A great deal of my lab research in some way involves short-chain fatty acids (SCFAs). And to be honest, the more we learn about SCFAs, the more it seems we don’t know! It’s increasingly evident that these bacterial metabolites play intricate but nuanced roles in host physiology. In this article series, I’ll talk about the potential benefits and detriments of SCFAs:
- A brief introduction to SCFAs
- The benefits of butyrate
- Decrypting the butyrate paradox: can excess butyrate be toxic?
- Does acetate make you fat? The skinny on acetate and metabolic syndrome
- The propionate-autism connection
In this first article, I’ll introduce what SCFAs are, where they go in the body, and the far-ranging effects they can have on physiology.
What are SCFAs?
SCFAs are a subset of fatty acids that contain 6 or less carbon molecules. They include acetate (C2), propionate (C3), butyrate (C4), pentanoic acid (C5), and hexanoic acid (C6). Recent scientific advances have mostly focused on C2, C3, and C4, so these three will be the primary focus of this article series. You can see their chemical structures below:
The mammalian digestive tract can’t metabolize certain fibers. Instead, dietary fibers like inulin, fructooligosaccharides, and resistant starch are readily fermented by microbes in the gut. SCFAs are a major product of this fermentation.
The highest levels of SCFAs are found in the colon. The ratio of acetate : propionate : butyrate is approximately 3 : 1 : 1, though proportions will vary depending on the diet, microbiota composition, and health status.1
Where do they go?
Short-chain fatty acids are either used locally by gut epithelial cells or transported across the gut epithelium into the portal vein. Butyrate is primarily used by colonic epithelial cells as an energy source, while propionate and acetate are primarily transported to the liver via the portal vein. Propionate is rapidly metabolized by hepatocytes (liver cells). Acetate can remain in the liver or be released to peripheral circulation.2
Signaling molecules and HDAC inhibitors
Short-chain fatty acids are potent signaling molecules, binding to specialized G-protein coupled receptors (GPCRs) and ultimately changing the biochemistry of cells and tissues. These receptors can be found on immune cells, nerve cells, thyroid, kidney, pancreas, spleen, liver, and other tissues.
They are also potent modifiers of gene expression, influencing the epigenetics of various cell types. Butyrate, in particular, is a potent inhibitor of histone deacetylases, enzymes that are responsible for determining how tightly coiled DNA is and therefore how much it is transcribed into RNA.
SCFAs exert wide-ranging effects
Through these mechanisms, SCFAs are able to exert wide ranging effects on host physiology. SCFAs dictate colonic motility, blood flow, and gastrointestinal pH, which can greatly influence the uptake and absorption of electrolytes and other nutrients.1 They are also important promoters of colonic health and intestinal barrier integrity, and play a major role in the maintenance of normal gut and immune function.
SCFAs have also been shown to influence the nervous system and the brain. Butyrate has been shown to regulate the activity of microglia, the immune cells of the brain3, while propionate has been hypothesized to be implicated in the development and progression of autism spectrum disorders,4 a topic I will cover in detail in part 5 of this series.
The production of SCFAs may also play a significant role in shaping gut microbial ecology. SCFAs exhibit broad-spectrum antimicrobial activity at low concentrations.5 Intriguingly, SCFAs are relatively inert antimicrobials towards the species of bacteria that produce them, but have quite potent antimicrobial activity toward other microbes.6
So, are SCFAs always good? Not necessarily. The overall effects of SFCAs on host health is widely debated. For example, despite stimulating satiety signaling, SCFAs have also been implicated in increased energy harvest from the diet.7 SCFAs may also be toxic in high concentrations or in particular disease conditions, a topic I will discuss extensively in part 3, part 4, and part 5 of this series.
Could altered SCFA levels be the cause of disease?
SCFAs may influence the pathogenesis of a wide range of diseases, including allergies, asthma, cancer, obesity, metabolic disease, autoimmune disease, and neurological diseases. Consider the following:
- Patients with IBD tend to have a lower representation of SCFA producers8 and lower fecal SCFAs9
- Type I diabetes patients have lower abundance of butyrate-producing bacteria10
- Fecal microbiota of patients with rheumatoid arthritis showed lower abundance of SCFA-producing Bifidobacteria and Bacteroidetes11
- Allergic children tend to have lower fecal SCFA compared to nonallergic children12
- SCFA receptor knockout mice have exacerbated development of allergic airway inflammation13
Ongoing research is still trying to determine the mechanism behind these associations. Fecal SCFA measurements have some major limitations (stay tuned for part 6), and whether altered SCFA levels are a cause or consequence of these diseases remains unknown. What is clear is that a better understanding of SCFAs is crucial to delineating the role of the gut and gut microbiota in chronic diseases.
Did you like this article? Stay tuned for more! In this 6 part series, I’ll cover the three most prevalent short-chain fatty acids and the intricate roles they play in human health. I’ll also discuss the benefits of butyrate, my reservations about butyrate supplementation, the role of acetate in metabolic syndrome, the propionate-autism connection, and current methods to measure SCFAs commonly used in clinical practice. Be sure to subscribe so you’ll be the first to know when a new article is released!
- Tazoe, H. et al. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 59 Suppl 2, 251–262 (2008).
- Pomare, E. W., Branch, W. J. & Cummings, J. H. Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J. Clin. Invest. 75, 1448–1454 (1985).
- Huuskonen, J., Suuronen, T., Nuutinen, T., Kyrylenko, S. & Salminen, A. Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br. J. Pharmacol. 141, 874–880 (2004).
- MacFabe, D. F. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb. Ecol. Health Dis. 23, (2012).
- Huang, C. B., Alimova, Y., Myers, T. M. & Ebersole, J. L. Short- and medium-chain fatty acids exhibit antimicrobial activity for oral microorganisms. Arch. Oral Biol. 56, 650–654 (2011).
- Alva-Murillo, N., Ochoa-Zarzosa, A. & López-Meza, J. E. Short chain fatty acids (propionic and hexanoic) decrease Staphylococcus aureus internalization into bovine mammary epithelial cells and modulate antimicrobial peptide expression. Vet. Microbiol. 155, 324–331 (2012).
- Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–131 (2006).
- Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl. Acad. Sci. U. S. A. 104, 13780–13785 (2007).
- Marchesi, J. R. et al. Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J. Proteome Res. 6, 546–551 (2007).
- Brown, C. T. et al. Gut Microbiome Metagenomics Analysis Suggests a Functional Model for the Development of Autoimmunity for Type 1 Diabetes. PLOS ONE 6, e25792 (2011).
- Vaahtovuo, J., Munukka, E., Korkeamäki, M., Luukkainen, R. & Toivanen, P. Fecal microbiota in early rheumatoid arthritis. J. Rheumatol. 35, 1500–1505 (2008).
- Böttcher, M. F., Nordin, E. K., Sandin, A., Midtvedt, T. & Björkstén, B. Microflora-associated characteristics in faeces from allergic and nonallergic infants. Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol. 30, 1590–1596 (2000).
- Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).