Fecal Short Chain Fatty Acids

Short chain fatty acids (SCFAs) are organic acids produced by bacterial fermentation of dietary fibre and resistant starch. Enterocytes and especially colonocytes depend on bacterial production of short chain fatty acids as a primary energy pathway substrate.

Under healthy conditions, starch and polysaccharides are fully digested in the small intestine yielding glucose, then undergoes fermentation by specific colonic anaerobic bacteria leading to the release of SCFAs.

Insoluble fibres such as cellulose and lignin are highly fermentable and generate greater quantities of SCFA in the colon while soluble fibres have a rather low fermentability but increase fecal bulking and decrease colonic transit time. 

SCFAs are also produced by specific colonic anaerobic bacteria within the mucosal epithelial cells of the gut. Other substances formed as by-products of bacterial activity are short-chain fatty acids, vitamin K, biotin, vitamin B12, thiamine and riboflavin.

Physiological function of SCFAs

SCFAs are a subset of saturated fatty acids containing six or less carbon molecules that include in varying proportions of acetate, propionate, butyrate, pentanoic (valeric) acid, and hexanoic (caproic) acid. 

SCFAs have important functions in the gut:

• Regulate absorption of water, electrolytes, and nutrients in the gut
• Maintain intestinal barrier function
• Feed the colonocytes
• Salvage unabsorbed carbohydrates
• Maintain commensal bacterial diversity
• Act as an anti-inflammatory

Some SCFAs such as isobutyrate and isovalerate are produced to a lesser extent during the catabolism of branched chain amino acids valine, leucine, and isoleucine and intermediate of fermentation in the microbiota such as lactate or ethanol can also be metabolized into SCFAs.

The “n-” prefix for butyrate is needed because isobutyrate is also produced in small percentages.

The percentages of each principal SCFA gives a view of the overall commensal bacteria metabolic output. If percentage of acetates are elevated, the acetate-producing targets are expected to be high.

Bacterial Targets for SCFA production

The production of SCFAs is a highly complex and dynamic process.  Specific bacteria targets are known to have the capacity for significant SCFA production.

Butyrate increases with fermentation of starch and inulin-type fructans. Certain microbiome targets for butyrate synthesis passes metabolic hydrogen to beta-hydroxybutyrate, propionaldehyde or acetaldehyde to form butyric, propionic, or acetic acids. Well-balanced commensal growth can sustain butyrate and hydrogen formation.

Butyrate Producers: B. crossotus, A. colihominis, Clostridium spp., C. eutactus, B. uniformis, Anaerostipes butyraticus from the Clostridium cluster XIVa, Anaerostipes caccae from the Clostridium caccae group, Roseburia spp., Faecalibacterium prausnitzii

Acetate, the most abundant SCFA in the colon is produced primarily via is carbohydrate fermentation by enteric bacteria and directly from acetyl-CoA and taken up by the liver. Acetate is used as an energy source, and a substrate for cholesterol and long-chain fatty acids synthesis.

Acetate comes from acetogenic bacteria, which synthesize acetate from hydrogen and carbon dioxide or formic acid.

Acetate Producers: Prevotella spp. Odoribacter spp. A. colihominis Clostridium spp. C. eutactus Lactobacillus spp. Ruminococcus bromii Veillonella spp. Bifidobacterium spp. A. muciniphila

Proprionate increases with fermentation of bran, β-glucan, pectin, pulses, wheat dextrin, and pyrodextrins. Propionate, a minor energy source for the colonocytes, acts as an anti-inflammatory and as a precursor for gluconeogenesis in the liver, also inhibiting acetate incorporation into cholesterol.

Overgrowth of propionate-producing microbes may be associated with elevated propionate SCFA levels. As intestinal propionate is absorbed and enters hepatic fatty acid synthesis, long chain fatty acids are produced and exported with lipoproteins for oxidation or incorporation into cell membranes by extra-hepatic tissues.

