Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)
Open accessAbstract
The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The stress-like effect and increased anxiety-like behavior might be explained by FFAR3 expression in the peripheral nervous system, activation of which results in increased sympathetic nervous system activity.
“This might be explained by the fact that FFAR3 is expressed in the peripheral nervous system, activation of which results in increased sympathetic nervous system activity”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Kimura et al., 2011
SCFAs can exert physiological effects in the CNS via two primary mechanisms: activation of G protein-coupled receptors (GPCRs) expressed in the liver, spleen, and large intestine and inhibition of histone deacetylases.
“SCFAs can exert physiological effects in the CNS via two primary mechanisms: activation of G protein–coupled receptors (GPCRs) expressed in the liver, spleen, and large intestine and inhibition of histone deacetylases (Kimura et al., 2011; Tan et al., 2014b).”
From Microbiome–microglia connections via the gut–brain axis (2019) · cites this paper as Kimura et al., 2011
Acetate, propionate and N-butyrate are mediators of the colonic inflammatory response, stimulate sympathetic nervous system and mucosal serotonin release.
“Acetate, propionate and N-butyrate are mediators of the colonic inflammatory response [154], stimulate sympathetic nervous system [155] and mucosal serotonin release [156].”
From Exercise-induced stress behavior, gut-microbiota-brain axis and diet: a systematic review for athletes (2016) · cites this paper as [155]
Cites
An obesity-associated gut microbiome with increased capacity for energy harvest
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006) · Nature · doi:10.1038/nature05414 · Cited by 12,444 · see citing works
Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43
Maslowski, K. M., Vieira, A. T., Ng, A., Kranich, J., Sierro, F., Yu, D., Schilter, H. C., Rolph, M. S., Mackay, F., Artis, D., et al. (2009) · Nature · doi:10.1038/nature08530 · Cited by 3,241 · see citing works
Energy contributions of volatile fatty acids from the gastrointestinal tract in various species
Bergman, E. N. (1990) · Physiological Reviews · doi:10.1152/physrev.1990.70.2.567 · Cited by 2,750 · see citing works
Oh, D. Y., Talukdar, S., Bae, E. J., Imamura, T., Morinaga, H., Fan, W., Li, P., Lu, W. J., Watkins, S. M., & Olefsky, J. M. (2010) · Cell · doi:10.1016/j.cell.2010.07.041 · Cited by 2,428 · see citing works
Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., Muir, A. I., Wigglesworth, M. J., Kinghorn, I., Fraser, N. J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211609200 · Cited by 2,409 · see citing works
Metabolic Syndrome and Altered Gut Microbiota in Mice Lacking Toll-Like Receptor 5
Vijay-Kumar, M., Aitken, J. D., Carvalho, F. A., Cullender, T. C., Mwangi, S., Srinivasan, S., Sitaraman, S. V., Knight, R., Ley, R. E., & Gewirtz, A. T. (2010) · Science · doi:10.1126/science.1179721 · Cited by 2,068 · see citing works
Transduction of Receptor Signals by ß-Arrestins
Lefkowitz, R. J., & Shenoy, S. K. (2005) · Science · doi:10.1126/science.1109237 · Cited by 1,729 · see citing works
Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis
Flint, H. J., Bayer, E. A., Rincón, M. T., Lamed, R., & White, B. A. (2008) · Nature Reviews Microbiology · doi:10.1038/nrmicro1817 · Cited by 1,710 · see citing works
Le Poul, E., Loison, C., Struyf, S., Springael, J.-Y., Lannoy, V., Decobecq, M.-E., Brezillon, S., Dupriez, V., Vassart, G., Van Damme, J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301403200 · Cited by 1,651 · see citing works
Samuel, B. S., Shaito, A., Motoike, T., Rey, F. E., Backhed, F., Manchester, J. K., Hammer, R. E., Williams, S. C., Crowley, J., Yanagisawa, M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0808567105 · Cited by 1,564 · see citing works
Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120
Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., & Tsujimoto, G. (2004) · Nature Medicine · doi:10.1038/nm1168 · Cited by 1,551 · see citing works
