Short Chain Fatty Acid Regulation of Intestinal Gene Expression

  • John A. Barnard
  • J. A. Delzell
  • N. M. Bulus
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 422)


The molecular pathways involved in regulation of intestinal epithelial cell proliferation and differentiation have not been characterized to the extent that analogous pathways have been defined for many other cell types, especially those in the hematopoietic lineages. Much of the published work on intestinal cells has focused on regulation by polypeptide growth factors and extracellular matrix proteins while relatively less attention has been given to the contributions of luminal factors to growth and differentiation. Notwithstanding, luminal fluid in the colon contains a number of putative growth regulators. Foremost among these is the four carbon short chain fatty acid (SCFA) butyrate. Herein, we will review selected aspects of the cell physiology and biology of butyrate. Emphasis will be given to studies in epithelial systems, although a larger body of work has been conducted in cells of hematopoietic origin. We will also emphasize our own studies using the HT-29 colon adenocarcinoma cell line as a model for study of early cellular and molecular events associated with butyrate-mediated growth and differentiation.


Ulcerative Colitis Short Chain Fatty Acid Sodium Butyrate Human Colon Carcinoma Cell Colon Adenocarcinoma Cell Line 
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  1. 1.
    M. Bugaut, and M. Bentejac. Biological effects of short-chain fatty acids in nonruminant mammals. Annu. Rev. Nutr. 13: 217 (1993).CrossRefGoogle Scholar
  2. 2.
    K.H. Soergel. Colonic fermentation: Metabolic and clinical consequences. Clin Investig 72: 742 (1994).CrossRefGoogle Scholar
  3. 3.
    W.E.W. Roediger. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21. 793–798 (1980).CrossRefGoogle Scholar
  4. 4.
    J.H. Cummings, E.W. Pomare, W.J. Branch, C.P. E. Naylor, G.T. McFarlane. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28: 1221 (1987).CrossRefGoogle Scholar
  5. 5. E. Titus, and G.A. Ahearn. Vertebrate gastrointestinal fermentation: transport mechanisms for volatile fatty acids. American Physiological Society (1992). Google Scholar
  6. 6.
    W.E.W. Roediger. Utilization of nutrients by isolated epithelial cells of the rat colon. Gastroenterology. 83: 424 (1982).Google Scholar
  7. 7.
    M.J. Koruda. Dietary fiber and gastrointestinal disease. Surgery. Gynecology Obstetrics 177: 209 (1993).Google Scholar
  8. 8.
    G. D’Argenio, V. Cosenza, M. Delle Cave, R lovino, N. Della Valle, G. Lombardi, and G. Mazzacca. Butyrate enemas in experimental colitis and protection against large bowel cancer in a rat model. Gastroenterology 110:1727 (1996).Google Scholar
  9. 9.
    L.C. Boffa, J.R. Lupton, M.R. Mariani, M. Ceppi, H. L. Newmark, A. Scalmati, and M. Lipkin. Modulation of colonic epithelial cell proliferation, histone acetylation, and luminal short chain fatty acids by variation of dietary fiber (wheat bran) in rats. Cancer Res. 52: 5906 (1992).Google Scholar
  10. 10.
    L.H. Augenlicht, A.Velcich, and B.G. Heerdt. Short-chain fatty acids and molecular and cellular mechanisms of colonic cell differentiation and transformation. Advances Exp Med Biol 375: 137 (1995).Google Scholar
  11. 11.
    T. Sakata. Stimulatory effect of short-chain fatty acids on epithelial cell proliferation in the rat intestine: a possible explanation for trophic effects of fermentable fibre, gut microbes and luminal trophic factors. J. Nutt: 58: 95 (1987).CrossRefGoogle Scholar
  12. 12.
    S.A. Kripke, A.D. Fox, J.M. Berman, R.G. Settle, and J.L. Rombeau. Stimulation of intestinal mucosal growth with intracolonic infusion of short-chain fatty acids. JPEN 13: 109 (1989).CrossRefGoogle Scholar
  13. 13.
