Short-chain fatty acids (SCFAs) are fatty acids with fewer than six carbon atoms, primarily produced by gut microbiota through saccharolytic fermentation—the anaerobic breakdown of nondigestible carbohydrates such as resistant starches, dietary fibers, and polysaccharides that escape digestion in the small intestine.
The most abundant and well-characterized SCFAs are acetate (C2), propionate (C3), and butyrate (C4), which together account for over 95% of the SCFA pool in the colon. Acetate is the most prevalent (≈60%), followed by propionate and butyrate. These metabolites are essential for maintaining host health, influencing metabolic, immune, gastrointestinal, and neurological functions. Smaller amounts of other SCFAs, such as formate (C1), isobutyrate, valerate (C5), isovalerate, and caproate (C6), are also produced, often through protein fermentation rather than saccharolytic processes. Though less studied, they may carry distinct physiological roles (Akthar et al., 2021; Fusco et al., 2023; Hays et al., 2024).
In addition to SCFAs, saccharolytic fermentation generates monosaccharides and gases like methane and carbon dioxide, reflecting the complex metabolic activity of gut microbes.
Mechanisms of action
Acetate and propionate are absorbed via the portal vein and utilized by the liver for lipid, glucose, and cholesterol metabolism. Butyrate, in contrast, is a primary energy source for colonocytes and plays a pivotal role in maintaining epithelial integrity and modulating immune responses (Rinninella et al., 2019).
SCFAs contribute to colonic homeostasis by stimulating epithelial cell proliferation, enhancing salt and water absorption, and preserving mucosal integrity (Blaak et al., 2020; Fusco et al., 2023; Hays et al., 2024). They also act as histone deacetylase inhibitors, influencing gene expression and exhibiting anti-cancer properties. They may help prevent colorectal and other cancers by reducing inflammation, reinforcing gut barrier integrity, and promoting cancer cell apoptosis. These effects are mediated through pathways such as GPR43 activation and suppression of the mTOR/S6K1 signaling cascade (Wang et al., 2024). Furthermore, SCFAs regulate appetite and gastrointestinal motility by activating hormones such as GLP-1, PYY, and leptin through FFAR2 and FFAR3 receptors (Chambers et al., 2018).
Beyond the gut, SCFAs impact systemic health. They modulate immune responses and reduce inflammation, with potential benefits for inflammatory bowel diseases (Akhtar et al., 2021; Xiong et al., 2022). Metabolically, they influence glucose homeostasis, lipid metabolism, and energy expenditure, offering therapeutic potential for obesity and type 2 diabetes (Blaak et al., 2020; Chambers et al., 2018; Nogal et al., 2021; Portincasa et al., 2022). SCFAs also play a role in cardiometabolic regulation and blood pressure control (Chambers et al., 2018; Nogal et al., 2021; Overby & Ferguson, 2021). Their involvement in the gut-brain axis suggests influence over mood, cognition, and neurological disorders, including depression and neurodegeneration (Cheng et al., 2024; Dalile et al., 2019; Li et al., 2025; Mirzaei et al., 2021; O'Riordan et al., 2022; Silva et al., 2020).
Benefits and limitations
SCFAs exhibit a wide range of health-promoting effects, anti-inflammatory, immunoregulatory, anti-obesity, anticancer, hepatoprotective, and neuroprotective (Hsu et al., 2024; Wang et al., 2024; Xiong et al., 2022). However, much of the current evidence stems from animal models, and further well-controlled human studies are essential to validate these findings and optimize dietary interventions (Blaak et al., 2020; Dalile et al., 2019).
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