Short-Chain Fatty Acids and the Colonic Epithelium
By John M. Mariadason, PhD, Peter R. Gibson, MD, and Leonard H. Augenlicht, PhD
Short-chain fatty acids (scfas) are a family of naturally occurring molecules that play an important role in the homeostasis of the colonic epithelium. SCFAs are carboxylic acids with a backbone of two (acetate) to eight (caprylate) carbon atoms, and are the principal anion found in the colonic lumen. The interest in SCFAs stems from two typical effects these molecules have on colonic epithelial cells (CECs). First, SCFAs are critical for the proper functioning of the normal colonic epithelium. Most important, SCFAs are the preferred energy source of normal CECs, or colonocytes. Second, SCFAs are potent inducers of cell cycle arrest, differentiation, and apoptosis when exposed to transformed CECs or colon cancer cell lines. The effects and mechanisms of action of SCFAs in both normal and transformed colonic epithelial cells will be reviewed, with particular attention paid to the most efficacious SCFA, the 4-carbon molecule butyrate.
SCFAs are produced in the colonic lumen by bacterial fermentation of dietary fiber.1 The concentration of SCFAs present in the human colon can vary between 100-300 mM (i.e., 60-180 mM acetate, 20-60 mM propionate, and 20-60 mM butyrate), and is dependent upon the amount of dietary fiber ingested (typically 8-18 g/day),2 and the degree to which the ingested fiber can be fermented by the resident colonic bacterial flora. Well-fermented fibers, such as oat bran, pectin, and guar gum, typically produce high levels of SCFAs in comparison to poorly fermented fibers, such as cellulose.3
Effects of SCFAs In Vivo
Pathologies associated with a lack of SCFAs in the colonic lumen. Several circumstances that result in low levels or the absence of luminal SCFAs have been described. The consistent onset of pathological states that result highlights the importance of SCFAs for the normal functioning of the colonic epithelium.
First, raising animals under germ-free conditions results in the absence of an intestinal microflora, and therefore in the inability of dietary fiber to be fermented. Although these animals can be raised to adult life without developing specific pathologies, changes in the physiology of their colonic epithelium include marked mucosal hypoplasia, reduced proliferative activity in the crypts, significantly reduced crypt column height, and prolonged cell cycle times.4
Second, luminal SCFA concentrations can become reduced following diversion of the fecal stream, as occurs following certain surgical interventions. Patients who have undergone such procedures often develop a type of inflammatory bowel disease known as diversion colitis.5 Importantly, the reintroduction of SCFAs into the colonic lumen via enema leads to the clinical improvement of this disease.5
Third, luminal SCFA concentrations can be reduced by the feeding of diets that provide minimal amounts of carbohydrate for fermentation, including total parenteral nutrition, or low residue "elemental" diets.6 Several studies in both humans and animals have demonstrated profound colonic atrophy to be associated with the feeding of these diets. Importantly, this atrophy can be reversed by the addition of fermentable fiber to the diet or by the intracolonic infusion of SCFAs.7,8
Fourth, luminal SCFA levels are highly dependent upon diet, and there is considerable epidemiological and experimental evidence suggesting a protective role for dietary fiber in the onset of colorectal cancer. Diets high in fat and low in fiber, common in Western countries, are generally associated with a higher incidence of colorectal cancer than diets low in fat and high in fiber, which are common in Asia, Latin America, and Africa.9 Furthermore, studies of migrant populations, such as the Japanese and Chinese, show that the incidence of colorectal cancer more than doubles in these populations when they emigrate to the United States, possibly due to alterations in dietary habits.10 There have now been more than 50 case-control and cohort studies examining dietary associations with colorectal cancer. Although some studies have shown no protective effect of dietary fiber, the majority have demonstrated an inverse correlation between dietary fiber intake and the incidence of colorectal cancer.10,11 While these studies provide circumstantial evidence that SCFAs may be protective against the onset of colorectal carcinogenesis, it is important to note that butyrate alone is sufficient to inhibit colon cancer cell growth in vivo.12
Pathologies associated with the abnormal utilization of butyrate by colonic epithelial cells. In 1980, Roediger demonstrated that colonocytes isolated from patients with ulcerative colitis (UC) had an impaired ability to metabolize butyrate, and speculated that UC may be a consequence of the energy deficient state in which the colonic epithelium subsequently exists.13 Consistent with this, inhibitors of SCFA oxidation, such as bromo-octanoate, induce severe colitis in rats.14 Importantly, SCFA enemas have been shown to have efficacy in the treatment of UC, as well as in experimentally induced colitis in rats.15