    W. Scheppach, R. Bartram, A. Richter, F. Richter, H. Liepold, G. Dusel, G. Hofstetter, J. Ruthlein, and H. Kasper. Effect of short-chain fatty acids on the human colonic mucosa in vitro. JPEN 16: 43 (1992).CrossRefGoogle Scholar
  14. 14.
    W. Scheppach, J. Sommer, T. Kirchner, G-M. Paganelli, P. Bartram, S. Christi, F. Richter, G. Dusel, and H. Kasper. Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 103: 51 (1992).Google Scholar
  15. 15.
    M.A.S. Chapman, M.F. Grahn, M.A. Boyle, M. Hutton, J. Rogers, and N.S. Williams. Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative colitis. Gut 35: 73 (1994).CrossRefGoogle Scholar
  16. 16.
    W. Frankel, J. Lew, B. Su, A. Bain, D. Klurfeld, E. Einhorn, R.P. MacDermott, and J. Rombeau. Butyrate increases colonocyte protein synthesis in ulcerative colitis. J. Surgical Res. 57: 210 (1994).CrossRefGoogle Scholar
  17. 17.
    A.H. Steinhart, A. Brzezinski, J.P. Baker. Treatment of refractory ulcerative proctosigmoiditis with butyrate enemas. American J. Gastroenterology 89: 179 (1994).Google Scholar
  18. 18.
    S.P. Perrine, G.D. Ginder, D.V. Faller, G.H. Dover, T. Ikuta, H.E. Witkowska, S. Cai, E.P. Vichinsky, N.F. Olivieri. A short term trial of butyrate to stimulate fetal globin gene expression in the ß globin gene disorders. N Engl J Med 328: 81–86 (1993).CrossRefGoogle Scholar
  19. 19.
    E.P.M. Candido, R. Reeves, J.R. Davie. Sodium butyrate inhibits histone acetylation in cultured cells. Cell 14: 105 (1978).CrossRefGoogle Scholar
  20. 20.
    J.A. D’Anna, R.A. Tobey, and L.R. Gurley. Concentration-dependent effects of sodium butyrate in Chinese hamster cells: cell-cycle progression, inner-histone acetylation, histone HI dephosphorylation, and induction of an H1-like protein. Biochemistry 19: 2656 (1980).CrossRefGoogle Scholar
  21. 21.
    D.E. Cosgrove and G.S. Cox. Effects of sodium butyrate and 5-azacytidine on DNA methylation in human tumor cell lines: variable response to drug treatment and withdrawal. Biochimica et Biophysica Acta 1087: 80 (1990).CrossRefGoogle Scholar
  22. 22.
    A. Toscani, D.R. Soprano, and K.J. Soprano. Molecular analysis of sodium butyrate-induced growth arrest. Oncogene Res. 3: 223 (1988).Google Scholar
  23. 23.
    S-J. Tang, L-W. Ko. Y-H.W. Lee, and F-F. Wang. Induction offos and sis proto-oncogenes and genes of the extracellular matrix proteins during butyrate induced glioma differentiation. Biochimica et Biophysica Acta 1048: 59 (1990).CrossRefGoogle Scholar
  24. 24.
    F.M. Foss, A. Veillette, O. Sartor, N. Rosen, and J.B. Bolen. Alterations in the expression of pp60“ and p56” associated with butyrate-induced differentiation of human colon carcinoma cells. Oncogene Res. 5: 13 (1989).Google Scholar
  25. 25.
    J.H. Stodart, M.A. Lane, and R.M. Niles. Sodium butyrate suppresses the transforming activity of an activated N-ras oncogene in human colon carcinoma cells. Experimental Cell Research 184: 16 (1989).CrossRefGoogle Scholar
  26. 26.
    Y.S. Chung, I.S. Song, R.H. Erickson, M.H. Sleisenger and Y.S. Kim. Effect of growth and sodium butyrate on brush border membrane-associated hydrolases in human colorectal cancer cell lines. Cancer Res. 45: 2976 (1985).Google Scholar
  27. 27.
    D. Tsao, A. Morita, A. Bella, Jr., P. Luu, and Y.S. Kim. Differential effects of sodium butyrate, dimethyl sulfoxide, and retinoic acid on membrane-associated antigen, enzymes, and glycoproteins of human rectal adenocarcinoma cells. Cancer Res. 42: 1052 (1982).Google Scholar
  28. 28.
