Skip to main content

Advertisement

SpringerLink
Log in

The effects of short-chain fatty acids on colon epithelial proliferation and survival depend on the cellular phenotype

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

An Erratum to this article was published on 01 December 2006

Abstract

Purpose: The short-chain fatty acids (SCFA) are produced via anaerobic bacterial fermentation of dietary fiber within the colonic lumen. Among them, butyrate is thought to protect against colon carcinogenesis. However, few studies analyze the effects of butyrate, and other SCFA, on normal epithelial cells and on epithelial regeneration during disease recovery. Since there are controversial in vitro studies, we have explored the effects of SCFA on different biological processes. Methods: We used both tumoral (HT-29) and normal (FHC) epithelial cells at different phenotypic states. In addition, we analyzed the in vivo activity of soluble dietary fiber and SCFA production in the proliferation rate and regeneration of intestinal epithelial cells. Results: The effect of butyrate on epithelial cells depends on the phenotypic cellular state. Thus, in nondifferentiated, high proliferative adenocarcinoma cells, butyrate significantly inhibited proliferation while increased differentiation and apoptosis, whereas other SCFA studied did not. However, in normal cells or in differentiated cultures as well as in in vivo studies, the normal proliferation and regeneration of damaged epithelium is not affected by butyrate or SCFA exposure. Conclusion: Although butyrate could exert antiproliferative effects in tumor progression, its production is safe and without consequences for the normal epithelium growth.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Andoh A, Kinoshita K, Rosenberg I, Podolsky DK (2001) Intestinal trefoil factor induces decay-accelerating factor expression and enhances the protective activities against complement activation in intestinal epithelial cells. J Immunol 167:3887–3893

    PubMed  CAS  Google Scholar 

  • Araki Y, Andoh A, Fujiyama Y, Itoh A, Bamba T (2002) In vitro alterations in fecal short chain fatty acids and organic anions induced by the destruction of intestinal microflora under hypotonic and aerobic conditions. Int J Mol Med 9:627–631

    PubMed  CAS  Google Scholar 

  • Augeron C, Laboisse CL (1984) Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate. Cancer Res 44:3961–3969

    PubMed  CAS  Google Scholar 

  • Bell CJ, Gall DG, Wallace JL (1995) Disruption of colonic electrolyte transport in experimental colitis. Am J Physiol 268:G622–G630

    PubMed  CAS  Google Scholar 

  • Breuer RI, Buto SK, Christ ML, Bean J, Vernia P, Paoluzi P, Di Paolo MC, Caprilli R (1991) Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Preliminary report. Dig Dis Sci 36:185–187

    Article  PubMed  CAS  Google Scholar 

  • Butzner JD, Parmar R, Bell CJ, Dalal V (1996) Butyrate enema therapy stimulates mucosal repair in experimental colitis in the rat. Gut 38:568–573

    Article  PubMed  CAS  Google Scholar 

  • Chantret I, Barbat A, Dussaulx E, Brattain MG, Zweibaum A (1988) Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines. Cancer Res 48:1936–1942

    PubMed  CAS  Google Scholar 

  • Cherbut C, Michel C, Lecannu G (2003) The prebiotic characteristics of fructooligosaccharides are necessary for reduction of TNBS-induced colitis in rats. J Nutr 133:21–27

    PubMed  CAS  Google Scholar 

  • Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Galvez J, Zarzuelo A (2005) In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-κB pathway. Eur J Immunol 35:584–592

    Article  PubMed  CAS  Google Scholar 

  • D’Argenio G, Mazzacca G (1999) Short-chain fatty acid in the human colon. Relation to inflammatory bowel diseases and colon cancer. Adv Exp Med Biol 472:149–158

    PubMed  CAS  Google Scholar 

  • D’Argenio G, Cosenza V, Sorrentini I, De Ritis F, Gatto A, Delle Cave M, D’Armiento FP, Mazzacca G (1994) Butyrate, mesalamine, and factor XIII in experimental colitis in the rat: effects on transglutaminase activity. Gastroenterology 106:399–404

