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 signaling. Increasing body of evidence support 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.

Sources

[1] Harig, J. M., Soergel, K. H., Komorowski, R. A., and Wood, C. M. (1989) Treatment of diversion colitis with short-chain-fatty acid irrigation, N Engl J Med 320, 23–28.

[2] Breuer, R. I., Buto, S. K., Christ, M. L., Bean, J., Vernia, P., Paoluzi, P., Di Paolo, M. C., and Caprilli, R. (1991) Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Preliminary report, Dig Dis Sci 36, 185–187.

[3] Vernia, P., Marcheggiano, A., Caprilli, R., Frieri, G., Corrao, G., Valpiani, D., Di Paolo, M. C., Paoluzi, P., and Torsoli, A. (1995) Short-chain fatty acid topical treatment in distal ulcerative colitis, Aliment Pharmacol Ther 9, 309–313.

[4] Binder, H. J. (2010) Role of colonic short-chain fatty acid transport in diarrhea, Annu Rev Physiol 72, 297–313.

[5] Cook, S. I., and Sellin, J. H. (1998) Review article: short chain fatty acids in health and disease, Aliment Pharmacol Ther 12, 499–507.

[6] Reichardt, N., Duncan, S. H., Young, P., Belenguer, A., McWilliam Leitch, C., Scott, K. P., Flint, H. J., and Louis, P. (2014) Phylogenetic distribution of three pathways for propionate production within the human gut microbiota, ISME J 8, 1323–1335.

[7] Ze, X., Duncan, S. H., Louis, P., and Flint, H. J. (2012) Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon, ISME J 6, 1535–1543.

[8] Louis, P., Young, P., Holtrop, G., and Flint, H. J. (2010) Diversity of human colonic butyrate-producing bacteria revealed by analysis of the butyryl-CoA:acetate CoA-transferase gene, Environ Microbiol 12, 304–314.

[9] van Hoek, M. J., and Merks, R. M. (2012) Redox balance is key to explaining full vs. partial switching to low-yield metabolism, BMC Systems Biology 6, 22.

[10] Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P., and Macfarlane, G. T. (1987) Short chain fatty acids in human large intestine, portal, hepatic and venous blood, Gut 28, 1221–1227.

[11] Cherrington, C. A., Hinton, M., Pearson, G. R., and Chopra, I. (1991) Short-chain organic acids at ph 5.0 kill Escherichia coli and Salmonella spp. without causing membrane perturbation, J Appl Bacteriol 70, 161–165.

[12] Prohaszka, L., Jayarao, B. M., Fabian, A., and Kovacs, S. (1990) The role of intestinal volatile fatty acids in the Salmonella shedding of pigs, Zentralbl Veterinarmed B 37, 570–574.

[13] Duncan, S. H., Louis, P., Thomson, J. M., and Flint, H. J. (2009) The role of pH in determining the species composition of the human colonic microbiota, Environ Microbiol 11, 2112–2122.

[14] Walker, A. W., Duncan, S. H., McWilliam Leitch, E. C., Child, M. W., and Flint, H. J. (2005) pH and peptide supply can radically alter bacterial populations and short-chain fatty acid ratios within microbial communities from the human colon, Appl Environ Microbiol 71, 3692–3700.

[15] Bergman, E. N. (1990) Energy contributions of volatile fatty acids from the gastrointestinal tract in various species, Physiol Rev 70, 567–590.

[16] Bloemen, J. G., Venema, K., van de Poll, M. C., Olde Damink, S. W., Buurman, W. A., and Dejong, C. H. (2009) Short chain fatty acids exchange across the gut and liver in humans measured at surgery, Clin Nutr 28, 657–661.

[17] Greenberg, N. A., Gassull, M. A., and Meier, R. (2006) Short-chain fatty acids: ready for prime time?, Nutr Clin Pract 21, 639–640; author reply 640.

[18] Yamashita, H., Fujisawa, K., Ito, E., Idei, S., Kawaguchi, N., Kimoto, M., Hiemori, M., and Tsuji, H. (2007) Improvement of obesity and glucose tolerance by acetate in Type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, Biosci Biotechnol Biochem 71, 1236–1243.