Self-citationFree fatty acids regulate insulin secretion from pancreatic β cells through GPR40
Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., Ogi, K., Hosoya, M., Tanaka, Y., Uejima, H., et al. (2003) · Nature · doi:10.1038/nature01478 · Cited by 1,538 · see citing works
Self-citationCahill, G. F. (2006) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.26.061505.111258 · Cited by 1,318 · see citing works
Teaching old receptors new tricks: biasing seven-transmembrane receptors
Rajagopal, S., Rajagopal, K., & Lefkowitz, R. J. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3024 · Cited by 826 · see citing works
βAR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance
Bachman, E. S., Dhillon, H., Zhang, C.-Y., Cinti, S., Bianco, A. C., Kobilka, B. K., & Lowell, B. B. (2002) · Science · doi:10.1126/science.1073160 · Cited by 782 · see citing works
Xiong, Y., Miyamoto, N., Shibata, K., Valasek, M. A., Motoike, T., Kedzierski, R. M., & Yanagisawa, M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2637002100 · Cited by 731 · see citing works
Acetate and Propionate Short Chain Fatty Acids Stimulate Adipogenesis via GPCR43
Hong, Y.-H., Nishimura, Y., Hishikawa, D., Tsuzuki, H., Miyahara, H., Gotoh, C., Choi, K.-C., Feng, D. D., Chen, C., Lee, H.-G., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0545 · Cited by 613 · see citing works
Cellular bioenergetics as a target for obesity therapy
Tseng, Y.-H., Cypess, A. M., & Kahn, C. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3138 · Cited by 591 · see citing works
Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry
Fukao, T., Lopaschuk, G. D., & Mitchell, G. A. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.11.001 · Cited by 395 · see citing works
Suppression of Sympathetic Nervous System During Fasting
Young, J. B., & Landsberg, L. (1977) · Science · doi:10.1126/science.867049 · Cited by 395 · see citing works
Medium-chain Fatty Acids as Ligands for Orphan G Protein-coupled Receptor GPR84*
Wang, J.-H., Wu, X.-S., Simonavicius, N., Tian, H., & Ling, L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608019200 · Cited by 391 · see citing works
Nutritional programming of the metabolic syndrome
Symonds, M. E., Sebert, S. P., Hyatt, M. A., & Budge, H. (2009) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2009.195 · Cited by 368 · see citing works
Zaibi, M. S., Stocker, C. J., O’Dowd, J. F., Davies, A., Bellahcene, M., Cawthorne, M. A., Brown, A., Smith, D. M., & Arch, J. R. S. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.04.027 · Cited by 341 · see citing works
Ketone body production and disposal: Effects of fasting, diabetes, and exercise
BALASSE, E. O., & Féry, F. (1989) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610050304 · Cited by 312 · see citing works
The Geometry of Leptin Action in the Brain: More Complicated Than a Simple ARC
Myers, M. G., Münzberg, H., Leinninger, G. M., & Leshan, R. L. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2008.12.001 · Cited by 294 · see citing works
Differentiation of mouse Neuro 2A cells into dopamine neurons
Tremblay, R. G., Sikorska, M., Sandhu, J. K., Lanthier, P. H., Ribecco‐Lutkiewicz, M., & Bani‐Yaghoub, M. (2009) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2009.11.004 · Cited by 280 · see citing works
Lehmann, D. M., Seneviratne, A. M. P. B., & Smrcka, A. V. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.041780 · Cited by 234 · see citing works
Regulation of adipokine production in human adipose tissue by propionic acid
Al-Lahham, S., Roelofsen, H., Priebe, M. G., Weening, D., Dijkstra, M., Hoek, A., Rezaee, F., Venema, K., & Vonk, R. J. (2010) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.2010.02278.x · Cited by 222 · see citing works
Albert, P. R., & Robillard, L. (2002) · Cellular Signalling · doi:10.1016/s0898-6568(01)00259-5 · Cited by 167 · see citing works
Nerve Growth Factor Modulates Synaptic Transmission between Sympathetic Neurons and Cardiac Myocytes
Lockhart, S. T., Turrigiano, G. G., & Birren, S. J. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-24-09573.1997 · Cited by 150 · see citing works
Inhibition of receptor/G protein coupling by suramin analogues.
