What are SCFAs?
SCFAs are small volatile aliphatic carboxylic acids containing one to five carbon atoms as given in Table 1. Acetate, propionate, and butyrate are the most common SCFAs in the human body (> 90%) and are found in the molar ratio of about 60:20:20 in the colon and feces (Takagi et al. PLoS One 2016). The concentration of SCFAs varies throughout the human intestine, with high levels in cecum, moderate levels in descending colon, and low concentrations in the terminal ileum (Koh et al. Cell 2016; Blaak et al. Benef Microbes 2020).
Production of SCFAs in the body
Gut microbiota are responsible for of the production of SCFAs and depends on dietary macronutrient composition including intake of fiber, composition of anaerobic microbes, and host properties. The biosynthesis of SCFAs is outlined in Figure 1.
Once synthesized in the intestine the SCFAs are transported into the blood by three types of transporters:
1) SCFA-bicarbonate co-transporter
2) Monocarboxylate transporters (MCT)1-4; transport also lactate and pyruvate
3) Sodium-dependent monocarboxylate transporter (SMCT, SLC5A8). SMCT1 prefers butyrate but transports also propionate and acetate (Teramae et al. Biomed Res 2010; Gupta et al. Life Sci 2006).
Acetate is the dominant SCFA in blood and intestine. There is a massive concentration gradient between the intestinal lumen and blood. Apparently, intestinal uptake is slower than either colonocyte metabolism or removal from the blood suggesting that transporters of colonocytes may be rate-limiting for SCFA metabolism, especially for propionate and butyrate (Blaak et al. Benef Microbes 2020; Figure 2).
Biological effects of SCFAs
Many beneficial biological effects have been ascribed to SCFAs on organs like the intestine, liver, pancreas, lungs, adipose tissue, brain, bone, and immune cells. This area of science is relatively new, and much of the data and knowledge are derived from rodent studies. Also, the existence of thousands of microbial species in the intestine with different expression depending on many external and host characteristics, makes this field complicated and difficult to translate into human conditions.
The intestinal effects of SCFAs are related to tighter (less leaky) epithelium, thereby inhibiting leakage of bacterial products like lipopolysaccharides (LPS). Tight-junction proteins (such as occludins, claudins, and junctional adhesion molecules) affect gut permeability. Butyrate may have a protective effect on the epithelial barrier by increasing claudin-1 and maintaining the integrity of the gut barrier through the redistribution of occludin and zonula occludens-1 (ZO-1). Butyrate can also influence mucus production by stimulating special cells named Goblet cells in the intestinal mucosa, protecting against foreign and harmful substances (Blaak et al. Benef Microbes 2020). Intestinal epithelium may also respond to SCFAs be enhancing release of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), thereby reducing satiety and increasing pancreatic insulin release. Propionate can be converted to glucose via intestinal gluconeogenesis (IGN) promoting satiety and reduced hepatic glucose formation.
Many types of immune cells like macrophages, neutrophils, regulatory T cells, CD4+ and CD8+ T cells, dendritic cells, and innate lymphoid cells (ILCs), seem to be beneficially influenced by SCFAs, mostly via G protein-coupled receptors like GPR41 and GPR43. Butyrate is a potent inducer of the expression of the anti-microbial protein cathelicidin (Schauber et al. Immunology 2006). SCFAs in the gut lumen are transported across the epithelial barrier into the bloodstream and to other organs like the pancreas, where SCFAs may regulate insulin secretion. Dietary fermentable fibers changed the microbiota of the murine gut and lung, particularly by altering the ratio of Firmicutes to Bacteroidetes. Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic lung inflammation, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease (Trompette et al. Nat Med 2014).
Supplementation of mice with propionate altered bone marrow hematopoiesis by generation of macrophage and dendritic cell precursors (Trompette et al. Nat Med 2014).
Effects on the nervous system
SCFAs may affect the brain by regulating expression of the gene encoding tryptophan hydroxylase, a key enzyme of the serotonin biosynthesis. SCFAs may also promote formation of neurons and microglia, improve memory, reduce nerve inflammation, and enhance blood-brain barrier (Silva et al. Front Endocrinol 2020).
The central nervous system and enteric nervous system communicate via vagal and autonomic pathways to modulate brain function as well as gastrointestinal functions like satiety. SCFAs may affect mood and cognitive processes via alteration of blood concentrations of tryptophan, precursor for the signaling molecule 5-hydroxytryptamine (5-HT) (Silva et al. Front Endocrinol 2020; Soty et al. Cell Metabol 2017).
SCFA as an energy source
SCFAs are probably the most important energy sources for colonocytes (epithelial cells in colon) and may provide up to 8 % of daily energy (Bergman Physiol Rev 1990) with butyrate contributing the most (Blaak et al. Benef Microbes 2020). Some studies suggest that SCFAs may reduce lipolysis (mobilization of fatty acids) as well as insulin-mediated fat accumulation in adipose tissue and reduce accumulation of hepatic and skeletal muscle lipids (Bongiovanni et al. Int J Sports Med 2021). These effects may be beneficial for optimal body weight and perhaps type 2 diabetes. However, the extra 8 % of energy provided by SCFA absorption may represent surplus energy and thereby promote enhanced body weight (Silva et al. Front Endocrinol 2020).
Biomarkers for gut microbiota and human health
SCFA may be used as biomarkers of a healthy gut because high levels might indicate many beneficial factors related to health. Fecal SCFAs are good biomarkers of the gut microbiota ecosystem and dynamics of SCFAs in the human body (Yamamura et al. Biosci Microbiota Food Health 2021). Two studies on the relation between serum SCFAs and multiple sclerosis (MS) have been recently published. Trend et al. (Sci Rep 2021) showed that serum propionate levels of CIS (clinically isolated syndrome)/MS patients, were significantly lower than among healthy controls. Several CIS/MS patients also had butyrate and acetate levels below levels from healthy controls. Olsson et al. (Front Immunol 2021) observed that serum acetate levels were lower in MS patients than in controls.
SCFAs may be important for many chronic disorders like neurodegenerative conditions, obesity, diabetes, immunological conditions, and intestinal disorders because SCFAs in blood seem to be closely related to the gut microbiota. The rapid development in knowledge about the thousands of species of intestinal microbes has initiated the interest for SCFAs as products of fermentation with many beneficial biological effects. One way to get a better impression of the importance of SCFAs is to measure them in biological samples like feces, blood, and perhaps saliva (Tsukahara et al. Anim Sci J 2014).
Vitas has ample experience in measuring SCFAs in various sample types like blood, plasma, serum, saliva, eye tissue, brain tissue, milk, cecal content, stool, and dried blood spots (DBS) from several species like humans, mouse, rats, and turkeys. Contact us if you need this type of biomarker analysis. Remember, we can do almost anything when it comes to analysis! Dont be afraid to ask!
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