The Role of Short-Chain Fatty Acids in Metabolic Diseases

What Are Short Chain Fatty Acids?

Short chain fatty acids (SCFAs), also known as volatile fatty acids, are a general term for organic fatty acids containing one to six carbon atoms, mainly including acetic acid, propionic acid and butyric acid.

SCFAs are mainly produced from undigested and absorbed carbohydrates (non-starch polysaccharides, resistant starch, sugar alcohols, oligosaccharides, etc.) and glycoproteins secreted by intestinal epithelial cells through fermentation by colonic anaerobic bacteria. The type, amount and function of SCFAs produced vary depending on the type of fermentation substrate and intestinal transit time, the type and number of enterobacteria, and other factors.

About 95% of SCFAs are absorbed into the blood via ion exchange, monocarboxylate transporter1, sodium-coupled monocarboxylate transporter1, or intercellular diffusion. After absorption, SCFAs are readily oxidized by intestinal epithelial cells and metabolized to provide approximately 5% to 10% of the body's energy. SCFAs also regulate intercellular fluid transport, promote sodium absorption, and reduce intestinal osmotic pressure.

Acetic acid is the main product of most bacterial fermentations. Most acetic acid is absorbed into the bloodstream and metabolized in the liver, mainly for lipid and cholesterol synthesis and as an energy source for peripheral tissues. Propionic acid is the main product of the fermentation of the phylum Bacillus, which is absorbed through the colon and can be used as a substrate for gluconeogenesis and can reduce cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Butyric acid is the main metabolite of thick-walled bacteriophage gate, which can be absorbed and utilized by colonic epithelial cells, and is the preferred source of energy for colon and cecum. Only a small amount of butyric acid enters the body circulation via the portal vein. Under physiological conditions, the concentration of total SCFAs in the colon is about 100 mmol/L, and the ratio of acetic acid, propionic acid and butyric acid is 4:1.7:1. The concentration of SCFAs in peripheral circulating blood is low, with acetic acid at about 100-150 μmol/L, propionic acid at about 4-5 μmol/L and butyric acid at about 1-3 μmol/L.

SCFAs inhibit intestinal inflammation and maintain colonic epithelial cell barrier function through two pathways: activation of G protein-coupled receptors and inhibition of histone deacetylase (HDAC). As important mediators of host brain-gut flora communication, SCFAs show a wide range of pharmacological effects on the regulation of various genes, such as anti-inflammatory, immunomodulatory and anti-tumor effects in the digestive system, which have been widely reported. In recent years, the role of SCFAs in regulating glycolipid metabolism has also become increasingly prominent.

Potential pathways through which SCFAs influence gut-brain communication (Silva et al., 2020).

SCFAs and Metabolic Diseases

SCFAs and obesity

The intestinal flora associated with obesity are mainly Phyllostomycetes and Phyllostomycetes, and a high-fat, high-carbohydrate diet reduces intestinal microbial diversity and abundance in humans. the mechanisms by which SCFAs control obesity are also not fully elucidated. Many studies suggest that SCFAs act on GPR41/43 to promote the secretion of hormones such as 5-hydroxytryptamine (5-HT), glucagon-like peptide 1 (GLP-1), peptideYY (PYY), and gastrointestinal inhibitory peptide (GIP) by L-cells in the gut by modulating the information feedback between the gut-brain axis. PYY) and gastrointestinal inhibitory polypeptide (GIP), thereby increasing satiety, regulating appetite, and decreasing gastric emptying and intestinal motility.

Functions of short-chain fatty acids (SCFAs) in the human body (Gutiérrez et al., 2021).

GPR41 is abundantly expressed in sympathetic ganglia, and propionate increases heart rate and energy expenditure by acting on GPR41 to cause the release of tension or adrenaline from muscle neurons.

Butyrate promotes fatty acid oxidation and thermogenesis by activating key factors in the body's energy homeostasis and fat storage processes, such as peroxisome proliferator-activated receptor γ coactivator 1α in cardiac muscle and adipose tissue, AMPK in muscle and liver tissue, and mitochondrial uncoupling protein 1 in brown adipose tissue.

