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), and 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.

To stay updated with our blog, subscribe below!
Image

Figure 1. The structures of 6 commonly measured SCFA in their anionic forms.

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.

Image

Figure 2. The concentration of short chain fatty acids in in vitro, animal, and human models varies. Comparisons to other oligosaccharides or xylitol refer to the in vitro studies. 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. 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 like less 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
  • increased 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.

Stephen Fleming 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.

References:
1. Stilling, R. M., van de Wouw, M., Clarke, G., Stanton, C., Dinan, T. G. & Cryan, J. F. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem. Int. 99, 110–132 (2016) doi:10.1016/j.neuint.2016.06.011.

2. 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 165, 1332–1345 (2016) doi:10.1016/j.cell.2016.05.041.

3. den Besten, G., van Eunen, K., Groen, A. K., Venema, K., Reijngoud, D. J. & Bakker, B. M. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54, 2325–2340 (2013) doi:10.1194/jlr.R036012.

4. Cummings, J. H., Pomare, E. W., Branch, H. W. J., Naylor, C. P. E. & MacFarlane, G. T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987) doi:10.1136/gut.28.10.1221.

5. Fitch, M. D. & Fleming, S. E. Metabolism of short-chain fatty acids by rat colonic mucosa in vivo. Am. J. Physiol. - Gastrointest. Liver Physiol. 277, (1999) doi:10.1152/ajpgi.1999.277.1.g31.

6. Zheng, L., Kelly, C. J., Battista, K. D., Schaefer, R., Lanis, J. M., Alexeev, E. E., Wang, R. X., Onyiah, J. C., Kominsky, D. J. & Colgan, S. P. Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor–Dependent Repression of Claudin-2. J. Immunol. 199, 2976–2984 (2017) doi:10.4049/jimmunol.1700105.

7. Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Toth, M., Korecka, A., Bakocevic, N., Ng, L. G., Kundu, P., Gulyas, B., Halldin, C., Hultenby, K., Nilsson, H., Hebert, H., Volpe, B. T., Diamond, B. & Pettersson, S. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158-263ra158 (2014) doi:10.1126/scitranslmed.3009759.

8. Ríos-Covián, D., Ruas-Madiedo, P., Margolles, A., Gueimonde, M., de los Reyes-Gavilán, C. G. & Salazar, N. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front. Microbiol. 7, (2016) doi:10.3389/fmicb.2016.00185.

9. do Carmo, M. M. R., Walker, J. C. L., Novello, D., Caselato, V. M., Sgarbieri, V. C., Ouwehand, A. C., Andreollo, N. A., Hiane, P. A. & dos Santos, E. F. Polydextrose: physiological function, and effects on health. Nutrients 8, 1–13 (2016) doi:10.3390/nu8090553.

10. EFSA Panel on Dietetic Products, N. and A. (NDA). Scientific Opinion on the substantiation of health claims related to polydextrose and changes in bowel function (ID 784), changes in short chain fatty acid (SCFA) production and/or pH in the gastro-intestinal tract (ID 784), decreasing potentially pathoge. EFSA J. 9, 1–18 (2011) doi:10.2903/j.efsa.2011.2256.

11. EFSA Panel on Dietetic Products, N. and A. (NDA). Polydextrose and maintenance of normal defecation: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006. EFSA J. 14, 1–12 (2016) doi:10.2903/j.efsa.2016.4480.

12. Röytiö, H. & Ouwehand, A. C. The fermentation of polydextrose in the large intestine and its beneficial effects. Benef. Microbes 5, 305–313 (2014) doi:10.3920/BM2013.0065.

13. Hernot, D. C., Boileau, T. W., Bauer, L. L., Middelbos, I. S., Murphy, M. R., Swanson, K. S. & Fahey, G. C. In Vitro Fermentation Profiles, Gas Production Rates, and Microbiota Modulation as Affected by Certain Fructans, Galactooligosaccharides, and Polydextrose. J. Agric. Food Chem. 57, 1354–1361 (2009) doi:10.1021/jf802484j.

14. Mäkeläinen, H. S., Mäkivuokko, H. A., Salminen, S. J., Rautonen, N. E. & Ouwehand, A. C. The effects of polydextrose and xylitol on microbial community and activity in a 4-stage colon simulator. J. Food Sci. 72, 153–159 (2007) doi:10.1111/j.1750-3841.2007.00350.x.

15. Probert, H. M., Apajalahti, J. H. A., Rautonen, N., Stowell, J. & Gibson, G. R. Polydextrose, lactitol, and fructo-oligosaccharide fermentation by colonic bacteria in a three-stage continuous culture system. Appl. Environ. Microbiol. 70, 4505–4511 (2004) doi:10.1128/AEM.70.8.4505-4511.2004.

16. Fava, F., Mäkivuokko, H., Siljander-Rasi, H., Putaala, H., Tiihonen, K., Stowell, J., Tuohy, K., Gibson, G. & Rautonen, N. Effect of polydextrose on intestinal microbes and immune functions in pigs. Br. J. Nutr. 98, 123–133 (2007) doi:10.1017/S0007114507691818.

17. Hengst, C., Ptok, S., Roessler, A., Fechner, A. & Jahreis, G. Effects of polydextrose supplementation on different faecal parameters in healthy volunteers. Int. J. Food Sci. Nutr. 60 Suppl 5, 96–105 (2009) doi:10.1080/09637480802526760.

18. Costabile, A., Fava, F., Röytiö, H., Forssten, S. D., Olli, K., Klievink, J., Rowland, I. R., Ouwehand, A. C., Rastall, R. a, Gibson, G. R. & Walton, G. E. Impact of polydextrose on the faecal microbiota: a double-blind, crossover, placebo-controlled feeding study in healthy human subjects. Br. J. Nutr. 108, 471–81 (2012) doi:10.1017/S0007114511005782.

19. Vester Boler, B. M., Rossoni Serao, M. C., Bauer, L. L., Staeger, M. A., Boileau, T. W., Swanson, K. S. & Fahey, G. C. Digestive physiological outcomes related to polydextrose and soluble maize fibre consumption by healthy adult men. Br. J. Nutr. 106, 1864–1871 (2011) doi:10.1017/S0007114511002388.

20. United States Food and Drug Administration. Scientific Evaluation of the Evidence on the Beneficial Physiological Effects of Isolated or Synthetic Non-digestible Carbohydrates Submitted as a Citizen Petition (21 CFR 10.30): Guidance for Industry. 1–16 (2018).

21. Bourassa, M. W., Alim, I., Bultman, S. J. & Ratan, R. R. Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health? Neurosci. Lett. 625, 56–63 (2016) doi:10.1016/j.neulet.2016.02.009.

Share this Post

Leave a Reply

Your email address will not be published.