2026: The Year of Fibre – Short-Chain Fatty Acids: Fibre’s Metabolic Messengers

Part Three of the Fibre Series

Welcome back to The Fibre Series. Last week, we explored fibre and the gut microbiome, looking at how different types of fibre feed distinct microbial communities and help shape this complex ecosystem. This week, we’re taking a deeper dive into short-chain fatty acids (SCFAs), small but powerful molecules that translate fibre intake into signals affecting metabolism, immunity, and hormonal regulation [1-3].

SCFAs are the primary biochemical link between dietary fibre and human physiology. They are not simply byproducts of fermentation, but act as active signalling molecules that influence metabolism, immune function, hormone release, and gene expression throughout the body [2-4].

From Fibre to SCFAs

Humans lack the enzymes required to digest most dietary fibres. As a result, these carbohydrates reach the colon largely intact, where gut microbes ferment them into three main SCFAs: acetate (C2), propionate (C3), and butyrate (C4) [1,2]. This process is highly organised and depends on microbial cross-feeding (a process where metabolic products generated by one group of microbes are used as substrates by others).

A good example of this can be see in can be seen in the fermentation of resistant starch. Certain bacteria known as primary degraders, such as Ruminococcus bromii, initiate the process by breaking down complex polysaccharides into smaller carbohydrates such as maltose and glucose [3,4]. These breakdown products are then utilised by secondary fermenters, which convert them into SCFAs. Beyond this, additional microbial groups further modify and balance these metabolites, shaping the final profile of fermentation products in the gut.

This layered approach to fibre metabolism means SCFA production depends not only on the amount of fibre consumed, but also on microbial diversity, functional redundancy, and fibre structure [4,5]. Diets low in fibre reduce both microbial diversity and enzymatic capacity, leading to diminished SCFA production, even when fibre intake is later increased [6].

Butyrate: Epithelial Fuel, Immune Modulator, Epigenetic Regulator

Butyrate is the most studied SCFA, largely because of its central role in maintaining gut and immune health [7]. In the colon, it serves as the primary energy source for colonocytes (primary cells lining the colon) helping to maintain epithelial integrity. Butyrate supports the strengthening of tight junctions between cells (essentially helping the cells seal together), promotes mucin production to strengthen the protective mucus layer, and helps maintain epithelial oxygen balance, limiting the expansion of oxygen-tolerant pathogenic bacteria [8,9].

Beyond its role in the gut barrier, butyrate acts as a powerful immune modulator. It promotes the differentiation of regulatory T cells (a specialised subpopulation of T-cells that maintain immune system homeostasis, self-tolerance, and prevent autoimmune diseases), suppresses NF-KB-mediated inflammatory signalling, and reduces the production of pro-inflammatory cytokines. These effects help maintain immune tolerance and prevent excessive inflammation. [10,11].

Butyrate further influences health through epigenetic regulation (The process of gene expression withoit the use of altering DNA). It functions as a histone deacetylase (HDAC) inhibitor, altering gene transcription patterns involved in inflammation, metabolism, and cell proliferation [12]. Consistent reductions in butyrate producing bacteria have been observed in inflammatory bowel disease, metabolic syndrome and several autoimmune conditions, highlighting the systemic importance of this SCFA [8,10,13].

Propionate: Hepatic Signalling and Glucose Homeostasis

Propionate, another SCFA, is primarily produced in the colon through microbial fermentation of fibres such as inulin-type fructans, resistant starches, and arabinoxylans (polysaccharides found in cell walls of certain cereal ingredients such as wheat and oats) [1,14]. Its production depends heavily on microbial cross-feeding (Bacteroides start the process to produce metabolites, and then microbes such as Veillonella and Phascolarctobacterium convert these into propionate) [14,15].

Once produced, propionate is rapidly absorbed by colonocytes and transported to the liver through the portal vein, where it serves as a key metabolic regulator [16]. In the liver, propionate influences gluconeogenesis, helping to regulate blood glucose production, and modulates cholesterol synthesis [16,17]. Propionate has also been shown to improve insulin sensitivity in peripheral tissues, linking fibre intake to systemic glucose regulation [18].

In addition, propionate plays a role in appetite and hormonal signalling. It stimulates the release of the now-famous glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), hormones involved in satiety and appetite control [19,20]. Human intervention studies demonstrate that increasing colonic propionate delivery improves insulin sensitivity and reduces weight gain, even in the absence of changes in calorie intake [19].