Beindl, W., Mitterauer, T., HOHENEGGER, M., IJzerman, A. P., Nanoff, C., & Freissmuth, M. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09262-4 · Cited by 120 · see citing works
Stoddart, L. A., Smith, N. J., Jenkins, L., Brown, A. J., & Milligan, G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805601200 · Cited by 114 · see citing works
Autonomic Dysfunction in Short-term Experimental Diabetes
Maeda, C. Y., Fernandes, T. R. G., Timm, H. B., et al. (1995) · Hypertension · doi:10.1161/01.hyp.26.6.1100 · Cited by 108 · see citing works
Feast or Famine: The Sympathetic Nervous System Response to Nutrient Intake
Landsberg, L. (2006) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-006-9010-7 · Cited by 88 · see citing works
Developmental programming of energy balance and the metabolic syndrome
Cottrell, E. C., & Ozanne, S. E. (2007) · Proceedings of The Nutrition Society · doi:10.1017/s0029665107005447 · Cited by 87 · see citing works
Sudden Cardiac Death in Association With the Ketogenic Diet
Bank, I., Shemie, S. D., Rosenblatt, B., Bernard, C., & Mackie, A. S. (2008) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2008.08.013 · Cited by 81 · see citing works
Bräutigam, M., Dreesen, R., & Herken, H. (1984) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1984.tb02690.x · Cited by 44 · see citing works
Prolonged QT interval corrected for heart rate during diabetic ketoacidosis in children
Kuppermann, N., Park, J., Glatter, K., Marcin, J. P., & Glaser, N. S. (2008) · Archives of Pediatrics & Adolescent Medicine · doi:10.1001/archpedi.162.6.544 · Cited by 41 · see citing works
Park, Y., Jun, D., Hur, E., Lee, S., Suh, B.-S., & Kim, K. (2005) · Endocrinology · doi:10.1210/en.2005-0959 · Cited by 21 · see citing works
Colonic Energy Salvage in Chronic Pancreatic Exocrine Insufficiency
Owira, P. M. O., & Winter, T. A. (2008) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/014860710803200163 · Cited by 16 · see citing works
Rosmaninho‐Salgado, J., Araújo, I. M., Álvaro, A. R., Duarte, E. P., & Cavadas, C. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04899.x · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites
Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016) · Cell · doi:10.1016/j.cell.2016.05.041 · Cited by 7,070 · see citing works
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286 · see citing works
The role of short-chain fatty acids in microbiota–gut–brain communication
Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0157-3 · Cited by 3,357 · see citing works
The role of short chain fatty acids in health and disease
Tan, J., McKenzie, C., Potamitis, M., Thorburn, A. N., Mackay, C. R., & Macia, L. (2014) · Advances in immunology · doi:10.1016/b978-0-12-800100-4.00003-9 · Cited by 2,425 · see citing works
Short-chain fatty acids in control of body weight and insulin sensitivity
Canfora, E. E., Jocken, J. W., & Blaak, E. E. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.128 · Cited by 2,298 · see citing works
Microbiota-Generated Metabolites Promote Metabolic Benefits via Gut-Brain Neural Circuits
De Vadder, F., Kovatcheva-Datchary, P., Goncalves, D., Vinera, J., Zitoun, C., Duchampt, A., Bäckhed, F., & Mithieux, G. (2014) · Cell · doi:10.1016/j.cell.2013.12.016 · Cited by 2,200 · see citing works
Kimura, I., Ozawa, K., Inoue, D., Imamura, T., Kimura, K., Maeda, T., Terasawa, K., Kashihara, D., Hirano, K., Tani, T., et al. (2013) · Nature Communications · doi:10.1038/ncomms2852 · Cited by 1,512 · see citing works