    R.H. Whitehead, G.P. Young, and P.S. Bhathal. Effects of short chain fatty acids on a new human colon carcinoma cell line (LIM 1215). Gut 27: 1457 (1986).CrossRefGoogle Scholar
  29. 29.
    B.G. Heerdt, M.A. Houston, J.J. Rediske, and L.H. Augenlicht. Steady-state levels of mitochondrial messenger RNA species characterize a predominant pathway culminating in apoptosis and shedding of HT29 human colonic carcinoma cells. Cell Growth Differentiation 7: 101 (1996).Google Scholar
  30. 30.
    A. Morita, D. Tsao, and Y.S. Kim. Effect of sodium butyrate on alkaline phosphatase in HRT-18, a human rectal cancer cell line. Cancer Res. 42: 4540 (1982).Google Scholar
  31. 31.
    F. Herz. Divergent effects of butyrate on the alkaline phosphatases of SW-620 cells. Biochimica et Biophysica Acta 1180:289 (1993).Google Scholar
  32. 32.
    R.A. Hodin, S. Meng, S. Archer, and R. Tang. Cellular growth state differentially regulates enterocyte gene expression in butyrate-treated HT-29 cells. Cell Growth Differentiation 7: 647 (1996).Google Scholar
  33. 33.
    I. Chantret, A. Barbat, E. Dussaulx, M.G. Brattain, and A. Zweibaum. Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines. Cancer Res. 48: 1936 (1988).Google Scholar
  34. 34.
    A. deFazio, Y-E. Chiew, C. Donoghue, C.S.L. Lee, and R.L. Sutherland. Effect of sodium butyrate on estrogen receptor and epidermal growth factor receptor gene expression in human breast cancer cell lines. J. Biological Chemistry 267: 18008 (1992).Google Scholar
  35. 35.
    K. Saini, G. Steele, and P. Thomas. Induction of carcinoembryonic-antigen-gene expression in human colorectal carcinoma by sodium butyrate. Biochem. J. 272: 541 (1990).Google Scholar
  36. 36.
    G. Deng, G. Liu, L. Hu, J.R. Gum, Jr., and Y.S. Kim. Transcriptional regulation of the human placenta-like alkaline phosphatase gene and mechanisms involved in its induction by sodium butyrate. Cancer Res. 52: 3378 (1992).Google Scholar
  37. 37.
    A. Souleimani, and C. Asselin. Regulation of c-fos expression by sodium butyrate in the human colon carcinoma cell line Caco-2. Biochemical and Biophysical Res. Comm. 193: 330 (1993).CrossRefGoogle Scholar
  38. 38.
    C.S. Morrow, M. Nakagawa, M.E. Goldsmith, M.J. Madden, and K.H. Cowan. Reversible transcriptional activation of mdrl by sodium butyrate treatment of human colon cancer cells. J. Biological Chemistry 269: 10739 (1994).Google Scholar
  39. 39.
    L.A. Johnson, S.J. Tapscott, and H. Eisen. Sodium butyrate inhibits myogenesis by interfering with the transcriptional activation function of MyoD and myogenin. Molecular and Cellular Biology 12: 5123 (1992).Google Scholar
  40. 40.
    J.G. Glauber, N.J. Wandersee, J.A. Little, and G.D. Ginder. 5’-flanking sequences mediate butyrate stimulation of embryonic globin gene expression in adult erythroid cells. Molecular and Cellular Biology 11: 4690 (1991).Google Scholar
  41. 4I.
    K.B. Marcu, S.A. Bossone, A. J. Patel. myc function and regulation. Annu Rev Biochem 61: 809 (1992).CrossRefGoogle Scholar
  42. 42.
    R. Bissonnette, F. Echeverri, A. Mahoubi, D.R. Green. Apoptotic cell death induced by c-mvc is inhibited by bcl-2. Nature 359: 552 (1992).CrossRefGoogle Scholar
  43. 43.
