Short-chain fatty acids (SCFAs)

Short-chain fatty acids have 2-5 (or 6) carbon atoms, with varying degrees of water solubility. SCFAs include acetate, propionate, and butyrate, which can be produced by microbial fermentation in intestines and absorbed through the portal vein.

SCFAs are predominantly metabolized by enterocytes (mainly butyrate) and hepatocytes (mainly propionate). Oxidation of fatty acids provides energy to cells, including tumour cells. Additionally, synthesis of fatty acids is elevated in growing tumours, which has been assessed using [1-11C]acetate (Vāvere et al., 2008) and 2-[18F]fluoropropionic acid ([18F]FPA) (Zhao et al., 2019; Zhang et al., 2019 and 2021).

Acetate (ethanoate) Propionate (propanoate) Butyrate (butanoate) Valerate (pentanoate) Isobutyrate (2-methylpropanoate) 2-Methylbutyrate (2-methylbutanoate) Isovalerate (3-methylbutanoate) Pivalate (trimethylacetate)

SCFAs include also a non-natural substrate pivalate (trimethylacetate), which cannot be oxidized to CO2 in mammalian cells; pivalate can be activated to a coenzyme A thioester in cells, and in humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination (Brass, 2002). [18F]Fluoro-pivalic acid ([18F]FPIA) has high tumour uptake and does not defluorinate like [18F]fluoroacetate (Pisanechi et al., 2013; Witney et al., 2014).


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Literature

Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015; 11: 577-591. doi: 10.1038/nrendo.2015.128.

Mann ER, Lam YK, Uhlig HH. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol. 2024; 24: 577–595. doi: 10.1038/s41577-024-01014-8.

Moschen I, Bröer A, Galić S, Lang F, Bröer S. Significance of short chain fatty acid transport by members of the monocarboxylate transporter family (MCT). Neurochem Res. 2012; 37(11): 2562-2568. doi: 10.1007/s11064-012-0857-3.

Mukhopadhya I, Louis P. Gut microbiota-derived short-chain fatty acids and their role in human health and disease. Nat Rev Microbiol. 2025. doi: 10.1038/s41579-025-01183-w.

O'Riordan KJ, Collins MK, Moloney GM, Knox EG, Aburto MR, Fülling C, Morley SJ, Clarke G, Schellekens H, Cryan JF. Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Mol Cell Endocrinol. 2022; 546: 111572. doi: 10.1016/j.mce.2022.111572.



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Updated at: 2025-06-05
Created at: 2025-06-02
Written by: Vesa Oikonen