Self-citationChambers, E. S., Viardot, A., Psichas, A., Morrison, D. J., Murphy, K. G., Zac-Varghese, S. E. K., MacDougall, K., Preston, T., Tedford, C., Finlayson, G. S., et al. (2015) · Gut · doi:10.1136/gutjnl-2014-307913 · Cited by 1,424 · see citing works
Martin, C. R., Osadchiy, V., Kalani, A., & Mayer, E. A. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.04.003 · Cited by 1,284 · see citing works
Pluznick, J. L., Protzko, R. J., Gevorgyan, H., Peterlin, Z., Sipos, A., Han, J., Brunet, I., Wan, L.-X., Rey, F., Wang, T., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215927110 · Cited by 1,191 · see citing works
Marques, F. Z., Nelson, E., Chu, P.-Y., Horlock, D., Fiedler, A., Ziemann, M., Tan, J. K., Kuruppu, S., Rajapakse, N. W., El-Osta, A., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.024545 · Cited by 1,065 · see citing works
Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity
Liou, A. P., Paziuk, M., Luevano, J.-M., Machineni, S., Turnbaugh, P. J., & Kaplan, L. M. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005687 · Cited by 1,007 · see citing works
Ketone bodies as signaling metabolites
Newman, J. C., & Verdin, E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.09.002 · Cited by 966 · see citing works
Commensal bacteria at the interface of host metabolism and the immune system
Brestoff, J. R., & Artis, D. (2013) · Nature Immunology · doi:10.1038/ni.2640 · Cited by 945 · see citing works
From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways
Rogers, G. B., Keating, D. J., Young, R. L., Wong, M.-L., Licinio, J., & Wesselingh, S. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.50 · Cited by 969 · see citing works
Scheiman, J., Luber, J. M., Chavkin, T. A., MacDonald, T., Tung, A., Pham, L.-D., Wibowo, M. C., Wurth, R. C., Punthambaker, S., Tierney, B. T., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0485-4 · Cited by 892 · see citing works
Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation
Kasubuchi, M., Hasegawa, S., Hiramatsu, T., Ichimura, A., & Kimura, I. (2015) · Nutrients · doi:10.3390/nu7042839 · Cited by 904 · see citing works
Self-citationβ-Hydroxybutyrate: A Signaling Metabolite
Newman, J. C., & Verdin, E. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064916 · Cited by 872 · see citing works
The neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis
Stilling, R. M., van de Wouw, M., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.06.011 · Cited by 891 · see citing works
van de Wouw, M., Boehme, M., Lyte, J. M., Wiley, N., Strain, C., O'Sullivan, O., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2018) · The Journal of Physiology · doi:10.1113/jp276431 · Cited by 789 · see citing works
Molecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
Gut microbiota-derived short-chain Fatty acids, T cells, and inflammation
Kim, C. H., Park, J., & Kim, M. (2014) · Immune Network · doi:10.4110/in.2014.14.6.277 · Cited by 704 · see citing works
The role of short chain fatty acids in appetite regulation and energy homeostasis
Byrne, C. S., Chambers, E. S., Morrison, D. J., & Frost, G. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.84 · Cited by 707 · see citing works
Fecal microbiota transplantation and emerging applications
Borody, T. J., & Khoruts, A. (2012) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2011.244 · Cited by 677 · see citing works
The Gut Microbiome and the Brain
Galland, L. (2014) · Journal of Medicinal Food · doi:10.1089/jmf.2014.7000 · Cited by 648 · see citing works
Clark, A., & Mach, N. (2016) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-016-0155-6 · Cited by 583 · see citing works
“thetic nervous system [155] and mucosal serotonin release [156].”
BackgroundKetogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice
Newman, J. C., Covarrubias, A. J., Zhao, M., Yu, X., Gut, P., Ng, C.-P., Huang, Y., Haldar, S., & Verdin, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.004 · Cited by 493 · see citing works
Microbiota-gut-brain axis: Modulator of host metabolism and appetite
van de Wouw, M., Schellekens, H., Dinan, T. G., & Cryan, J. F. (2017) · The Journal of Nutrition · doi:10.3945/jn.116.240481 · Cited by 461 · see citing works
Microbiome–microglia connections via the gut–brain axis
Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K., & Mazmanian, S. K. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20180794 · Cited by 471 · see citing works
“SCFAs can exert physiological effects in the CNS via two primary mechanisms: activation of G protein–coupled receptors (GPCRs) expressed in the liver, spleen, and large intestine and inhibition of histone deacetylases (Kimura et al., 2011; Tan et al., 2014b).”
BackgroundMikulska, J., Juszczyk, G., Gawrońska-Grzywacz, M., & Herbet, M. (2021) · Brain Sciences · doi:10.3390/brainsci11101298 · Cited by 450 · see citing works
Natarajan, N., Hori, D., Flavahan, S., Steppan, J., Flavahan, N. A., Berkowitz, D. E., & Pluznick, J. L. (2016) · Physiological Genomics · doi:10.1152/physiolgenomics.00089.2016 · Cited by 441 · see citing works
Miyamoto, J., Igarashi, M., Watanabe, K., Karaki, S.-I., Mukouyama, H., Kishino, S., Li, X., Ichimura, A., Irie, J., Sugimoto, Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11978-0 · Cited by 392 · see citing works
Self-citationControl of lymphocyte functions by gut microbiota-derived short-chain fatty acids
Kim, C. H. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00625-0 · Cited by 404 · see citing works
A novel SCFA receptor, the microbiota, and blood pressure regulation
Pluznick, J. (2014) · Gut Microbes · doi:10.4161/gmic.27492 · Cited by 374 · see citing works
Towards microbial fermentation metabolites as markers for health benefits of prebiotics
Verbeke, K. A., Boobis, A. R., Chiodini, A., Edwards, C. A., Franck, A., Kleerebezem, M., Nauta, A., Raes, J., van Tol, E. A. F., & Tuohy, K. M. (2015) · Nutrition Research Reviews · doi:10.1017/s0954422415000037 · Cited by 343 · see citing works
The Human Gut Microbiome and Body Metabolism: Implications for Obesity and Diabetes
Devaraj, S., Hemarajata, P., & Versalovic, J. (2013) · Clinical Chemistry · doi:10.1373/clinchem.2012.187617 · Cited by 321 · see citing works
Regulation of Ketone Body Metabolism and the Role of PPARα
Grabacka, M., Pierzchalska, M., Dean, M., & Reiss, K. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17122093 · Cited by 305 · see citing works
Caprio, M., Infante, M., Moriconi, E., Armani, A., Fabbri, A., Mantovani, G., Mariani, S., Lubrano, C., Poggiogalle, E., Migliaccio, S., et al. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-019-01061-2 · Cited by 283 · see citing works
Nankova, B. B., Agarwal, R., MacFabe, D. F., & La Gamma, E. F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103740 · Cited by 294 · see citing works
Xiao, W., Su, J., Gao, X., Yang, H., Weng, R., Ni, W., & Gu, Y. (2022) · Microbiome · doi:10.1186/s40168-022-01255-6 · Cited by 252 · see citing works