Collectively, therefore, these studies demonstrate that the presence of SCFAs in the colonic lumen, and their normal metabolism by CECs, is essential for the health of the colonic mucosa. These studies also suggest that SCFAs play an important role in regulating pathways of colonic epithelial cell maturation. Colonic epithelial cell maturation is a highly evolved process involving the topographical organization of cell proliferation, differentiation, and apoptosis into different zones along the length of the colonic crypt. Briefly, stem cells located at the base of the crypt divide, giving rise to progenitor cells that differentiate along one of three cell lineages—absorptive, goblet, or enteroendocrine—as they migrate up the crypt axis toward the lumenal surface. Finally, cells are lost from the crypt by a combination of processes involving apoptosis and/or cell shedding.16
The onset of atrophy in the absence of luminal SCFAs, and the reversal of this effect following the re-introduction of SCFAs, suggests a role for these compounds in regulating colonic epithelial cell proliferation.8 SCFAs also appear to be important for the maintenance of normal rates of apoptosis in the colon, as mice that are unable to metabolize butyrate because of homozygous deletion of the short-chain acyl-CoA dehydrogenase (Scad) gene, show abnormally low levels of apoptosis in the colonic epithelium.17 There is also indirect evidence that SCFAs may regulate programs of colonic epithelial cell differentiation, as markers of cell differentiation, including barrier function and brush border hydrolase and mucin expression, can be altered by modulating colonic SCFA production through dietary intervention.18,19 SCFAs, therefore, are important regulators of colonic epithelial cell maturation in vivo. These effects have also been examined in several studies using short-term cultures of isolated CECs, ex vivo, and more extensively, in transformed colonic epithelial cells in vitro.
Effects of SCFAs on Normal Colonic Epithelial Cells, Ex Vivo
The effect of SCFAs on cell proliferation, differentiation, and apoptosis in normal colonic epithelium has been studied in isolated colonic epithelial cells in primary culture and in colonic mucosa mounted in Ussing chambers. In the few studies reported, butyrate has been shown to stimulate proliferation and reduce markers of cell differentiation in isolated human colonocytes ex vivo, and to reduce the "mass apoptosis" that occurs when guinea pig proximal colon is mounted in Ussing chambers.20,36 The limitation of these ex vivo studies is that the viability of colonic epithelial cells steadily decreases following their isolation. Furthermore, the methods used to isolate colonic epithelial cells may themselves be injurious to the cells.21 Investigators, therefore, have turned to model systems of the colonic epithelium—colon cancer cell lines—to more thoroughly investigate the effects of SCFAs on CECs.
Effects of SCFAs on Transformed Colonic Epithelial Cells
Effect of SCFAs on cell proliferation. A potent and consistent effect of butyrate on transformed cell lines in vitro is the inhibition of cell proliferation. This effect has been demonstrated in a variety of transformed cells of both colonic epithelial and non-colonic origin.22,23 Butyrate inhibits cell proliferation by inducing cells to arrest in the G0/G1 phase of the cell cycle. Consistent with this, the expression of several key regulators of the G0/G1 transition, such as cyclins, cyclin-dependent kinases, Rb-E2F, and the cyclin-cdk inhibitor, p21WAF-1, are regulated by butyrate. Butyrate also modulates the expression of several oncogenes, including p53, c-myc, Ha-ras, c-src, and c-fos.24-26
Effect of SCFAs on cell differentiation. Further to its inhibitory effects on cell proliferation in vitro, butyrate is a strong inducer of cell differentiation in transformed cells. Several markers of intestinal epithelial cell differentiation, including the brush border hydrolases, carcinoembryonic antigen, transepithelial resistance (a measure of tight junction formation), and dome formation (a measure of water transport), have all been shown to be induced by butyrate in a variety of colon cancer cell lines.27,28
The effects of butyrate on cell differentiation also appear to be lineage specific, as the markers of cell differentiation induced by butyrate are primarily those associated with the absorptive cell lineage, while markers such as MUC-2 and ITF, that are more specific for the goblet cell lineage, are actively downregulated by butyrate.29,30 Butyrate, therefore, may promote absorptive cell differentiation while simultaneously inhibiting goblet cell differentiation.
