Short Chain Fatty Acids: Deceptively Simple

Short chain fatty acids (SCFA) are deceptively simple. There are six of them that are routinely studied (acetate, propionate, butyrate, isovalerate, valerate, and isobutyrate), because they are cheap and relatively straightforward to analyze. Their simplicity belies a much more complex story that is often overlooked. There are many review papers on the subject1–3, but we felt an abridged version was needed to impress the complexity of the system in which SFCA are produced and utilized by the body and its various tissues.

What is a short chain fatty acid?

SCFA are organic acids with fewer than 6 carbons, typically known for their role as products of intestinal fermentation. There are many, but most research has focused on the "big three": acetate, propionate, and butyrate. In addition to these SCFA, other commonly investigated SCFA include isovalerate, valerate, and isobutyrate. Sometimes these three are referred to as “branched chain fatty acids,” even though valerate isn’t actually branched. Whether they are linear or branched, they’re still all “short” (< 6 carbons), so we refer to them as SCFA in this article.

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Where are short chain fatty acids produced?

SCFA are perhaps most well known as metabolites produced primarily from bacterial fermentation of nondigestible fibers in the colon. There is special scientific interest in the effects of fibers, probiotics, and other modulators of the intestinal microbiota on the production of these volatile compounds. While the concentration of SCFA are relatively high in the colon (typically greatest in the cecum and lowest towards the distal end and in feces)4, they can be found in a variety of organs as well. Bones, adipocytes, plasma, and even the brain contain some SCFA2.

What do short chain fatty acids do?
  • Lower the pH of the luminal contents of the colon3
  • Feed colonocytes5
  • Inhibit histone deacetylases1, allowing DNA to be transcribed
  • Promote barrier stability in the intestine and the brain6,7
  • Feed other bacteria8
  • Stimulate fatty acid oxidation (for use as energy), inhibit lipolysis, and inhibit de novo synthesis (fat formation)3

Based on this list, it seems that SCFA have very positive effects in the body. If a person consumes fiber, their gut bacteria ferment that fiber, produce SCFA, and the presence of SCFA in the colon increase, leading to health benefits, right? Like all biology, understanding the contribution of SCFA to health is much less straightforward.

Polydextrose: A case study

Polydextrose is a highly branched glucose polymer that is gradually and partially fermented, with about ~60% excreted in feces9. This means that rather than being rapidly and completely fermented upon entry to the colon as some fibers are, there is sustained fermentation and SCFA production throughout its transit.

A review by do Carmo et al.,9 details the potential of polydextrose consumption to exhibit multiple health benefits, including improving mineral absorption of calcium, altering gut microbial composition, improving blood glucose and lipid metabolism, and reducing fecal transit time, among others. But the residual, multi-million dollar research question is how? A common explanation is that the increased production of SCFA in the GI tract resulting from bacterial utilization of fiber, and the subsequent absorption and transit of SCFA to distant tissues via the bloodstream, allows SCFA to exert modulatory effects on gene expression and certain cell receptors (e.g. G-protein coupled receptors). Although this represents a plausible mechanism, the direct link between fiber consumption, increased SCFA production, cellular action, and beneficial health outcomes has not been established.

This lack of direct evidence is reflected in the opinions of the European Food and Safety Administration10, who found insufficient evidence that changes in SCFA could be considered beneficial effects for a number of fermentable fibers, including polydextrose. Furthermore, they concluded that the mechanism of the bulking effect for polydextrose could not be attributed to alterations in bacterial mass or SCFA production11.

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Figure 2. The concentration of short chain fatty acids in in vitro, animal, and human models varies. There is not clear agreement on whether SCFA in the colon should increase or decrease in response to fermentation of polydextrose. Superscripts indicate reference number. PDX, polydextrose.

The role of fermentative metabolites in human health remains elusive. Indeed, a recent review by Röytiö & Ouwehand12 highlights the inconsistencies in this data. As seen in Figure 2, the authors show that across in vitro, preclinical, and clinical studies, there was no consistent pattern of increased SCFA production in the colon with polydextrose consumption. For in vitro studies, fermentation of polydextrose typically lead to increased production of SCFA, but that was relative to the controls and other oligosaccharides investigated13-15. But preclinical and clinical data paint a different story. Polydextrose consumption reduced colonic SCFA in pigs16, and human data suggested either no effect or decreased fecal SCFA17-19. In a more consistent fashion, the branched chain fatty acids, which are generally considered proteolytic metabolites, repeatedly decreased across studies12.

How should these results be interpreted? In this case of mixed evidence, SCFA feel less like of a useful biomarker and more like a complex mechanism requiring extensive (and expensive) research.

A snapshot in time

Samples of colonic contents are mere snapshots in time. Though we are able to estimate rates of fermentation and production of SCFA in vitro, it’s exceedingly difficult to measure in vivo production. den Besten describes how this has been successfully (and unsuccessfully) accomplished using radio-labelled and C-labelled SCFA3. But these tools are not accessible to many researchers. Thus, many are left with static measures of SCFA in colonic samples, which simply reflect the summation of input and output through the large intestine. The concentration may increase or decrease relative to another experimental group, but static concentrations do not reflect the flux of SCFA that occur with changes in production and absorption by the host, or as a result of cross-feeding other microbes. This does not suggest that SCFA are useless biomarkers. But it does suggest that fiber products would be better positioned if they could clearly elucidate direct health benefits to the host. Indeed, the United States Food and Drug Administration20 requires that fibers that are isolated or synthetically produced demonstrate at least one of the following health benefits:

  • decrease of blood glucose, insulin, or pressure
  • decrease in fasting cholesterol
  • improved laxation
  • incrased mineral absorption
  • increased satiety

Perhaps SCFA are best thought of as supporting evidence towards health benefits, rather than the benefit themselves. They provide a mechanistic link and as such, are certainly a worthwhile addition to any research program supporting the health benefits of a fiber product.

About the author: Stephen Fleming is President and Co-founder of Traverse Science. He believes science doesn’t have to be hard and should accelerate business, not slow it down. He has a background in neuroscience and nutrition from the University of Illinois at Urbana-Champaign where he studied oligosaccharide intake and brain development for his PhD. If you want to learn more, follow him and Traverse Science on LinkedIn, and connect with us at engage@traversescience.com.

About the company: Traverse Science is a nutrition consulting firm working with ingredient suppliers and consumer packaged goods companies in the human and animal nutrition space. We work with clients to get science done, whether that means organizing and conducting a study, analyzing new or long-forgotten data, or writing a manuscript for peer review or guidance document for internal use. As teams change, time runs short, or projects pivot, we provide the muscle and the know-how to finish your nutrition science and get your projects out the door – whatever that means for you. We believe that science doesn’t have to be hard, and we’re here to make it easy.

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