Kase, Y., Nishiyama, M., & Chang, E. B. (2018) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2018/7415975 · Cited by 21
“The genus Allobaculum contains butyrate-producing members (our group, unpublished), and butyrate is the main energy source for colonocytes [48].”
Antiallergic activity of Lactobacillus plantarum against peanut allergy in a Balb/c mouse model
Yang, X., Liu, Y., Guo, X., Bai, Q., Zhu, X., Ren, H., Chen, Q., Yue, T., & Long, F. (2019) · Food and Agricultural Immunology · doi:10.1080/09540105.2019.1631261 · Cited by 21
“immune system, thus, there are extensive functional interactions between the gut microbiota and host metabolism or immunity (Donohoe et al., 2011).”
BackgroundKovács, D., Vántus, V. B., Vámos, E., Kálmán, N., Schicho, R., Gallyas, F., & Radnai, B. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/7308897 · Cited by 23
“At the same time, enzymes of CAC and OXPHOS were downregulated [23].”
BackgroundInfluentialCrosstalk between butyrate oxidation in colonocyte and butyrate-producing bacteria
Park, B., Kim, J. Y., Riffey, O. F., Walsh, T. J., Johnson, J., & Donohoe, D. R. (2024) · iScience · doi:10.1016/j.isci.2024.110853 · Cited by 25
Gao, D., Shen, Y., Xu, L., Sun, Y., Hu, H., Xu, B., Wang, Z., & Xu, H. (2024) · Drug Resistance Updates · doi:10.1016/j.drup.2024.101158 · Cited by 22
He, F., Zheng, Y., Elsabagh, M., Fan, K., Zha, X., Zhang, B., Wang, M., & Zhang, H. (2025) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/s40104-025-01196-8 · Cited by 21
“Research indicates that basal autophagy levels are significantly reduced in the colonic epithelium of germ-free mice compared to their conventionally raised counterparts [137].”
Chu, B., Zhu, Y., Su, J.-H., Xia, B., Zou, Y., Nie, J., Zhang, W., & Wang, J. (2020) · Veterinary Research · doi:10.1186/s13567-020-00823-8 · Cited by 20
Pravda, J. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i31.4263 · Cited by 23
The emerging microbiome‐based approaches to IBD therapy: From SCFAs to urolithin A
Rudiansyah, M., Jasim, S. A., Azizov, B., Samusenkov, V. O., Abdelbasset, W. K., Yasin, G., Mohammad, H. J., Jawad, M. A., Mahmudiono, T., Hosseini‐Fard, S. R., et al. (2022) · Journal of Digestive Diseases · doi:10.1111/1751-2980.13131 · Cited by 20
“as an anti-inflammatory agent and a critical energy source for colonocytes, butyrate is essential for maintaining healthy epithelial tissue.(69,70) SCFAs can influence cell growth, development, and gene expression directly or indirectly at the cellular level.”
BackgroundZhao, Y., Wang, H., Wang, H., Liu, H., Zhang, Y., Zhang, J., Pi, Y., Yang, P., & Wang, Q. (2023) · Aquatic Toxicology · doi:10.1016/j.aquatox.2023.106439 · Cited by 20
Wang, Z., He, H. F., Chen, M., Ni, M., Yuan, D., Cai, H., Chen, Z., Li, M., & Xu, H. (2023) · BMC Microbiology · doi:10.1186/s12866-023-02869-y · Cited by 20
“SCFAs are also important nutrients for intestinal epithelial cells [13, 14].”
BackgroundMarullo, A. L., & O’Halloran, K. D. (2023) · Experimental Physiology · doi:10.1113/ep091063 · Cited by 24
“Butyrate is transported into colonocyte mitochondria where it undergoes β -oxidation to acetyl-CoA, which enters the TCA cycle resulting in the reduction of NAD + to NADH, which enters the electron transport chain producing ATP and CO 2 (Donohoe et al., 2011).”
BackgroundFecal Microbiota Transplant: Benefits and Risks
Weil, A. A., & Hohmann, E. L. (2015) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofv005 · Cited by 20
“reverse insulin resistance in diet-induced obesity in mice [7, 8].”
BackgroundLiu, Y., Upadhyaya, B., Fardin‐Kia, A. R., Juenemann, R. M., & Dey, M. (2016) · Food & Function · doi:10.1039/c6fo00856a · Cited by 21
Microbial Metabolism in the Mammalian Gut
Hall, A., & Versalovic, J. A. (2018) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000001857 · Cited by 20
“SCFAs (particularly butyrate, propionate, and acetate) are products of microbial carbohydrate fermentation, and serve as principal energy sources for enterocytes and colonocytes in the mammalian gut (73).”
BackgroundGut dysbiosis mediates the association between antibiotic exposure and chronic disease
Guarner, F., Fernández, L. B., Cruchet, S., Damião, A. O. M. C., Saito, A. M., Lopez, J. P. R., Silva, L. R., & Díaz, M. Á. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1477882 · Cited by 24
Exploring the Connections: Autophagy, Gut Microbiota, and Inflammatory Bowel Disease Pathogenesis
Subramanian, A., Jahabardeen, A., Thamaraikani, T., Kumarasamy, V., Begum, M. Y., Sekar, M., Subramaniyan, V., Wong, L. S., & Fatease, A. M. A. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s483958 · Cited by 19
“113–115 Understanding the reciprocal effects between gut microbiota and autophagy is essential for grasping the molecular mechanisms that drive the progression of inflammatory bowel disease (IBD).”
Lin, L., Li, Q., Yan, Y., Zhang, C., Wang, W., Ni, F., & Wang, X. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.03.003 · Cited by 23
Metataxonomic Analysis of Individuals at BMI Extremes and Monozygotic Twins Discordant for BMI
Finnicum, C. T., Doornweerd, S., Dolan, C. V., Luningham, J. M., Beck, J. J., Willemsen, G. A. H. M., Ehli, E. A., Boomsma, D. I., IJzerman, R. G., Davies, G. E., et al. (2018) · Twin Research and Human Genetics · doi:10.1017/thg.2018.26 · Cited by 19
“The second group of individuals (n = 30) were MZ twins (15 pairs) discordant for BMI (mean BMI difference 4.2 ± 1.9 kg/m2 (range 1.0–8.2) that have been previously described in detail elsewhere (Doornweerd et al., 2016; Table 1).”
MethodInfluentialCai, J.-A., Zhang, Y.-Z., Yu, E.-D., Ding, W.-Q., Jiang, Q.-W., Cai, Q.-C., & Zhong, L. (2023) · Nutrients · doi:10.3390/nu15132940 · Cited by 9
“These metabolites were involved in several metabolic pathways that have been implicated in CRC pathogenesis, such as fatty acid degradation [34], tryptophan metabolism [51], primary bile acid biosynthesis [52], purine metabolism [53], thiamine metabolism [54], sphingolipid metabolism [55], and nicotinate and nicotinam…”
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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