    PubMed  CAS  Google Scholar 

  • Darzynkiewicz Z, Traganos F, Xue SB, Melamed MR (1981) Effect of n-butyrate on cell cycle progression and in situ chromatin structure of L1210 cells. Exp Cell Res 136:279–293

    Article  PubMed  CAS  Google Scholar 

  • Edwards C (1994) The nutritional impact of the intestinal microflora. S Afr Med J Suppl:38S–39S

    Google Scholar 

  • El-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, Hill DE, Healy E, Rees JL, Hamilton SR et al (1995) Topological control of p21Waf1/Cip1 expression in normal and neoplastic tissues. Cancer Res 55:2910–2919

    PubMed  CAS  Google Scholar 

  • Foss FM, Veillette A, Sartor O, Rosen N, Bolen JB (1989) Alterations in the expression of pp60c-src and p56lck associated with butyrate-induced differentiation of human colon carcinoma cells. Oncogene Res 5:13–23

    PubMed  CAS  Google Scholar 

  • Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O’neil DA, Macfarlane GT (2005) Synbiotic therapy (Bifidobacterium longum/synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 54:242–249

    Article  PubMed  CAS  Google Scholar 

  • Graz CJ, Cowley HM (1997) Energy state in HT-29 cells is linked to differentiation. In Vitro Cell Dev Biol Anim 33:277–281

    Article  PubMed  CAS  Google Scholar 

  • Gryfe R, Swallow C, Bapat B, Redston M, Gallinger S, Couture J (1997) Molecular biology of colorectal cancer. Curr Probl Cancer 21:233–300

    Article  PubMed  CAS  Google Scholar 

  • Harig JM, Soergel KH, Komorowski RA, Wood CM (1989) Treatment of diversion colitis with short-chain-fatty acid irrigation. N Engl J Med 320:23–28

    Article  PubMed  CAS  Google Scholar 

  • Hill MJ (1995) Bacterial fermentation of complex carbohydrate in the human colon. Eur J Cancer Prev 4:353–358

    Article  PubMed  CAS  Google Scholar 

  • Hinnebusch BF, Meng S, Wu JT, Archer SY, Hodin RA (2002) The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J Nutr 132:1012–1017

    PubMed  CAS  Google Scholar 

  • Ioachim EE, Katsanos KH, Michael MC, Tsianos EV, Agnantis NJ (2004) Immunohistochemical expression of cyclin D1, cyclin E, p21/waf1 and p27/kip1 in inflammatory bowel disease: correlation with other cell-cycle-related proteins (Rb, p53, ki-67 and PCNA) and clinicopathological features. Int J Colorectal Dis 19:325–333

    Article  PubMed  Google Scholar 

  • Jacobs LR (1987) Effect of dietary fiber on colonic cell proliferation and its relationship to colon carcinogenesis. Prev Med 16:566–571

    Article  PubMed  CAS  Google Scholar 

  • Kagnoff MF, Eckmann L (1997) Epithelial cells as sensors for microbial infections. J Clin Invest 100:6–10

    Article  PubMed  CAS  Google Scholar 

  • Kalina U, Koyama N, Hosoda T, Nuernberger H, Sato K, Hoelzer D, Herweck F, Manigold T, Singer MV, Rossol S, Bocker U (2002) Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulating of the proximal promoter region. Eur J Immunol 32:2635–2643

    Article  PubMed  CAS  Google Scholar 

  • Kaur P, Potten CS (1986) Cell migration velocities in the crypts of the small intestine after cytotoxic insult are not dependent on mitotic activity. Cell Tissue Kinet 19:601–610

    PubMed  CAS  Google Scholar 

  • Mandal M, Olson DJ, Sharma T, Vadlamudi RK, Kumar R (2001) Butyric acid induces apoptosis by up-regulating Bax expression via stimulation of the c-Jun N-terminal kinase/activation protein-1 pathway in human colon cancer cells. Gastroenterology 120:71–78

    Article  PubMed  CAS  Google Scholar 

  • Marchetti C, Migliorati G, Moraca R, Riccardi C, Nicoletti I, Fabiani R, Mastrandrea V, Morozzi G (1997) Deoxycholic acid and SCFA-induced apoptosis in the human tumor cell-line HT-29 and possible mechanisms. Cancer Lett 114:97–99

