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Short chain fatty acids (SCFAs) - Friend or foe?

Gut microbiota ferment indigestible dietary fiber to generate SCFAs, mainly acetate, propionate and butyrate. Due to their anti-inflammatory properties, short-chain fatty acids may have a wide range of beneficial effects on your body including chronic diseases like neurodegenerative conditions, obesity, diabetes, immunological conditions, and intestinal disorders. Thus, looking after your friendly gut bacteria can be a good investment.

Author
Christian A. Drevon – Vitas Analytical Services
Christian A. Drevon Consultant

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).

Table 1. SCFA containing 1-5 carbon atoms (Bongiovanni et al. Int J Sports Med 2021, 42, 1143-58) – Vitas Analytical Services
Table 1. SCFA containing 1-5 carbon atoms (Bongiovanni et al. Int J Sports Med 2021, 42, 1143-58)

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.

Figure 1. Biosynthesis of SCFAs via carbohydrate fermentation and bacterial cross-feeding. Bacterial conversion of dietary fiber in the gut à synthesis of acetate, butyrate, and propionate. Acetate from pyruvate via acetyl-CoA and also via the Wood-Ljungdahl pathway. Butyrate is produced from 2 molecules of acetyl-CoA, yielding acetoacetyl-CoA, which is converted to butyryl-CoA via β-hydroxybutyryl-CoA and crotonyl-CoA. Propionate can be formed from phosphoenolpyruvate through the succinate pathway or the acrylate pathway, in which lactate is reduced to propionate. Gut microbes can also produce propionate through the propanediol pathway from fucose and rhamnose (Bongiovanni et al. Int J Sports Med 2021, 42, 1143–58). – Vitas Analytical Services
Figure 1. Biosynthesis of SCFAs via carbohydrate fermentation and bacterial cross-feeding. Bacterial conversion of dietary fiber in the gut à synthesis of acetate, butyrate, and propionate. Acetate from pyruvate via acetyl-CoA and also via the Wood-Ljungdahl pathway. Butyrate is produced from 2 molecules of acetyl-CoA, yielding acetoacetyl-CoA, which is converted to butyryl-CoA via β-hydroxybutyryl-CoA and crotonyl-CoA. Propionate can be formed from phosphoenolpyruvate through the succinate pathway or the acrylate pathway, in which lactate is reduced to propionate. Gut microbes can also produce propionate through the propanediol pathway from fucose and rhamnose (Bongiovanni et al. Int J Sports Med 2021, 42, 1143–58).

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).

Figure 2. SCFAs molar ratio (R) and concentration from suddenly dead and/or patients undergoing surgery. Acetate is the most abundant SCFA in the large intestine, portal vein, hepatic vein, and peripheral blood. If 1 kg of luminal matter is equivalent to 1 L, the drop in concentration from the colon to the portal vein indicates that ~ 99.5% of the SCFAs is used by the gut mucosa. The drop in concentrations between the portal and hepatic veins indicates that the remaining propionate and butyrate may be extracted by the liver; less for acetate (Blaak et al. Benef Microbes 2020). – Vitas Analytical Services
Figure 2. SCFAs molar ratio (R) and concentration from suddenly dead and/or patients undergoing surgery. Acetate is the most abundant SCFA in the large intestine, portal vein, hepatic vein, and peripheral blood. If 1 kg of luminal matter is equivalent to 1 L, the drop in concentration from the colon to the portal vein indicates that ~ 99.5% of the SCFAs is used by the gut mucosa. The drop in concentrations between the portal and hepatic veins indicates that the remaining propionate and butyrate may be extracted by the liver; less for acetate (Blaak et al. Benef Microbes 2020).

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.

Intestinal effects

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.

Immunological effects

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).

 

Figure 3. Luminal acetate and propionate sensed by GPR41/43 release peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), affect satiety and intestinal transit. Propionate can be converted to glucose by intestinal gluconeogenesis (IGN) and promote satiety and reduced hepatic glucose formation. Luminal butyrate is anti-inflammatory via GPR109A and inhibits histone deacetylases. SCFAs can act on the enteric nervous system (ENS) by stimulating motility or immune cells sensed by GPR41/43 and reduce inflammation. Blood SCFA can activate G-coupled Rs in the lungs, pancreas, adipose tissue, bone marrow, brain, liver, and muscles (Bongiovanni et al. Int J Sports Med 2021). – Vitas Analytical Services
Figure 3. Luminal acetate and propionate sensed by GPR41/43 release peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), affect satiety and intestinal transit. Propionate can be converted to glucose by intestinal gluconeogenesis (IGN) and promote satiety and reduced hepatic glucose formation. Luminal butyrate is anti-inflammatory via GPR109A and inhibits histone deacetylases. SCFAs can act on the enteric nervous system (ENS) by stimulating motility or immune cells sensed by GPR41/43 and reduce inflammation. Blood SCFA can activate G-coupled Rs in the lungs, pancreas, adipose tissue, bone marrow, brain, liver, and muscles (Bongiovanni et al. Int J Sports Med 2021).

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.

Conclusions

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!

References

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·         Bergman EN. Energy contributions of volatile fatty-acids from the gastrointestinal-tract in various species. Physiol Rev 1990, 70, 567-90

·         Blaak et al. Short chain fatty acids in human gut and metabolic health. Benef Microbes 2020, 11, 411–55 doi:10.3920/BM2020.005

·         Bongiovanni et al. The athlete and gut microbiome: short-chain fatty acids as potential ergogenic aids for exercise and training. Int J Sports Med 2021, 42, 1143–58 DOI 10.1055/a-1524-2095

·         Gupta et al. SLC5A8(SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci 2006, 78, 2419-25

·         Koh et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabo- lites. Cell 2016, 165, 1332-45. doi:10.1016/j.cell.2016.05.041

·         Olsson et al. Serum short-chain fatty acids and associations with inflammation in newly diagnosed patients with multiple sclerosis and healthy controls. Front Immunol 2021 https://doi.org/10.3389/fimmu.2021.661493

·         Schauber et al. Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology 2006, 118, 509-19. https://doi.org/10.1111/j.1365- 2567.2006.02399.x  

·         Silva et al. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front Endocrinol 2020, 11, 25. https://doi.org/10.3389/fendo.2020.00025

·         Soty et al. Gut-brain glucose signaling in energy homeostasis. Cell Metabol 2017, 25, 1231-42 https://doi.org/10.1016/j.cmet.2017.04.032   

·         Takagi et al. A single-batch fermentation system to simulate human colonic microbiota for high-throughput evaluation of prebiotics. PLoS One 2016, 11, e0160533. doi:10.1371/ journal.pone.0160533

·         Teramae et al. The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract. Biomed Res 2010, 31, 239-49 https://doi.org/10.2220/biomedres.31.239  

·         Trend et al. Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis. Sci Rep 2021, 11, 5244 https://doi.org/10.1038/s41598-021-84881-8

·         Trompette et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014, 20159-66 https://doi.org/10.1038/nm.3444

·         Tsukahara et al. High-sensitivity detection of short-chain fatty acids in porcine ileal, cecal, portal and abdominal blood by gas chromatography-mass spectrometry. Anim Sci J 2014, 85, 494-8 doi: 10.1111/asj.12188

·         Yamamura et al. Associations of gut microbiota, dietary intake, and serum short-chain fatty acids with fecal short-chain fatty acids. Biosci Microbiota Food Health 2021, 39, 11-7 https://doi.org/10.12938/bmfh.19-010