SCFA and diabetes

Significant changes in the composition ratio of intestinal flora in diabetic patients have been reported. Compared to the healthy group, type 2 diabetes mellitus (T2DM) patients showed significantly lower concentrations of SCFAs in stool and body; the abundance of Aspergillus spp. in the intestine was increased, while the abundance of Pseudomonas spp. and Proteus spp. were significantly reduced resulting in an increase in the proportion of P. thick-walled/ P. mellitus.

The fasting glucose level, insulin resistance index, serum total cholesterol (TC), triglyceride (TG) level, ALT and AST activities were significantly reduced in SCFA-treated obese mice, suggesting that SCFAs significantly improved glucose metabolism and lipid metabolism in obese mice caused by high-fat diet.

Host genetics, gut microbiota SCFAs and risk of diabetes (Lau et al., 2019)

The mechanism by which SCFAs improve blood glucose levels may be related to several factors.

(i) SCFAs act on colonic epithelial endocrine cells to promote gastrointestinal hormone release, regulate insulin release and insulin sensitivity, and promote intestinal gluconeogenesis, which in turn affects glucose metabolism. In human NClh716 cells, HuTu-80 cells and human colon primary cells, acetic acid, propionic acid and butyric acid could promote the expression and secretion of PYY to different degrees by acting on GPR43 and inhibiting histone deacetylase. Acetic acid and propionic acid promoted the secretion of GLP-1 in the mouse intestine, and this promotion effect was diminished after knockdown of the GPR41 gene. The loss of GLP-1 receptor in mice resulted in loss of hepatic insulin sensitivity and glucose tolerance.

(ii) SCFAs can improve insulin resistance and regulate islet β-cell function. SCFAs inhibit insulin signaling in adipocytes by stimulating PPAR receptor coactivator PGC-1α and inhibiting adipose accumulation in adipose tissue, thus improving insulin resistance. GPR41/43 is also expressed in islet cells.

(iii) SCFAs affect bile acid metabolism through intestinal bacteria. Primary bile acids are produced in the liver from cholesterol and excreted into the intestine with bile. There is an interaction with the intestinal flora, with primary bile acids acting as antimicrobial agents by disrupting bacterial cell membranes, and intestinal bacteria further metabolizing and modifying bile acids to secondary bile acids. By binding to its receptors TGR5 and FXR, bile acids regulate GLP-1 synthesis in intestinal L cells, promote glucose homeostasis, and improve insulin sensitivity, thereby affecting glucolipid metabolism in patients with T2DM.

SCFA and hyperlipidemia

Studies have shown that continuous administration of oligofructose to mice significantly increased SCFA levels and reduced hepatic steatosis and elevated serum ALT/AST, TC, TG, and low density lipoprotein (LDL) caused by high fat and high sugar. It also decreases inflammation, reduces oxidative stress, hepatocyte apoptosis or lipid deposition, and reduces circulatory lipid levels.

The mechanisms by which SCFAs regulate hyperlipidemia are still under further investigation. It was found that propionic acid inhibits the synthesis of fatty acids and cholesterol in the liver, butyric acid inhibits the synthesis of hepatic cholesterol, and the demand for cholesterol by the liver allows the transfer of blood cholesterol to the liver thereby reducing blood cholesterol concentrations.

Mechanisms linking the anti-atherosclerotic activity of short-chain fatty acids (SCFAs) and cholesterol transport and synthesis in the intestine and liver (Vourakis et al., 2021)

Creative Proteomics has extensive experience in SCFAs analysis. Based on GC-FID and GC-MS platform, we can help our customers with lipidomics analysis and facilitate basic research.

References

1. Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020). The role of short-chain fatty acids from gut microbiota in gut-brain communication. Frontiers in endocrinology, 11, 25.
2. Gutiérrez-Cuevas, J., Sandoval-Rodriguez, A., Meza-Rios, A., Monroy-Ramírez, H. C., Galicia-Moreno, M., García-Bañuelos, J., ... & Armendariz-Borunda, J. (2021). Molecular mechanisms of obesity-linked cardiac dysfunction: an up-date on current knowledge. Cells, 10(3), 629.
3. Lau, W. L., & Vaziri, N. D. (2019). Gut microbial short-chain fatty acids and the risk of diabetes. Nature Reviews Nephrology, 15(7), 389-390.
4. Vourakis, M., Mayer, G., & Rousseau, G. (2021). The role of gut microbiota on cholesterol metabolism in atherosclerosis. International Journal of Molecular Sciences, 22(15), 8074.