Effect of SCFAs on apoptosis. Butyrate has also been shown to be a potent inducer of apoptosis in several colon cancer cell lines.31,32 Furthermore, the apoptotic response induced by butyrate involves a cascade of events, including dissipation of the mitochondrial membrane potential, release of cytochrome c from the mitochondrion, PARP cleavage, and caspase activation.33 Butyrate-induced apoptosis in certain cases is also associated with reduced Bcl-2 levels and increased Bax and Bak expression.34,35
Comparison of the Effects of SCFAs In Vivo and In Vitro
Butyrate, therefore, appears to induce seemingly contrasting effects in normal colonic epithelial cells in vivo and ex vivo and in transformed colonic epithelial cells in vitro. To summarize, butyrate, in general, tends to stimulate cell proliferation and possibly inhibit apoptosis in normal colonic epithelial cells, although a role of SCFA metabolism in regulating apoptotic pathways in the colon has also been reported.17 However, butyrate potently reduces proliferation and stimulates cell differentiation and apoptosis in colon cancer cell lines.36 These seemingly contradictory effects of butyrate in normal and transformed cells are referred to as the "butyrate paradox."20 To understand the basis of this paradox, the mechanism of action of butyrate needs to be understood, and the fundamental differences between normal and transformed cells must be considered.
Mechanisms of Action of Butyrate
Butyrate appears to have two general modes of action.
1) Butyrate may exert its cellular effects as a consequence of its metabolism and from the consequent energy production.
2) Butyrate may exert its effects through inhibition of the enzyme histone deacetylase and by subsequent alterations of gene expression.
Butyrate as an energy source. SCFAs produced in the colon have been estimated to provide approximately 10% of the daily energy requirement of humans.37 This was also recently demonstrated in mice by Augenlicht et al, who showed that scad-/- mice that are unable to metabolize SCFAs gained weight at an equal rate compared to wild type littermates when fed a low fiber diet, but significantly more slowly when dietary carbohydrate was supplemented with wheat bran fiber.17
In comparison to the whole organism, the dependence of CECs on SCFAs—particularly butyrate—is much greater, with SCFAs supplying up to 70% of their oxidative energy.38 Oxidation of butyrate requires activation with coenzyme-A (CoA) prior to its metabolism in the mitochondria.37 The four-carbon butyryl-CoA is then converted by a series of steps (b-oxidation pathway) to two molecules of acetyl-CoA that are then channeled into the Krebs cycle, with CO2 released and energy (ATP) generated. Thus, one molecule of butyrate generates 27 ATP, which compares well with the 36 ATP produced from glucose.39
The acetyl-CoA generated from the b-oxidation of butyrate is also utilized in the synthesis of the ketone bodies, acetoacetate and b-hydroxybutyrate, which can be utilized as alternate energy sources by colonocytes.40 The acetyl-CoA generated may also contribute to lipid and sterol synthesis, which may contribute to the assembly of colonocyte cell membranes, or may enter the circulation.37
Inhibition of histone deacetylases (HDACs). It is also well established that butyrate is a potent inducer of histone acetylation.41 Histone acetylation and deacetylation involves the reversible transfer of the acetyl moiety of acetyl-CoA to the e-amino group of lysine residues in histone proteins.42 The reaction is catalyzed be histone acetyltransferases (HATs) and can be reversed by histone deacetylases (HDACs). Butyrate induces histone hyper-acetylation by reducing the rate of histone deacetylation, through inhibition of HDAC.43 While the mechanism by which butyrate inhibits HDAC is unclear, its effects are independent of gene transcription and protein synthesis, as addition of butyrate to cell extracts is sufficient to inhibit histone deacetylation. One hypothesis is that butyrate may directly activate a phosphatase, which subsequently results in HDAC inhibition.44
The effect of histone hyper-acetylation appears to be twofold. First, it has been known for some time that there is a correlation between hyper-acetylated histones and transcriptionally active chromatin, and it is possible that acetylation makes chromatin less condensed and thus more accessible to trans-acting transcription factors. Second, it is thought that acetylation at specific lysine residues is important for histone deposition during DNA replication.45
