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is your body enhanced for short-chain fatty acid production?

The Role Of Short-Chain Fatty Acids

Michael Lathrop 3 min reading

By Jun Kim Ph.D.

One of the most frequently mentioned groups of molecules in the gut microbiome studies is probably short-chain fatty acids (SCFAs). SCFAs are a group of molecules that result from the fermentation of dietary fibers by the gut microbiota. Dietary fibers are carbohydrates that are not digestible by human cells and get passed to the bacteria in the cecum and large intestine. Recently there has been an increasing number of studies showing that SCFAs can affect metabolic syndrome, bowel disorders, cancer, ulcerative colitis, Crohn’s disease, and antibiotic-associated diarrhea 1–4. This article will discuss some of the established molecular mechanisms behind how SCFAs affect the human body.

What are Short-Chain Fatty Acids?

SCFAs are saturated aliphatic organic acids that consist of one to six carbons. Among them, acetate, propionate, and butyrate are the most abundant (>95%) molecules 5. 

Genomic studies have identified the major groups of bacteria that produce SCFAs. While acetate production is shared broadly among different groups, propionate, butyrate, and lactate production are more conserved by specific groups and substrates. 

Which Bacteria Produce SCFAs?

Akkermansia municiphilla have been identified as a major producer of propionate 6. Deoxy-sugars such as fucose and rhamnose are substrates particularly for propionate because of the metabolic pathways involved. Synthesis of butyrate is especially affected by the fermentation of starch, and this process of dominated by Ruminococcus bromii 7. 

Interestingly, only a small number of groups that consists of Faecalibacterium prausnitzii, Eubacterium rectale, Eubacterium hallii, and Ruminococcus bromii, have been observed to be responsible for the major fraction of butyrate production8.

How Do SCFAs Influence the Gut Microbiome?

SCFAs affect the microbial community and the host in many ways. SCFAs are required for chemical balance in the anaerobic environment of the gut 9. Most SCFAs are absorbed by the host in exchange for bicarbonate (base), and therefore, the luminal pH is significantly affected by the microbial SCFA production and the neutralizing capacity of bicarbonate. 

As the concentration of SCFAs decline from the proximal to the distal colon, the pH increases from the cecum to rectum 10. The lower pH in the ileum to the cecum is important because it affects the gut microbiota composition. For example, lower pH prevents overgrowth of pH-sensitive pathogenic bacteria such as Enterobacteriaceae and Clostridia11– 13. 

At pH 5.5, the butyrate-producing bacteria such as Roseburia spp. and Faecalibacterium prausnitzii, both belonging to the Firmicutes phylum, comprised 20% of the total population 14. 

When fermentable dietary fibers become more limiting in the more distal parts of the large intestine, the pH increases to 6.5. This uptick causes butyrate-producing bacteria to almost completely disappear. Meanwhile, the acetate- and propionate-producing Bacteroides-related bacteria become dominant.

Benefits of SCFAs for Metabolism

SCFAs produced by the gut microbiota can be found in the blood throughout the body and affect lipid, glucose, and cholesterol metabolism. A major portion of the SCFAs is used as an energy source. 

In humans, SCFAs provide ~10% of the daily caloric requirements 15. Up to 70% of the acetate is taken up by the liver, where it is used as a substrate for other essential molecules such as cholesterol, long-chain fatty acids, glutamine, and glutamate 16. The liver also takes up propionate, where it is involved in the synthesis of glucose 17. 

SCFA concentrations are sensed by some G protein-coupled receptors (GPCRs) that are involved in the regulation of lipid and glucose metabolism. 

For example, SCFA activates the process of breaking down fatty acid while inhibiting their synthesis. A known mechanism involves AMP-activated protein kinase (AMPK) pathway and leptin up-regulation. Overall this reduces the amount of fatty acid and leads to a decrease in body weight 18–21. Through the related pathways, SCFA also affects glucose metabolism 22, 23.

SCFAs and the Immune System

How SCFA affects the immune system is an exciting new area of research. It has been shown that butyrate can regulate immune and inflammatory response by modulating nuclear factor-kappa β (NF-кB) activation and histone deacetylation in immune cells 24, 25. 

Moreover, recent studies have shown a potential role of propionate and butyrate in the activation of regulatory T cells (as discussed here, regulatory T cells are a type of immune cells that can suppress immune responses) 26, 27. 

SCFA reduces inflammatory response against commensal bacteria, and therapeutic effects have been shown in inflammatory bowel disease and radiation proctitis 28, 29. A reduced number of butyrate-producing groups have been observed in type-2 diabetes 30.

SCFA represents a key molecular link between the gut microbiome and the host. It has been shown to be actively involved in the regulation of host metabolism and cell signaling. 

An increasing body of evidence supports the crucial role of SCFA in shaping the immune system. Prebiotics and probiotics have shown wide-ranging benefits, but understanding the function of molecules produced by microbiota is needed to identify the important signals between the microbiome and host. Such information can lead to new strategies to manipulate the microbiota in a predictable way to have a clinically beneficial effect.

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Resources

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