    Article  PubMed  CAS  Google Scholar 

  • McIntyre A, Gibson PR, Young GP (1993) Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. Gut 34:386–391

    Article  PubMed  CAS  Google Scholar 

  • Medina V, Afonso JJ, Alvarez-Arguelles H, Hernandez C, Gonzalez F (1998) Sodium butyrate inhibits carcinoma development in a 1,2-dimethylhydrazine-induced rat colon cancer. JPEN J Parenter Enteral Nutr 22:14–17

    Article  PubMed  CAS  Google Scholar 

  • Merritt AJ, Potten CS, Watson AJ, Loh DY, Nakayama K, Nakayama K, Hickman JA (1995) Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia. J Cell Sci 108:2261–2271

    PubMed  CAS  Google Scholar 

  • Merritt AJ, Allen TD, Potten CS, Hickman JA (1997) Apoptosis in small intestinal epithelial from p53-null mice: evidence for a delayed, p53-independent G2/M-associated cell death after gamma-irradiation. Oncogene 14:2759–2766

    Article  PubMed  CAS  Google Scholar 

  • Milovic V, Teller IC, Turchanowa L, Caspary WF, Stein J (2000) Effect of structural analogues of propionate and butyrate on colon cancer cell growth. Int J Colorectal Dis 15:264–270

    Article  PubMed  CAS  Google Scholar 

  • Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL (1989) Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology 96:795–803

    PubMed  CAS  Google Scholar 

  • Parker SL, Tong T, Bolden S, Wingo PA (1996) Cancer statistics, 1996. CA Cancer J Clin 46:5–27

    Article  PubMed  CAS  Google Scholar 

  • Potten CS (1995) Structure, function and proliferative organization of the mammalian gut. In: Potten CS, Hendry JH (eds) Radiation and gut. Elsevier, New York

    Google Scholar 

  • Potter JD (1996) Nutrition and colorectal cancer. Cancer Causes Control 7:127–146

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Cabezas ME, Galvez J, Lorente MD, Concha A, Camuesco D, Azzouz S, Osuna A, Redondo L, Zarzuelo A (2002) Dietary fiber down-regulates colonic TNFα and nitric oxide production in the trinitrobenzenesulfonic acid-induced colitic rats. J Nutr 132:3263–3271

    PubMed  CAS  Google Scholar 

  • Roediger WE (1980) Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man. Gut 21:793–798

    Article  PubMed  CAS  Google Scholar 

  • Rombeau JL, Kripke SA (1990) Metabolic and intestinal effects of short-chain fatty acids. JPEN J Parenter Enteral Nutr 14:181S–185S

    Article  PubMed  CAS  Google Scholar 

  • Ruemmele FM, Dionne S, Qureshi I, Sarma DS, Levy E, Seidman EG (1999) Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose)polymerase (PARP). Cell Death Differ 6:729–735

    Article  PubMed  CAS  Google Scholar 

  • Sanchez de Medina F, Galvez J, Romero JA, Zarzuelo A (1996) Effect of quercitrin on acute and chronic experimental colitis in the rat. J Pharmacol Exp Ther 278:771–779

    Google Scholar 

  • Scheppach W, Sommer H, Kirchner T, Paganelli GM, Bartram P, Christl S, Richter F, Dusel G, Kasper H (1992) Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. Gastroenterology 103:51–56

    PubMed  CAS  Google Scholar 

  • Senagore AJ, MacKeigan JM, Scheider M, Ebrom JS (1992) Short-chain fatty acid enemas: a cost-effective alternative in the treatment of nonspecific proctosigmoiditis. Dis Colon Rectum 35:923–927

    Article  PubMed  CAS  Google Scholar 

  • Siavoshian S, Blottiere HM, Cherbut C, Galmiche JP (1997a) Butyrate stimulates cyclin D and p21 and inhibits cyclin-dependent kinase 2 expression in HT-29 colonic epithelial cells. Biochem Biophys Res Commun 232:169–172