While the effects of butyrate on modulating gene expression have long been believed to be a result of alterations in histone acetylation, it is only relatively recently, since the discovery of other HDAC inhibitors, that this mechanism of butyrate has become more firmly established. For example, a number of recent studies have compared the effects of butyrate with that of the specific HDAC inhibitor, TSA.46 These studies have demonstrated that many of the effects of butyrate on colon cancer cells, including the inhibition of cell proliferation and the stimulation of apoptosis, can be mimicked by TSA. Furthermore, several genes that are regulated by butyrate, including p21WAF-1, are similarly regulated by TSA.47,48 Also, overexpression of HDAC can reverse the effects of butyrate and TSA on the expression of some of these genes, therefore providing insight into the mechanism by which butyrate elicits these effects.47
Resolving the Butyrate Paradox
The better understanding of the mechanisms of action of butyrate has provided insights into why butyrate exerts contrasting effects in normal and transformed CECs. In 1985, Jass proposed that the contrasting effects of butyrate may be a result of the differential rates at which these cells are able to metabolize butyrate.49 It is well established that butyrate is rapidly and preferentially metabolized by normal CECs.40 This rapid metabolism, and subsequent energy production, is consistent with the trophic response of butyrate in normal CECs cells previously starved of SCFAs.8 The rapid metabolism of butyrate, however, is likely to prevent its intracellular concentration from achieving levels high enough for efficient inhibition of HDAC. Subsequently, the HDAC-dependent effects of butyrate, such as the inhibition of cell proliferation and the induction of apoptosis, do not predominate in normal CECs. On the other hand, we have recently demonstrated that the rate of butyrate utilization in transformed cells is extremely slow, with undifferentiated Caco-2 cells unable to completely utilize a concentration of 2 mM butyrate over 120 hours.50 This slower rate of butyrate utilization would mean its intracellular concentration is likely to be high, resulting in the ability to efficiently inhibit HDAC. Subsequently, treatment of colon cancer cells with butyrate shifts the balance to the HDAC-dependent effects of cell cycle arrest, differentiation, and apoptosis, and reduces the oxidation-dependent effects on proliferation. Importantly, we have also demonstrated that as Caco-2 cells undergo spontaneous differentiation in culture, and assume a more normal phenotype, the rate at which they metabolize butyrate increases. Simultaneously, Caco-2 cells become refractory to the HDAC-dependent effects of butyrate.50
Conclusions
SCFAs, therefore, are an essential family of compounds necessary for the proper maintenance and function of the normal colonic epithelium. Their absence from the colonic lumen or their inability to be metabolized by CECs is associated with pathological states, including ulcerative and diversion colitis. Diets high in fiber, which generate high luminal SCFA concentrations, are associated with a reduced incidence of colorectal cancer, suggesting these molecules may have considerable chemopreventive value. Finally, their effects on transformed CECs, including the induction of cell cycle arrest, differentiation, and apoptosis, suggest SCFAs may also have considerable chemotherapeutic potential. This potential is further heightened by the ability of SCFAs to selectively induce these effects in transformed colonic epithelial cells. (Dr. Mariadason is a Post-doctorate Fellow and Dr. Augenlicht is Professor of Medicine and Cell Biology, Department of Oncology, Albert Einstein Cancer Center/Montefiore Medical Center, Bronx, NY. Dr. Gibson is an Associate Professor of Medicine, Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Australia.
References
1. McFarlane GT, McFarlane S. Human colonic microbiota: Ecology, physiology, and metabolic potential of intestinal bacteria. Scand J Gastroenterol 1997;222(Supp):3-9.
2. McFarlane GT, Gibson GR. Microbiological aspects of the production of short-chain fatty acids in the large bowel. In: Physiological and Clinical Aspects of Short-chain Fatty Acids. Cummings JH, Rombeau JL, Sakata T, eds. Cabridge University Press; 1995:87-105.
3. McIntyre A, Young GP, Taranto T, et al. Different fibers have different regional effects on luminal contents of rat colon. Gastroenterol 1991;101:1274-1281.
4. Alam M, Midtvedt T, Uribe A. Differential cell kinetics in the ileum and colon of germfree rats. Scand J Gastroenterol 1994;29:445-451.
5. Harig JM, Soergel KH, Komorowski V., et al. Treatment of diversion colitis with short chain fatty acid irrigation. N Engl J Med 1989;320:23-28.
6. Goodlad RA, Lee CY, Wright NA. Cell proliferation in the small intestine and colon of intravenously fed rats: Effects of urogastrone-epidermal growth factor. Cell Prolif 1992;25:393-404.
