The Role Of Short-Chain Fatty Acids

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 fermentation of dietary fibers by the gut microbiota. Dietary fibers are carbohydrates that are not digestible by human cells and gets passed to the bacteria in the cecum and large intestine. Recently there has been an increasing number of studies showing that SCFAs can affect the 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.

SCFAs are saturated aliphatic organic acids that consist of one to six carbons. Among them, acetate, propionate, and butyrate [Image are the most abundant (>95%) molecules5. 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. 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 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, has been observed to be responsible for the major fraction of butyrate production[8].

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 and the butyrate-producing bacteria almost completely disappear while the acetate- and propionate-producing bacteroides-related bacteria become dominant.

SCFAs produced by the gut microbiota can be found in 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 regulation of lipid and glucose metabolism. For example, SCFA activates the process of breaking down fatty acid, while inhibiting its 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].

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 cells24, 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 signalling. Increasing body of evidence supports a 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 microbiome and host. Such information can lead to new strategies to manipulate the microbiota in a predictable way to have a clinically beneficial effect.

Disclaimer: The above article is sponsored by Thyrve, the world’s first Gut Health Program that incorporates microbiome testing and personalized probiotics to ensure a healthier gut, happier life, and a brighter future. 

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