Butyrate Abstracts 1

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Butyrate: implications for intestinal function

         (Leonel and Alvarez-Leite 2012) Download

PURPOSE OF REVIEW: Butyrate is physiologically produced by the microbial fermentation of dietary fibers and plays a plurifunctional role in intestinal cells. This review examines the recent findings regarding the role and mechanisms by which butyrate regulates intestinal metabolism and discusses how these findings could improve the treatment of several gastrointestinal disorders. RECENT FINDINGS: Butyrate is more than a primary nutrient that provides energy to colonocytes and acts as a cellular mediator in those cells through several mechanisms. One remarkable property of butyrate is its ability to inhibit histone deacetylases, which is associated with the direct effects of butyrate and results in gene regulation, immune modulation, cancer suppression, cell differentiation, intestinal barrier regulation, oxidative stress reduction, diarrhea control, visceral sensitivity and intestinal motility modulation. All of these actions make butyrate an important factor for the maintenance of gut health. SUMMARY: From studies published over 30 years, there is no doubt of the important role that butyrate plays in maintaining intestinal homeostasis. However, despite these effects, clinical studies are still required to validate the routine use of butyrate in clinical practice and, specifically, in the treatment of intestinal diseases.

Histone deacetylase inhibition and dietary short-chain Fatty acids

         (Licciardi, Ververis et al. 2011) Download

Changes in diet can also have dramatic effects on the composition of gut microbiota. Commensal bacteria of the gastrointestinal tract are critical regulators of health and disease by protecting against pathogen encounter whilst also maintaining immune tolerance to certain allergens. Moreover, consumption of fibre and vegetables typical of a non-Western diet generates substantial quantities of short-chain fatty acids (SCFAs) which have potent anti-inflammatory properties. Dietary interventions such as probiotic supplementation have been investigated for their pleiotropic effects on microbiota composition and immune function. Probiotics may restore intestinal dysbiosis and improve clinical disease through elevated SCFA levels in the intestine. Although the precise mechanisms by which such dietary factors mediate these effects, SCFA metabolites such as butyrate also function as histone deacetylase inhibitors (HDACi), that can act on the epigenome through chromatin remodeling changes. The aim of this review is to provide an overview of HDAC enzymes and to discuss the biological effects of HDACi. Further, we discuss the important relationship between diet and the balance between health and disease and how novel dietary interventions such as probiotics could be alternative approach for the prevention and/or treatment of chronic inflammatory disease through modulation of the intestinal microbiome.

Butyrate induces expression of 17beta-hydroxysteroid dehydrogenase type 1 in HT29 and SW707 colorectal cancer cells

         (Rawluszko, Krokowicz et al. 2011) Download

Epidemiological studies have revealed that butyrate and 17beta-estradiol (E2) may decrease the incidence of colorectal cancer (CRC). In peripheral tissue, E2 can be produced locally by 17beta-hydroxysteroid dehydrogenase 1 (HSD17B1) estrone (E1) reduction. Using quantitative real-time polymerase chain reaction and western blotting analysis, we found that sodium butyrate significantly upregulates HSD17B1 long and short transcripts and protein levels in HT29 and SW707 CRC cells. Chromatin immunoprecipitation analysis showed that upregulation of these transcript levels correlated with an increase in binding of Polymerase II to proximal and distal promoters of HSD17B1. Moreover, we observed that upregulation of HSD17B1 protein levels was associated with increased conversion of E1 to E2 in HT29 and SW707 CRC cells. Since sodium butyrate increases the conversion of E1 to E2, our findings may support the validity of butyrate in the prophylaxis of CRC incidence.

Dietary inhibitors of histone deacetylases in intestinal immunity and homeostasis

         (Schilderink, Verseijden et al. 2013) Download

Intestinal epithelial cells (IECs) are integral players in homeostasis of immunity and host defense in the gut and are under influence of the intestinal microbiome. Microbial metabolites and dietary components, including short chain fatty acids (acetate, propionate, and butyrate, SCFAs), have an impact on the physiology of IECs at multiple levels, including the inhibition of deacetylases affecting chromatin remodeling and global changes in transcriptional activity. The number and diversity of butyrate-producing bacteria is subject to factors related to age, disease, and to diet. At physiological levels, SCFAs are inhibitors of histone deacetylases (HDACs) which may explain the transcriptional effects of SCFAs on epithelial cells, although many effects of SCFAs on colonic mucosa can be ascribed to mechanisms beyond HDAC inhibition. Interference with this type of post-translational modification has great potential in cancer and different inflammatory diseases, because HDAC inhibition has anti-proliferative and anti-inflammatory effects in vitro, and in in vivo models of intestinal inflammation. Hence, the influence of dietary modulators on HDAC activity in epithelia is likely to be an important determinant of its responses to inflammatory and microbial challenges.