Hou, Y.-F., Shan, C., Zhuang, S.-Y., Zhuang, Q.-Q., Ghosh, A., Zhu, K.-C., Kong, X.-K., Wang, S.-M., Gong, Y.-L., Yang, Y.-Y., et al. (2021) · Microbiome · doi:10.1186/s40168-020-00988-6 · Cited by 231 · see citing works
Liu, Q., Xi, Y., Wang, Q., Liu, J., Li, P., Meng, X., Liu, K., Chen, W., Liu, X., & Liu, Z. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.04.005 · Cited by 241 · see citing works
Huo, R., Zeng, B., Zeng, L., Cheng, K., Li, B., Luo, Y., Wang, H., Zhou, C., Fang, L., Li, W., et al. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00489 · Cited by 221 · see citing works
Liu, J., Li, H., Gong, T., Chen, W., Mao, S., Kong, Y., Yu, J., & Sun, J. (2020) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c02807 · Cited by 199 · see citing works
Butyrate Ameliorates Allergic Airway Inflammation by Limiting Eosinophil Trafficking and Survival
Theiler, A., Bärnthaler, T., Platzer, W., Richtig, G., Peinhaupt, M., Rittchen, S., Kargl, J., Ulven, T., Marsh, L. M., Marsche, G., et al. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2019.05.002 · Cited by 198 · see citing works
Dietary fiber and its associations with depression and inflammation
Swann, O. G., Kilpatrick, M., Breslin, M., & Oddy, W. H. (2020) · Nutrition Reviews · doi:10.1093/nutrit/nuz072 · Cited by 185 · see citing works
The Impact of Artificial Sweeteners on Body Weight Control and Glucose Homeostasis
Pang, M. D., Goossens, G. H., & Blaak, E. E. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2020.598340 · Cited by 180 · see citing works
Aoki, R., Onuki, M., Hattori, K., Ito, M., Yamada, T., Kamikado, K., Kim, Y.-G., Nakamoto, N., Kimura, I., Clarke, J. M., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01125-7 · Cited by 167 · see citing works
Self-citationParkinson’s Disease and Gut Microbiota
Hirayama, M., & Ohno, K. (2021) · Annals of Nutrition and Metabolism · doi:10.1159/000518147 · Cited by 158 · see citing works
Role of the Gut Microbiome in Autism Spectrum Disorders
Pulikkan, J., Mazumder, A., & Grace, T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-05542-4_13 · Cited by 142 · see citing works
The role of the microbiome in the neurobiology of social behaviour
Sarkar, A., Harty, S., Johnson, K. V. ‐., Moeller, A. H., Carmody, R. N., Lehto, S. M., Erdman, S. E., Dunbar, R. I. M., & Burnet, P. W. J. (2020) · Biological Reviews · doi:10.1111/brv.12603 · Cited by 135 · see citing works
Beneficial effects of butyrate on brain functions: A view of epigenetic
Alpino, G. D. C. Á., Pereira-Sol, G. A., Dias, M. D. M. E., Aguiar, A. S. D., & Peluzio, M. D. C. G. (2024) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2137776 · Cited by 110 · see citing works
Biobaku, F., Ghanim, H., Batra, M., & Dandona, P. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01833 · Cited by 104 · see citing works
Cerebral Metabolic Changes During Sleep
Aalling, N. N., Nedergaard, M., & DiNuzzo, M. (2018) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-018-0868-9 · Cited by 101 · see citing works
Zhou, S., Wang, Y., Jacoby, J. J., Jiang, Y., Zhang, Y., & Yu, L. L. (2017) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.7b01803 · Cited by 94 · see citing works
Gu, X., Zhou, J., Zhou, Y., Wang, H., Si, N., Ren, W., Zhao, W., Fan, X., Gao, W., Wei, X., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00779-7 · Cited by 81 · see citing works
From taxonomy to metabolic output: what factors define gut microbiome health?