7. Goodlad RA, Lenton W, Ghatei MA, et al. Effects of an elemental diet, inert bulk and different types of dietary fiber on the response of the intestinal epithelium to refeeding in the rat and relationship to plasma gastrin, enteroglucagon, and PYY concentrations. Gut 1987;28:171-180.
8. Kripke SA, Fox AD, Berman JM, et al. Stimulation of intestinal mucosal growth with intracolonic infusion of short-chain fatty acids. J Parenter Enteral Nutr 1989;13:109-116.
9. Cassidy A, Bingham SA, Cummings JH. Starch intake and colorectal cancer risk: An international comparison. Br J Cancer 1994;69:937-942.
10. Levin B. Nutrition and colorectal cancer. Cancer 1992;70:1723-1726.
11. Fuchs CS, Giovannucci EL, Colditz GA, et al. Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 1999;340:169-176.
12. Otaka M, Singhal A, Hakomori S. Antibody-mediated targeting of differentiation inducers to tumor cells: Inhibition of colon cancer cell growth in vitro and in vivo. A preliminary note. Biochem Biophys Res Commun 1989;158:202-208.
13. Roediger WEW. The colonic epithelium in ulcerative colitis: An energy deficiency disease? Lancet 1980;2:712-715.
14. Roediger WEW, Nance S. Metabolic induction of experimental colitis by inhibition of fatty acid oxidation. Br J Exp Pathol 1986;67:773-782.
15. D’Argenio G, Cosenza V, Sorrentini I, et al. Butyrate, mesalamine, and Factor XIII in experimental colitis in the rat: Effects on transglutaminase activity. Gastroenterol 1994;106:399-404.
16. Gordon JI. Understanding gastrointestinal epithelial cell biology: Lessons from mice with help from worms and flies. Gastroenterol 1993;104:315-324.
17. Augenlicht LH, Anthony GM, Church TL, et al. Short-chain fatty acid metabolism, apoptosis, and Apc-initiated tumorigenesis in the mouse gastrointestinal mucosa. Cancer Res 1999;59:6005-6009.
18. Gibson PR, Nov R, Fielding M, et al. Relationship of hydrolase activities to epithelial cell turnover in distal colonic mucosa of normal rats. J Gastroenterol Hepatol 1999;14:866-872.
19. Mariadason JM, Catto-Smith A, Gibson PR. Modulation of distal colonic epithelial barrier function by dietary fibre in normal rats. Gut 1999;44:394-399.
20. Gibson PR, Moeller I, Kagelari O, et al. Contrasting effects of butyrate on the expression of phenotypic markers of differentiation in neoplastic and non-neoplastic colonic epithelial cells in vitro. J Gastroenterol Hepatol 1992;7:165-172.
21. Gibson P, Rosella O. Interleukin 8 secretion by colonic crypt cells in vitro: Response to injury suppressed by butyrate and enhanced in inflammatory bowel disease. Gut 1995;37:536-543.
22. Kim YS, Tsao D, Siddiqui B, et al. Effects of sodium butyrate and dimethylsulfoxide on biochemical properties of human colon cancer cells. Cancer 1980;45:1185-1192.
23. Krupitza G, Grill S, Harant H, et al. Genes related to growth and invasiveness are repressed by sodium butyrate in ovarian carcinoma cells. Br J Cancer 1996;73:433-438.
24. Buquet-Fagot C, Lallemand F, Charollais RH, et al. Sodium butyrate inhibits the phosphorylation of the retinoblastoma gene product in mouse fibroblasts by a transcription-dependent mechanism. J Cell Physiol 1996;166:631-636.
25. Barnard JA, Warwick G. Butyrate rapidly induces growth inhibition and differentiation in HT-29 cells. Cell Growth Differ 1993;4:495-501.
26. Souleimani A, Asselin C. Regulation of c-fos expression by butyrate in the human colon carcinoma cell line Caco-2. Biochem Biophys Res Commun 1993;193:330-336.
27. Chung YS, Song IS, Erickson EH, et al. Effect of growth and sodium butyrate on brush border membrane-associated hydrolases in human colorectal cancer cell lines. Cancer Res 1985;45:2976-2982.
28. Mariadason JM, Barkla DH, Gibson PR. Effect of short-chain fatty acids on paracellular permeability in Caco-2 intestinal epithelium model. Am J Physiol 1997;272:G705-G712.