Colonic health: fermentation and short chain fatty acids

         (Wong, de Souza et al. 2006) Download

Interest has been recently rekindled in short chain fatty acids (SCFAs) with the emergence of prebiotics and probiotics aimed at improving colonic and systemic health. Dietary carbohydrates, specifically resistant starches and dietary fiber, are substrates for fermentation that produce SCFAs, primarily acetate, propionate, and butyrate, as end products. The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time. SCFAs are readily absorbed. Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate enters the peripheral circulation to be metabolized by peripheral tissues. Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease. Acetate is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis. However, propionate, a gluconeogenerator, has been shown to inhibit cholesterol synthesis. Therefore, substrates that can decrease the acetate: propionate ratio may reduce serum lipids and possibly cardiovascular disease risk. Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification. Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect. Butyrate irrigation (enema) has also been suggested in the treatment of colitis. More human studies are now needed, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation. Short-term and long-term human studies are particularly required on SCFAs in relation to markers of cancer risk. These studies will be key to the success of dietary recommendations to maximize colonic disease prevention.

Synergistic effects of sodium butyrate, a histone deacetylase inhibitor, on increase of neurogenesis induced by pyridoxine and increase of neural proliferation in the mouse dentate gyrus

         (Yoo, Kim et al. 2011) Download

We previously observed that pyridoxine (vitamin B(6)) significantly increased cell proliferation and neuroblast differentiation without any neuronal damage in the hippocampus. In this study, we investigated the effects of sodium butyrate, a histone deacetylase (HDAC) inhibitor which serves as an epigenetic regulator of gene expression, on pyridoxine-induced neural proliferation and neurogenesis induced by the increase of neural proliferation in the mouse dentate gyrus. Sodium butyrate (300 mg/kg, subcutaneously), pyridoxine (350 mg/kg, intraperitoneally), or combination with sodium butyrate were administered to 8-week-old mice twice a day and once a day, respectively, for 14 days. The administration of sodium butyrate significantly increased acetyl-histone H3 levels in the dentate gyrus. Sodium butyrate alone did not show the significant increase of cell proliferation in the dentate gyrus. But, pyridoxine alone significantly increased cell proliferation. Sodium butyrate in combination with pyridoxine robustly enhanced cell proliferation and neurogenesis induced by the increase of neural proliferation in the dentate gyrus, showing that sodium butyrate treatment distinctively enhanced development of neuroblast dendrites. These results indicate that an inhibition of HDAC synergistically promotes neurogenesis induced by a pyridoxine and increase of neural proliferation.


References

Leonel, A. J. and J. I. Alvarez-Leite (2012). "Butyrate: implications for intestinal function." Curr Opin Clin Nutr Metab Care 15(5): 474-9. [PMID: 22797568]

Licciardi, P. V., K. Ververis, et al. (2011). "Histone deacetylase inhibition and dietary short-chain Fatty acids." ISRN Allergy 2011: 869647. [PMID: 23724235]

Rawluszko, A. A., P. Krokowicz, et al. (2011). "Butyrate induces expression of 17beta-hydroxysteroid dehydrogenase type 1 in HT29 and SW707 colorectal cancer cells." DNA Cell Biol 30(9): 661-9. [PMID: 21563966]

Schilderink, R., C. Verseijden, et al. (2013). "Dietary inhibitors of histone deacetylases in intestinal immunity and homeostasis." Front Immunol 4: 226. [PMID: 23914191]

Wong, J. M., R. de Souza, et al. (2006). "Colonic health: fermentation and short chain fatty acids." J Clin Gastroenterol 40(3): 235-43. [PMID: 16633129]

Yoo, D. Y., W. Kim, et al. (2011). "Synergistic effects of sodium butyrate, a histone deacetylase inhibitor, on increase of neurogenesis induced by pyridoxine and increase of neural proliferation in the mouse dentate gyrus." Neurochem Res 36(10): 1850-7. [PMID: 21597935]