Wilmanski, T., Rappaport, N., Diener, C., Gibbons, S. M., & Price, N. D. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1907270 · Cited by 73 · see citing works
Gut hormones and gut microbiota: implications for kidney function and hypertension
Afsar, B., Vaziri, N. D., Aslan, G., Tarim, K., & Kanbay, M. (2016) · Journal of the American Society of Hypertension · doi:10.1016/j.jash.2016.10.007 · Cited by 63 · see citing works
Kasubuchi, M., Watanabe, K., Hirano, K., Inoue, D., Li, X., Terasawa, K., Konishi, M., Itoh, N., & Kimura, I. (2017) · Scientific Reports · doi:10.1038/s41598-017-05423-9 · Cited by 59 · see citing works
Self-citationRegulation of energy expenditure and substrate oxidation by short-chain fatty acids
Sukkar, A. H., Lett, A. M., Frost, G., & Chambers, E. S. (2019) · Journal of Endocrinology · doi:10.1530/joe-19-0098 · Cited by 54 · see citing works
Qin, W., Ying, W., Hamaker, B., & Zhang, G. (2021) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/1541-4337.12808 · Cited by 48 · see citing works
Slob, E. M. A., Brew, B. K., Vijverberg, S. J. H., Dijs, T., van Beijsterveldt, C. E. M., Koppelman, G. H., Bartels, M., Dolan, C. V., Larsson, H., Lundström, S., et al. (2021) · International Journal of Epidemiology · doi:10.1093/ije/dyaa168 · Cited by 43 · see citing works
“Bacteria excrete metabolites, such as short-chain fatty acids, in turn altering the immune system and interacting with nerve cells via sympathetic nervous system stimulation.(15,16) Third, the microbiome-gut-brain axis is developed in early life; over years the microbiome composition may affect central nervous system…”
BackgroundHu, C., Li, F., Duan, Y., Yin, Y., & Kong, X. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01767 · Cited by 41 · see citing works
Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy
Nehls, M. (2016) · Journal of Molecular Psychiatry · doi:10.1186/s40303-016-0018-8 · Cited by 41 · see citing works
Zhang, T., Han, Y., Wang, J., Hou, D., Deng, H., Deng, Y. L., & Song, Z. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00176 · Cited by 38 · see citing works
“One principle product of gastrointestinal bacteria is shortchain fatty acids, which include butyric acid, propionic acid, and acetic acid, and the enteric nervous system can be affected by these substances; these metabolites can also influence the sympathetic system (Kimura et al., 2011), increase mucosal serotonin re…”
BackgroundMashaqi, S., & Gozal, D. (2020) · Sleep Medicine · doi:10.1016/j.sleep.2020.03.020 · Cited by 40 · see citing works
Gut microbial metabolites in cancer therapy
Song, P., Peng, Z., & Guo, X. (2025) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2024.06.016 · Cited by 38 · see citing works
Agbaga, M.-P., Tam, B. M., Wong, J. S., Yang, L. L., Anderson, R. E., & Moritz, O. L. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.13-13099 · Cited by 26 · see citing works
Drobny, A., Ngo, P. A., Neurath, M. F., Zunke, F., & López-Posadas, R. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.655123 · Cited by 24 · see citing works
- Authors
- Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., Kobayashi, M., Hirasawa, A., & Tsujimoto, G.
- Affiliations
- Kyoto University (JP)
- Tokyo Women's Medical University (JP)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-04-25
- Volume
- 108
- Issue
- 19
- Pages
- 8030-8035
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3093469
- OpenAlex
- W2157201312
- Cited by
- 1,106
- References
- 41
- Citations by year
- 2026: 81 · 2025: 106 · 2024: 102 · 2023: 89 · 2022: 132 · 2021: 124 · 2020: 103 · 2019: 78 · 2018: 66 · 2017: 47 · 2016: 59 · 2015: 34 · 2014: 33 · 2013: 23 · 2012: 22
- FWCI
- 11.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Kowa Company
- Ministry of Education, Culture, Sports, Science and Technology
- Kowa Life Science Foundation
- Astellas Pharma
- Astellas Foundation for Research on Metabolic Disorders
- Japan Society for the Promotion of Science (22790065, 21390021)
- Japan Science and Technology Agency
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- short-chain fatty acids, ketone bodies, GPR41, sympathetic nervous system, energy homeostasis, energy expenditure, propionate, beta-hydroxybutyrate, sympathetic ganglia, colonic fermentation, starvation, diabetes mellitus, metabolic homeostasis
- MeSH terms
- Action Potentials, Animals, Base Sequence, Energy Metabolism, Fatty Acids, Volatile, Humans, Ketone Bodies, Mice, Inbred C57BL, Propionates, Sympathetic Nervous System, Signal Transduction, Mice, Knockout, 3-Hydroxybutyric Acid, RNA, Small Interfering, Receptors, G-Protein-Coupled, Mice, Gene Knockdown Techniques, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