[19] Lin, H. V., Frassetto, A., Kowalik, E. J., Jr., Nawrocki, A. R., Lu, M. M., Kosinski, J. R., Hubert, J. A., Szeto, D., Yao, X., Forrest, G., and Marsh, D. J. (2012) Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms, PLoS One 7, e35240.

[20] Kondo, T., Kishi, M., Fushimi, T., and Kaga, T. (2009) Acetic acid upregulates the expression of genes for fatty acid oxidation enzymes in liver to suppress body fat accumulation, J Agric Food Chem 57, 5982–5986.

[21] Kondo, T., Kishi, M., Fushimi, T., Ugajin, S., and Kaga, T. (2009) Vinegar intake reduces body weight, body fat mass, and serum triglyceride levels in obese Japanese subjects, Biosci Biotechnol Biochem 73, 1837–1843.

[22] Sakakibara, S., Yamauchi, T., Oshima, Y., Tsukamoto, Y., and Kadowaki, T. (2006) Acetic acid activates hepatic AMPK and reduces hyperglycemia in diabetic KK-A(y) mice, Biochem Biophys Res Commun 344, 597–604.

[23] Boillot, J., Alamowitch, C., Berger, A. M., Luo, J., Bruzzo, F., Bornet, F. R., and Slama, G. (1995) Effects of dietary propionate on hepatic glucose production, whole-body glucose utilization, carbohydrate and lipid metabolism in normal rats, Br J Nutr 73, 241–251.

[24] Luhrs, H., Gerke, T., Muller, J. G., Melcher, R., Schauber, J., Boxberge, F., Scheppach, W., and Menzel, T. (2002) Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis, Scand J Gastroenterol 37, 458–466.

[25] Maeda, T., Towatari, M., Kosugi, H., and Saito, H. (2000) Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells, Blood 96, 3847–3856.

[26] Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., Liu, H., Cross, J. R., Pfeffer, K., Coffer, P. J., and Rudensky, A. Y. (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation, Nature 504, 451–455.

[27] Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., Takahashi, M., Fukuda, N. N., Murakami, S., Miyauchi, E., Hino, S., Atarashi, K., Onawa, S., Fujimura, Y., Lockett, T., Clarke, J. M., Topping, D. L., Tomita, M., Hori, S., Ohara, O., Morita, T., Koseki, H., Kikuchi, J., Honda, K., Hase, K., and Ohno, H. (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature 504, 446–450.

[28] Vernia, P., Fracasso, P. L., Casale, V., Villotti, G., Marcheggiano, A., Stigliano, V., Pinnaro, P., Bagnardi, V., and Caprilli, R. (2000) Topical butyrate for acute radiation proctitis: randomised, crossover trial, Lancet 356, 1232–1235.

[29] Vernia, P., Annese, V., Bresci, G., d’Albasio, G., D’Inca, R., Giaccari, S., Ingrosso, M., Mansi, C., Riegler, G., Valpiani, D., Caprilli, R., Gruppo Italiano per lo Studio del, C., and del, R. (2003) Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial, Eur J Clin Invest 33, 244–248.

[30] Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D., Peng, Y., Zhang, D., Jie, Z., Wu, W., Qin, Y., Xue, W., Li, J., Han, L., Lu, D., Wu, P., Dai, Y., Sun, X., Li, Z., Tang, A., Zhong, S., Li, X., Chen, W., Xu, R., Wang, M., Feng, Q., Gong, M., Yu, J., Zhang, Y., Zhang, M., Hansen, T., Sanchez, G., Raes, J., Falony, G., Okuda, S., Almeida, M., LeChatelier, E., Renault, P., Pons, N., Batto, J. M., Zhang, Z., Chen, H., Yang, R., Zheng, W., Li, S., Yang, H., Wang, J., Ehrlich, S. D., Nielsen, R., Pedersen, O., Kristiansen, K., and Wang, J. (2012) A metagenome-wide association study of gut microbiota in type 2 diabetes, Nature 490, 55–60.