Proprionate producers: P. vulgatus Prevotella spp. Odoribacter spp. Clostridium spp. Veillonella spp. Coprococcus eutactus, Ruminococcus spp., Akkermansia muciniphila

Metabolic role of SCFAs

Oxidation of sugars cleaved from dietary fibres occurs with release of NADH that is recycled to NAD+ by production of short chain fatty acids or molecular hydrogen, depending on the strain of the microbe.

A study measuring intestinal pH and short-chain fatty acids suggests that patients with IBS may have increased bacterial fermentation in the colon, but not the small intestine.

ATP-binding cassette (ABC) transporters in Bifidobacterium longum is crucial for the uptake and transport of substrates, such as fructose, required for acetate production. Firmicutes phyla may be an excellent scavenger of acetate through their ABC transporters and can uptake acetate to produce butyrate and propionate as fermentative by-products.

These phyla could exist in a delicate balance in the gut lumen whereby acetate from Bacteroidetes is used to produce butyrate and propionate by Firmicutes.

Management for optimal SCFA levels

Results are reported as total fecal SCFA concentration, with individual SCFASs expressed as a percentage. A suboptimal SCFA report is indicative of an imbalanced microbiome or diet.

A low fecal SCFA test result can be a consequence of low production or high absorption.

Low SCFA levels may be caused by:

• Diarrhea which can lead to decreased SCFA production
• Constipation which can be associated with increased SCFA absorption
• Inflammation seen as low SIgA, high Calprotectin
• Chronic antibiotic use
• Poor dietary Fibre
• Dysbiosis

A high fecal SCFA test result can be a consequence of high production or low absorption.

Therapeutic considerations for high SCFAs: Investigate SIBO, imbalance of commensal bacteria ( typically high), elevated steatocrit or Methanobrevibacter smithii.

Key butyrate producers are found in dietary fibres, some resistant starch, fructooligosaccharides (FOS), and beta glucan, guar gum and 2'-fucosyllactose (2'-FL).

Robustly growing Coprococcus spp. can utilize butyrate and produce acetate. This metabolic function is absent in the F. prausnitzii and Roseburia spp. targets that only produce butyrate from simple sugars. Elevation of F. prausnitzii and Roseburia spp. is likely to have low acetate with SCFA patterns dominated by butyrate.

Inulin, pectin supplementation has been shown to increase acetate levels.

Guar gum can support propionate levels.

Conclusion

There is increasing evidence implicating the gut microbiota as critical contributors to SCFA production, host health and gut/immune homeostasis.

Prebiotics favouring the growth of beneficial bacteria and beneficial probiotic bacteria are effective in altering balance and may modulate the production of SCFAs.

SCFAs are the preferential fuel for colonic epithelial cells and have trophic effects on the epithelium. SCFAs have been studied as possible therapeutic agents in diversion colitis, ulcerative colitis, radiation proctitis, pouchitis and antibiotic-associated diarrhoea, therefore, a specific therapeutic role for SCFAs may be the effector of the beneficial role of fibre in prevention of colon cancer.

Additional Resources

Basson A, Trotter A, Rodriguez-Palacios A, Cominelli F. Mucosal Interactions between Genetics, Diet, and Microbiome in Inflammatory Bowel Disease. Front Immunol. 2016;7:290.

Boets E, Deroover L, Houben E, et al. Quantification of in Vivo Colonic Short Chain Fatty Acid Production from Inulin. Nutrients. 2015;7(11):8916-8929.

Cook, S. I., & Sellin, J. H. (1998). Review article: short chain fatty acids in health and disease. Alimentary pharmacology & therapeutics, 12(6), 499–507. https://doi.org/10.1046/j.1365-2036.1998.00337.x

Mahowald, M. A. et al, 2009. Characterizing a model human gut microbiota composed of members of its two dominant bacterial phyla. Proceedings of the National Academy of Sciences of the United States of America, 106(14), 5859–5864. https://doi.org/10.1073/pnas.0901529106

Tan, J., McKenzie, C., Potamitis, M., Thorburn, A. N., Mackay, C. R., & Macia, L. (2014). The role of short-chain fatty acids in health and disease. Advances in Immunology, 121, 91–119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9