    Article  CAS  Google Scholar 

  • Siavoshian S, Blottiere HM, Le Foll E, Kaeffer B, Cherbut C, Galmiche JP (1997b) Comparison of the effect of different short chain fatty acids on the growth and differentiation of human colonic carcinoma cell lines in vitro. Cell Biol Int 21:281–287

    Article  CAS  Google Scholar 

  • Souleimani A, Asselin C (1993) Regulation of c-myc expression by sodium butyrate in the colon carcinoma cell line Caco-2. FEBS Lett 326:45–50

    Article  PubMed  CAS  Google Scholar 

  • Tokumasa A, Katsuno T, Tanaga TS, Yokote K, Saito Y, Suzuki Y (2004) Reduction of Smad3 accelerates re-epithelialization in a murine model of colitis. Biochem Biophys Res Commun 317:377–383

    Article  PubMed  CAS  Google Scholar 

  • Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532

    Article  PubMed  CAS  Google Scholar 

  • Waseem NH, Lane DP (1990) Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci 96:121–129

    PubMed  CAS  Google Scholar 

  • Weiss TS, Herfarth H, Obermeier F, Ouart J, Vogl D, Scholmerich J, Jauch KW, Rogler G (2004) Intracellular polyamine levels of intestinal epithelial cells in inflammatory bowel disease. Inflamm Bowel Dis 10:529–535

    Article  PubMed  CAS  Google Scholar 

  • Whitehead RH, Young GP, Bhathal PS (1986) Effects of short chain fatty acids on a new human colon carcinoma cell line (LIM 1215). Gut 27:1457–1463

    Article  PubMed  CAS  Google Scholar 

  • Whitlock JP Jr, Augustine R, Schulman H (1980) Calcium-dependent phosphorylation of histone H3 in butyrate-treated HeLa cells. Nature 287:74–76

    Article  PubMed  CAS  Google Scholar 

  • Xaus J, Comalada M, Cardo M, Valledor AF, Celada A (2001) Decorin inhibits macrophage colony-stimulating factor proliferation of macrophages and enhances cell survival through induction of p27Kip1 and p21Waf1. Blood 98:2124–2133

    Article  PubMed  CAS  Google Scholar 

  • Young GP, McIntyre A, Albert V, Folino M, Muir JG, Gibson PR (1996) Wheat bran suppresses potato starch-potentiated colorectal tumorigenesis at the aberrant crypt stage in a rat model. Gastroenterology 110:508–514

    Article  PubMed  CAS  Google Scholar 

  • Zhang ZH, Ouyang Q, Gan HT (2004) Targeting cyclooxygenase-2 with sodium butyrate and NSAIDs on colorectal adenoma/carcinoma cells. World J Gastroenterol 10:2954–2957

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Spanish Ministry of Science and Technology (SAF2002-02592) and from Instituto de Salud “Carlos III” (PI021732), with funds from the European Union, and from Junta de Andalucía (CTS-164). EB is recipient of a fellowship from the Ministry of Science and Technology, Spain. MC is member of the “Juan de la Cierva” program, Ministry of Science and Technology, Spain. The authors want to thank Dr. M.E. Rodríguez-Cabezas for editorial assistance and Dr. M.N. Rodríguez-Cabezas for technical assistance.

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, University of Granada, Campus Universitario “La Cartuja” s/n, 18071, Granada, Spain

    Mònica Comalada, Elvira Bailón, Oscar de Haro, Antonio Zarzuelo & Julio Gálvez

  2. Department of Immunology and Animal Sciences, Puleva Biotech, S.A., Granada, Spain

    Federico Lara-Villoslada & Jordi Xaus

Authors
  1. Mònica Comalada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elvira Bailón
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oscar de Haro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federico Lara-Villoslada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jordi Xaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Zarzuelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julio Gálvez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mònica Comalada.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s00432-006-0172-y.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Comalada, M., Bailón, E., de Haro, O. et al. The effects of short-chain fatty acids on colon epithelial proliferation and survival depend on the cellular phenotype. J Cancer Res Clin Oncol 132, 487–497 (2006). https://doi.org/10.1007/s00432-006-0092-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-006-0092-x

Keywords

Search

Navigation