The Pharmacology and Function of Receptors for Short-Chain Fatty Acids
Abstract
Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼ 15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic β-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.
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?
Short-chain fatty acids bind to G protein-coupled receptors, including GPR43/FFAR2, GPR41/FFAR3, GPR109a/HCAR2, and GPR164, which are expressed in a vast array of cells from the gastrointestinal mucosa to the immune and nervous systems.
“SCFAs bind to G protein-coupled receptors (GPCRs). The best-studied SCFA receptors are GPR43 and GPR41, later renamed free fatty acid receptor (FFAR2) and FFAR3, as well as GPR109a/HCAR2 (hydrocarboxylic acid receptor) and GPR164, which are expressed in a vast array of cells, from the gastrointestinal mucosa to the immune and nervous systems (82, 83).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [83]
Cites
Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly-Y, M., Glickman, J. N., & Garrett, W. S. (2013) · Science · doi:10.1126/science.1241165 · Cited by 5,413 · see citing works
Unravelling the pathogenesis of inflammatory bowel disease
Xavier, R. J., & Podolsky, D. K. (2007) · Nature · doi:10.1038/nature06005 · Cited by 4,364 · 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
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
He, W., Miao, F. J.-P., Lin, D. C.-H., Schwandner, R. T., Wang, Z., Gao, J., Chen, J.-L., Tian, H., & Ling, L. (2004) · Nature · doi:10.1038/nature02488 · Cited by 909 · cited 1× · see citing works
“Previous studies had shown that positively charged amino acids within the TM regions are essential for the binding and function of other GPCRs whose ligands contain a carboxylic acid group (Stitham et al., 2003; He et al., 2004; Tunaru et al., 2005; Sabirsh et al., 2006).”
Background
Flagged first, then by citations
Cited by
Sorted by citations
Formation of propionate and butyrate by the human colonic microbiota
Louis, P., & Flint, H. J. (2017) · Environmental Microbiology · doi:10.1111/1462-2920.13589 · Cited by 3,028 · see citing works
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00025 · Cited by 3,043 · see citing works
“The best-studied SCFA receptors are GPR43 and GPR41, later renamed free fatty acid receptor (FFAR2) and FFAR3, as well as GPR109a/HCAR2 (hydrocarboxylic acid receptor) andGPR164, which are expressed in a vast array of cells, from the gastrointestinal mucosa to the immune and nervous systems (82, 83).”
BackgroundThe 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
Role of gut microbiota-generated short-chain fatty acids in metabolic and cardiovascular health
Chambers, E. S., Preston, T., Frost, G., & Morrison, D. J. (2018) · Current Nutrition Reports · doi:10.1007/s13668-018-0248-8 · Cited by 691 · see citing works
The function of gut microbiota in immune-related neurological disorders: a review
Sittipo, P., Choi, J., Lee, S., & Lee, Y. K. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02510-1 · Cited by 221 · see citing works
Chidambaram, S. B., Essa, M. M., Rathipriya, A. G., Bishir, M., Ray, B., Mahalakshmi, A. M., Tousif, A. H., Sakharkar, M. K., Kashyap, R. S., Friedland, R. P., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107988 · Cited by 204 · see citing works
Russo, E., Giudici, F., Fiorindi, C., Ficari, F., Scaringi, S., & Amedei, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02754 · Cited by 204 · see citing works
Metabolic messengers: glucagon-like peptide 1
Gribble, F. M., & Reimann, F. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00327-x · Cited by 199 · see citing works
Probiotics, fibre and herbal medicinal products for functional and inflammatory bowel disorders
Currò, D., Ianiro, G., Pecere, S., Bibbò, S., & Cammarota, G. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13632 · Cited by 160 · see citing works
Impact of dietary fats on brain functions
Chianese, R., Coccurello, R., Viggiano, A., Scafuro, M., Fiore, M., Coppola, G., Operto, F. F., Fasano, S., Laye, S., Pierantoni, R., et al. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666171017102547 · Cited by 159 · see citing works
Frye, R. E., Rose, S., Chacko, J., Wynne, R., Bennuri, S. C., Slattery, J. C., Tippett, M., Delhey, L., Melnyk, S., Kahler, S. G., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.189 · Cited by 130 · see citing works
Can we ‘seize’ the gut microbiota to treat epilepsy?
De Caro, C., Iannone, L. F., Citraro, R., Striano, P., De Sarro, G., Constanti, A., Cryan, J. F., & Russo, E. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.002 · Cited by 110 · see citing works
Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating
Brierley, D. I., & de Lartigue, G. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15603 · Cited by 92 · see citing works
- Authors
- Bolognini, D., Tobin, A. B., Milligan, G., & Hodge, D.
- Affiliations
- University of Leicester (GB)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 89
- Issue
- 3
- Pages
- 388-398
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2273066997
- Cited by
- 267
- References
- 4
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 22 · 2023: 33 · 2022: 32 · 2021: 42 · 2020: 32 · 2019: 22 · 2018: 25 · 2017: 10 · 2016: 15
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/K019856/1, BB/K019864/1, 1653478, BB/L02781X/1, BB/L027887/1, 1062317)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- short-chain fatty acid receptors, FFAR2, GPR43, GPR41, G protein-coupled receptors, deorphanization, acetate, propionate, butyrate, gut fermentation, pancreatic beta cells, enteroendocrine cells, genetic models, therapeutic target
- MeSH terms
- Animals, Fatty Acids, Volatile, Humans, Immunity, Cellular, Receptors, Cell Surface, Receptors, G-Protein-Coupled
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
