SCFA are one of the most studied examples of bacterial metabolites. Metabolites are compounds that form as a result of chemical changes in bacterial cells. SCFA are described as a link between what we eat and what happens in the large intestine. However, in this area it is easy to confuse an observation from a cell culture with a conclusion about humans.
Read more: What bacterial metabolites are and where they come from in fermentation
What short-chain fatty acids are
SCFA stands for short-chain fatty acids. These are fatty acids with a chain of two to six carbon atoms. For comparison, fatty acids in vegetable oil usually have sixteen to eighteen carbon atoms.
In the human digestive tract, they form mainly in the large intestine, when bacteria ferment food without oxygen. The substrate, which means the starting material, is made of food components that were not digested in the upper part of the digestive tract.
Read more: Gut microbiota – how it develops and what shapes it throughout life
Three compounds are described most often: acetate, propionate and butyrate. Measurements on human material show that they make up most of the SCFA in the large intestine. Their approximate molar ratio is 60:20:20, but these values differ between people and between parts of the intestine.
The three described most often: acetate, propionate, butyrate
| Compound | Share of SCFA in the large intestine | Main path of further changes described in the literature |
|---|---|---|
| Acetate | About 60 per cent of the total | Absorbed into the blood; also found in the general circulation |
| Propionate | About 20 per cent of the total | Largely taken up by the liver |
| Butyrate | About 20 per cent of the total | Used locally by the cells of the lining of the large intestine |
Acetate
Acetate, the anion of acetic acid, is the most common SCFA in the large intestine. A wide group of bacteria produces it, so the production of this compound is not linked to a small set of species.
Of the three compounds, acetate passes into the bloodstream the most. That is why it appears in studies on metabolism outside the gut itself. Some of these observations come from animal models and some from measurements in people. Conclusions about cause and effect in these studies remain careful.
Propionate
Propionate forms through several metabolic pathways, which are different in different groups of bacteria. Scientists have described these pathways and linked them to specific groups of microorganisms. This is one of the better documented parts of the picture.
A large part of propionate is taken up and processed by the liver. Its effect on the processes there was studied mainly in animal models and in vitro, which means on cell cultures outside the body. There are fewer data from studies with people, and they usually come from small groups (Louis and Flint, 2017).
Butyrate
A smaller group of bacteria produces butyrate than acetate. Unlike the other two compounds, butyrate is mostly used on the spot by the cells of the lining of the large intestine. These cells are called colonocytes.
Because of this, it is the most studied of the three compounds in the context of the gut itself. Most observations about how it acts on the cells of the gut lining come from in vitro studies and animal models. To apply these results to humans, separate clinical studies are necessary.
Where they come from in the gut
The starting point is material that was not digested in the stomach or the small intestine. This is mainly dietary fibre and resistant starch, and to a smaller degree proteins and peptides.
Read more: Dietary fibre – how much we really eat and how much institutions recommend
Bacteria in the large intestine break down this material by fermentation, which is a way to get energy without oxygen. SCFA are a product of these changes, and the bacteria release them into the inside of the gut. Gases also form in this process.
The amount and ratio of SCFA depend on three things: the type of substrate, the make-up of the microbiota and the time food needs to pass through the intestine. So measurements in different people give different results, even with a similar diet.
Why SCFA are studied so much
The first reason is that they can be measured. SCFA can be measured in stool, gut contents and blood using chromatography. This gives a clear number.
The second reason is their position in a chain of connections. They link what reaches the large intestine with the make-up of the microbiota and with the processes in the host’s body.
The third reason is a wider interest in bacterial metabolites as research material. You can see this in the definition of a postbiotic that ISAPP published in 2021. It covers preparations of inanimate microorganisms or their components.
Read more: Postbiotics – what they are and how they differ from probiotics and prebiotics
What we know and what we do not know
The biochemical basics are relatively well documented: the pathways in which SCFA form, the groups of bacteria that produce them and the approximate ratio of these compounds in the human large intestine. These findings are based on measurements on human material and on studies of bacterial cultures.