29. Tran CP, Familari M, Parker LM, et al. Short-chain fatty acids inhibit intestinal trefoil factor gene expression in colon cancer cells. Am J Physiol 1998;275:G85-94.
30. Velcich A, Palumbo L, Jarry A, et al. Patterns of expression of lineage-specific markers during the in vitro-induced differentiation of HT29 colon carcinoma cells. Cell Growth Differ 1995;6:749-757.
31. Hague A, Manning AM, Hanlon KA, et al. Sodium butyrate induces apoptosis in human colonic tumor cell lines in a p53-independent pathway: Implications for the possible role of dietary fiber in the prevention of large bowel cancer. Int J Cancer 1993;55:498-505.
32. Heerdt BG, Houston MA, Augenlicht LH. Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines. Cancer Res 1994;54:3288-3293.
33. Heerdt BG, Houston MA, Anthony GM, et al. Initiation of growth arrest and apoptosis of MCF-7 mammary carcinoma cells by tributyrin, a triglyceride analogue of the short-chain fatty acid butyrate, is associated with mitochondrial activity. Cancer Res 1999;59:1584-1591.
34. Hague A, Diaz GD, Hicks DJ, et al. bcl-2 and bak may play a pivotal role in sodium butyrate-induced apoptosis in colonic epithelial cells; However overexpression of bcl-2 does not protect against bak-mediated apoptosis. Int J Cancer 1997;72:898-905.
35. Mandal M, Wu X, Kumar R. Bcl-2 deregulation leads to inhibition of sodium butyrate-induced apoptosis in human colorectal carcinoma cell lines. Carcinogenesis 1997;18:229-232.
36. Luciano L, Hass R, Busche R, et al. Withdrawal of butyrate from the colonic mucosa triggers "mass apoptosis" primarily in the G0/G1 phase of the cell cycle. Cell Tissue Res 1996;286:81-92.
37. Livesy G, Elia M. Short-chain fatty acids as an energy source in the colon: Metabolism and clinical implications. In: Physiological and clinical aspects of short-chain fatty acids. Cummings JH, Rombeau JL, Sakata T, eds. Cambridge University Press; 1995:427-481.
38. Roediger WEW. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 1980;21:793-798.
39. Stryer L. In: Biochemistry. New York: W.H Freeman and Company; 1988.
40. Roediger WEW. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterol 1982;83:424-429.
41. Riggs MG, Whittaker RG, Neumann, JR, et al. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 1977;268:462-465.
42. Loidl P. Histone acetylation: Facts and questions. Chromosoma 1994;103:441-449.
43. Sealy L, Chalkley R. The effect of sodium butyrate on histone modification. Cell 1978;14:115-121.
44. Cuisset L, Tichonicky L, Delpech M. A protein phosphatase is involved in the inhibition of histone deacetylation by sodium butyrate. Biochem Biophys Res Commun 1998;246:760-764.
45. Vettese-Dadey M, Grant PA, Hebbes G, et al. Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro. EMBO J 1996;15:2508-2518.
46. Yoshida M, Kijima M, Akita M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 1990;265:17174-17179.
47. Archer SY, Meng S, Shei A, et al. p21WAF1 is required for butyrate-mediated growth inhibition of colon cancer cells. Proc Natl Acad Sci U S A 1998;95:6791-6796.
48. Bordonaro M, Mariadason JM, Aslam F, et al. Butyrate-induced apoptotic cascade in colonic carcinoma cells: Modulation of the beta-catenin-Tcf pathway and concordance with effects of sulindac and trichostatin A but not curcumin. Cell Growth Differ 1999;10:713-720.
49. Jass JR. Diet, butyric acid and differentiation of gastrointestinal tract tumors. Med Hypoth 1985;18:113-118.
50. Mariadason JM, Wilson AJ, Augenlicht LA, et al. Resistance to butyrate-induced cell differentiation and apoptosis during spontaneous Caco-2 cell differentiation. Submitted; 2000.
All of the following statements regarding short-chain fatty acids are true except:
a. They are carboxylic acids with a backbone of 2-8 carbon atoms.
b. They are the principal cation found in the colonic lumen.
c. They are critical for proper function of the normal colonic epithelium.
d. They are the preferred energy source of normal colonic epithelial cells.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content