    M.F. Melhem, A.I. Meisler, G.C. Finley, W.H. Bryce, M.O. Jones, [.1. Tribby, J.M. Pipas, and R.A. Koski. Distribution of cells expressing myc proteins in human colorectal epithelium, polyps, and malignant tumors. Cancer Res. 52: 5853, (1992).Google Scholar
  44. 44.
    K.M. Herold, and P.G. Rothberg. Evidence for a labile intermediate in the butyrate induced reduction of the level of c-myc RNA in SW837 rectal carcinoma cells. Oncogene 3: 423, (1988).Google Scholar
  45. 45.
    J.A. Barnard, G. Warwick. Butyrate rapidly induces growth inhibition and differentiation in HT-29 cells. Cell Growth and Differentiation 4: 495, (1993).Google Scholar
  46. 46.
    D.P. Heruth, G.W. Zirnstein, J.F. Bradley, and P.G. Rothberg. Sodium butyrate causes an increase in the block to transcriptional elongation in the c-myc gene in SW837 rectal carcinoma cells. J. Biological Chemistry 268: 20466 (1993).Google Scholar
  47. 47.
    A. Souleimani, C. Asselin. Regulation of c-myc expression by sodium butyrate in the colon carcinoma cell line Caco-2. FEBS Lett 326:45, (1993).Google Scholar
  48. 48.
    G. Krupitza, S. Grill, H. Harant, W. Huila, T. Szekeres, H. Huber, and C. Dirrich. Genes related to growth and invasiveness are repressed by sodium butyrate in ovarian carcinoma cells. British J. Cancer 73: 433 (1996).CrossRefGoogle Scholar
  49. 49.
    C.W. Taylor, Y.S. Kim, K.E. Childress-Fields, and L.C. Yeoman. Sensitivity of nuclear c-myc levels and induction to differentiation-inducing agents in human colon tumor cell lines. Cancer Letters 62: 95 (1992).CrossRefGoogle Scholar
  50. 50.
    A. Hague, A.M. Manning, K.A. Hanlon, L.I. Huschtscha, D. Hart, and C. Paraskeva. Sodium butyrate induces apoptosis in human colonic tumor cell lines in a p53-independent pathway: implications for the possible role of dietary fibre in the prevention of large-bowel cancer. Int. J. Cancer 55: 498 (1993).CrossRefGoogle Scholar
  51. 51.
    A. Hague, D.J.E. Elder, D.J. Hicks, C. Paraskeva. Apoptosis in colorectal tumor cells: Induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate. Int J Cancer 60: 400, (1995).CrossRefGoogle Scholar
  52. 52.
    M. Mandal, and R. Kumar. Bc1–2 expression regulates sodium butyrate-induced apoptosis in human MCF-7 breast cancer cells. Cell Growth Differentiation 7: 311 (1996).Google Scholar
  53. 53.
    L. Staiano-Coico, L. Khandke, J.F. Krane, S. Sharif, A.B. Gottlieb, J.G. Krueger, L. Heim, B. Rigas, and P.J. Higgins. TGF-a and TGF-ß expression during sodium-N-butyrate-induced differentiation of human keratinocytes: evidence for subpopulation-specific up-regulation of TGF-13 mRNA in suprabasal cells. Experimental Cell Res. 191: 286 (1990).CrossRefGoogle Scholar
  54. 54.
    P. Schroy, J. Rifkin, R.J. Coffey, S. Winawer, E. Friedman. Role of transforming growth factor 13 I in induction of colon carcinoma differentiation by hexamethylene bisacetamide. Cancer Res 50: 261, (1990).Google Scholar
  55. 55.
    E. Wintersberger, I. Mudrak, and U. Wintersberger. Butyrate inhibits mouse fibroblasts at a control point in the GI phase. J. Cellular Biochemistry 21: 239 (1983).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • John A. Barnard
    • 1
    • 2
  • J. A. Delzell
    • 1
  • N. M. Bulus
    • 1
  1. 1.Department of PediatricsVanderbilt University School of MedicineNashvilleUSA
  2. 2.Associate Professor, Department of Pediatrics, Division of Gastroenterology and NutritidnVanderbilt University School of MedicineNashvilleUSA

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