Conclusions about effects are less certain. Most observations about how SCFA act on cells and tissues come from in vitro studies and animal models. Results from such studies are preliminary. They are not a basis for statements about effects in humans.
There is also a formal issue. The list of claims permitted by Regulation (EU) No 432/2012 has no claims about SCFA. So communication about food and supplements cannot say that SCFA have a health effect.
Limits of current research
This part is important, because without it the picture would be incomplete. The main problems with research methods described in the literature are:
- Indirect measurement. Most studies measure the concentration of SCFA in stool. It shows the difference between production and absorption, not production alone. So a lower result can mean lower production or better absorption.
- Most data come from models. A large part of the data about mechanisms comes from cell cultures and animal studies. The body and the microbiota of animals are different from those of humans.
- Correlation, not cause. Many observational studies with people show that certain SCFA levels appear together with other measurements. This does not show which one affects the other.
- Differences between people. The make-up of the microbiota and how fast food passes through the gut differ between people. So the same change in diet gives different results in different people.
- Different methods. The way samples are collected and stored, and the method used to measure them, affect the result. This makes it hard to compare publications.
What affects the amount of SCFA that forms in the gut
The best documented factor is the supply of substrate that can ferment, which means fibre and resistant starch. Studies with people have shown that a change in the amount and type of fibre in the diet changes the SCFA levels in stool. However, the size of the change differs between participants.
The second factor is the make-up of the microbiota. Not all bacteria produce the same compounds, so the presence of certain groups affects the ratio of SCFA.
The third factor is how long food takes to pass through the gut. If the contents pass through the large intestine faster, there is less time for fermentation. This also affects the measured result.
Summary
Short-chain fatty acids are the best known example of metabolites of the gut microbiota. We know what they are, in which pathways they form and in what approximate ratio they occur in the human large intestine.
However, knowledge about how they act on the body is largely based on in vitro studies and animal models. Studies with people are most often observational. Keep this difference in mind, because an observation from a cell culture and a conclusion about humans are two different kinds of findings.
FAQ
Can you measure your own SCFA level?
Research laboratories and some commercial laboratories measure SCFA in stool. However, the result is hard to interpret, because the level in stool shows the difference between production and absorption. There are also no widely accepted reference ranges for a single person.
Can you take SCFA directly?
These compounds are available as laboratory chemicals and additives, and butyrate is sometimes used in products of different forms. Studies on taking them by mouth were done in vitro and on animal models. There are fewer studies with people, and they use different methods. Communication about food supplements must follow the limits of Regulation (EU) No 432/2012.
Does all fibre produce the same amount of SCFA?
No. Different types of fibre ferment to different degrees and at different speeds, and some types, for example cellulose, ferment poorly. The make-up of the microbiota also matters, so the same product gives different results in different people.
Sources
- Koh A., De Vadder F., Kovatcheva-Datchary P., Bäckhed F., From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites, Cell, 2016, vol. 165, no. 6, pp. 1332-1345.
- Cummings J.H., Pomare E.W., Branch W.J. et al., Short chain fatty acids in human large intestine, portal, hepatic and venous blood, Gut, 1987, vol. 28, no. 10, pp. 1221-1227.
- Gibson G.R., Hutkins R., Sanders M.E. et al., Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics, Nature Reviews Gastroenterology & Hepatology, 2017, vol. 14, no. 8, pp. 491-502.
- Salminen S., Collado M.C., Endo A. et al., The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics, Nature Reviews Gastroenterology & Hepatology, 2021, vol. 18, no. 9, pp. 649-667.
- Louis P., Flint H.J., Formation of propionate and butyrate by the human colonic microbiota, Environmental Microbiology, 2017, vol. 19, no. 1, pp. 29-41.
- Commission Regulation (EU) No 432/2012 of 16 May 2012 establishing a list of permitted health claims made on foods, other than those referring to the reduction of disease risk and to children’s development and health.