Acetate: Systemic Energy and Neuroendocrine Signalling

Acetate is the most abundant SCFA produced in the gut. Unlike butyrate and propionate, acetate circulates widely throughout the body, making it a key systemic messenger [2,21]. After absorption, acetate enters both portal and peripheral circulation, reaching tissues such as the liver, muscle, and adipose tissue, where it serves as a substrate for lipid and cholesterol synthesis [21,22].

Notably, acetate has been seen to cross the blood brain barrier, allowing it to influence central nervous system function and appetite regulation [23]. Its neuroendocrine effects include modulation of hypothalamic pathways involved in energy balance and regulation of parasympathetic activity, which influences digestion and metabolic rate [23,24]. Acetate also stimulates GLP-1 and PYY secretion, reinforcing its role in linking microbial activity to appetite and metabolic control [2,20].

SCFA Signalling Pathways: How the Body “Reads” Fibre Intake

SCFAs exert their effects through multiple overlapping biological pathways, helping explain how fibre intake produces coordinated, whole-body responses rather than isolated gut effects. One key mechanism involves activation of G-protein-coupled receptors (GPCRs) expressed on intestinal, immune, and metabolic cells. SCFAs bind to receptors such as GPR41 (FFAR3), involved in energy expenditure and sympathetic nervous system activity, and GPR43 (FFAR2), which influences immune regulation and insulin sensitivity. GPR109A, activated primarily by butyrate, mediates anti-inflammatory signalling and supports colonocyte health [1,25].

SCFAs also act through epigenetic mechanisms. Butyrate, and to a lesser extent propionate, inhibit histone deacetylases (HDAC) activity, leading to sustained changes in gene expression related to inflammation, metabolism, and cell differentiation [12]. These effects may persist beyond the immediate presence of SCFAs, providing a potential mechanism for longer-term dietary adaptation.

When SCFA Production Is Disrupted

Low fibre intake, limited plant diversity, frequent antibiotic exposure, and diets dominated by ultra processed foods (UPFs) (when we talk about UPFs, we are referring to foods that lack nutritional diversity, high in fat, salt and sugar and low in fibre and protein toghether redcued micronutrient profile) reduce the gut microbiome’s capacity to produce SCFAs [6,13,26].

Reduced SCFA availability is associated with increased gut permeability, low-grade systemic inflammation, impaired glucose and lipid metabolism, and altered immune tolerance [6,13,26]. These mechanisms help explain the strong association between low fibre dietary patterns and metabolic and inflammatory disease risk [27].

Crucially, restoring SCFA production is not achieved through single fibre additions or short term supplementation. It requires fibre diversity and microbial recovery, reinforcing the importance of long-term dietary patterns rich in varied plant foods rather than quick fixes [4–6].

SCFAs illustrate that fibre is not passive bulk. It is a metabolic input that the microbiome converts into signals regulating immunity, hormones, energy balance, and gene expression, a reminder that what we feed our microbes ultimately shapes our physiology.

Next in The Fibre Series

Next week, we’ll explore fibre and metabolic health, diving into its effects on blood sugar control, cholesterol metabolism, and satiety hormones — including the now-infamous GLP-1.

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19. Kimura I., Ozawa K., Inoue D., et al. (2013). SCFA receptor GPR43 regulates insulin-mediated fat accumulation. Nat Commun, 4, 1829.

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21. Ríos-Covián D., Ruas-Madiedo P., Margolles A., et al. (2016). Intestinal short-chain fatty acids and their link with diet and human health. Front Microbiol, 7, 185.

22. den Besten G., van Eunen K., Groen A.K., et al. (2013). The role of SCFAs in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res, 54(9), 2325–2340.

23. Frost G., Sleeth M.L., Sahuri-Arisoylu M., et al. (2014). Acetate reduces appetite via central homeostatic mechanisms. Nat Commun, 5, 3611.

24. Perry R.J., Peng L., Barry N.A., et al. (2016). Acetate mediates a microbiome–brain–β-cell axis. Nature, 534(7606), 213–217.

25. Kimura I., Ozawa K., Inoue D., et al. (2013). SCFA receptor GPR43 regulates insulin-mediated fat accumulation. Nat Commun, 4, 1829.

26. Sonnenburg E.D., Sonnenburg J.L. (2014). Starving the gut microbiota: consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metab, 20(5), 779–786.

27. Makki K., Deehan E.C., Walter J., Bäckhed F. (2018). Impact of dietary fiber on gut microbiota in host health and disease. Cell Host & Microbe, 23(6), 705–715.