Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission

Published:April 20, 2010DOI:https://doi.org/10.1016/j.clnu.2010.04.002


      Background & Aims

      Butyrate, produced by colonic fermentation of dietary fibers is often hypothesized to beneficially affect colonic health. This study aims to assess the effects of butyrate on inflammation and oxidative stress in subjects with chronically mildly elevated parameters of inflammation and oxidative stress.


      Thirty-five patients with ulcerative colitis in clinical remission daily administered 60 ml rectal enemas containing 100 mM sodium butyrate (n=17) or saline (n=18) during 20 days (NCT00696098). Before and after the intervention feces, blood and colonic mucosal biopsies were obtained. Parameters of antioxidant defense and oxidative damage, myeloperoxidase, several cytokines, fecal calprotectin and CRP were determined.


      Butyrate enemas induced minor effects on colonic inflammation and oxidative stress. Only a significant increase of the colonic IL-10/IL-12 ratio was found within butyrate-treated patients (p=0.02), and colonic concentrations of CCL5 were increased after butyrate compared to placebo treatment (p=0.03). Although in general butyrate did not affect colonic glutathione levels, the effects of butyrate enemas on total colonic glutathione appeared to be dependent on the level of inflammation.


      Although UC patients in remission were characterized by low-grade oxidative stress and inflammation, rectal butyrate enemas showed only minor effects on inflammatory and oxidative stress parameters.


      Non-standard abbreviations:

      CAI (Clinical Activity Index;CRP, C-reactive protein), EGS (Endoscopic Grading System), GCLC (glutamate-cysteine ligase, catalytic subunit), GSH (glutathione), GSSG (glutathione disulfide), GST (glutathione-s-transferase), IFN (interferon), MDA (malondialdehyde), MCP-1 (monocyte chemotactic protein-1), SCFA (short-chain fatty acids), tGSH (total GSH), TEAC (trolox equivalent antioxidant capacity), UC (ulcerative colitis), XDH (xanthine dehydrogenase)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Nutrition
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ajani U.A.
        • Ford E.S.
        • Mokdad A.H.
        Dietary fiber and C-reactive protein: findings from national health and nutrition examination survey data.
        J Nutr. 2004; 134: 1181-1185
        • Bingham S.A.
        • Day N.E.
        • Luben R.
        • Ferrari P.
        • Slimani N.
        • Norat T.
        • et al.
        Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study.
        Lancet. 2003; 361: 1496-1501
        • Poullis A.
        • Foster R.
        • Shetty A.
        • Fagerhol M.K.
        • Mendall M.A.
        Bowel inflammation as measured by fecal calprotectin: a link between lifestyle factors and colorectal cancer risk.
        Cancer Epidemiol Biomarkers Prev. 2004; 13: 279-284
        • Streppel M.T.
        • Ocke M.C.
        • Boshuizen H.C.
        • Kok F.J.
        • Kromhout D.
        Dietary fiber intake in relation to coronary heart disease and all-cause mortality over 40 y: the Zutphen Study.
        Am J Clin Nutr. 2008; 88: 1119-1125
        • Hamer H.M.
        • Jonkers D.
        • Venema K.
        • Vanhoutvin S.
        • Troost F.J.
        • Brummer R.J.
        Review article: the role of butyrate on colonic function.
        Aliment Pharmacol Ther. 2008; 27: 104-119
        • Roediger W.E.
        Utilization of nutrients by isolated epithelial cells of the rat colon.
        Gastroenterology. 1982; 83: 424-429
        • Vanhoutvin S.A.
        • Troost F.J.
        • Hamer H.M.
        • Lindsey P.J.
        • Koek G.H.
        • Jonkers D.M.
        • et al.
        Butyrate-induced transcriptional changes in human colonic mucosa.
        PLoS One. 2009; 4: e6759
        • Segain J.P.
        • Raingeard de la Bletiere D.
        • Bourreille A.
        • Leray V.
        • Gervois N.
        • Rosales C.
        • et al.
        Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn’s disease.
        Gut. 2000; 47: 397-403
        • Miller S.J.
        • Zaloga G.P.
        • Hoggatt A.M.
        • Labarrere C.
        • Faulk W.P.
        Short-chain fatty acids modulate gene expression for vascular endothelial cell adhesion molecules.
        Nutrition. 2005; 21: 740-748
        • Hamer H.M.
        • Jonkers D.M.A.E.
        • Bast A.
        • Vanhoutvin S.A.L.W.
        • Fischer M.A.J.G.
        • Kodde A.
        • et al.
        Butyrate modulates oxidative stress in the colonic mucosa of healthy humans.
        Clin Nutr. 2009; 28: 88-93
        • Rosignoli P.
        • Fabiani R.
        • De Bartolomeo A.
        • Spinozzi F.
        • Agea E.
        • Pelli M.A.
        • et al.
        Protective activity of butyrate on hydrogen peroxide-induced DNA damage in isolated human colonocytes and HT29 tumour cells.
        Carcinogenesis. 2001; 22: 1675-1680
        • Rodriguez-Cabezas M.E.
        • Galvez J.
        • Lorente M.D.
        • Concha A.
        • Camuesco D.
        • Azzouz S.
        • et al.
        Dietary fiber down-regulates colonic tumor necrosis factor alpha and nitric oxide production in trinitrobenzenesulfonic acid-induced colitic rats.
        J Nutr. 2002; 132: 3263-3271
        • Grisham M.B.
        Oxidants and free radicals in inflammatory bowel disease.
        Lancet. 1994; 344: 859-861
        • Pravda J.
        Radical induction theory of ulcerative colitis.
        World J Gastroenterol. 2005; 11: 2371-2384
        • Scheppach W.
        • Sommer H.
        • Kirchner T.
        • Paganelli G.M.
        • Bartram P.
        • Christl S.
        • et al.
        Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis.
        Gastroenterology. 1992; 103: 51-56
        • Vernia P.
        • Marcheggiano A.
        • Caprilli R.
        • Frieri G.
        • Corrao G.
        • Valpiani D.
        • et al.
        Short-chain fatty acid topical treatment in distal ulcerative colitis.
        Aliment Pharmacol Ther. 1995; 9: 309-313
        • Holmes E.W.
        • Yong S.L.
        • Eiznhamer D.
        • Keshavarzian A.
        Glutathione content of colonic mucosa: evidence for oxidative damage in active ulcerative colitis.
        Dig Dis Sci. 1998; 43: 1088-1095
        • Welcker K.
        • Martin A.
        • Kolle P.
        • Siebeck M.
        • Gross M.
        Increased intestinal permeability in patients with inflammatory bowel disease.
        Eur J Med Res. 2004; 9: 456-460
        • Xiang J.Y.
        • Ouyang Q.
        • Li G.D.
        • Xiao N.P.
        Clinical value of fecal calprotectin in determining disease activity of ulcerative colitis.
        World J Gastroenterol. 2008; 14: 53-57
        • Fernandez-Banares F.
        • Hinojosa J.
        • Sanchez-Lombrana J.L.
        • Navarro E.
        • Martinez-Salmeron J.F.
        • Garcia-Puges A.
        • et al.
        Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn’s Disease and Ulcerative Colitis (GETECCU).
        Am J Gastroenterol. 1999; 94: 427-433
        • Hanai H.
        • Kanauchi O.
        • Mitsuyama K.
        • Andoh A.
        • Takeuchi K.
        • Takayuki I.
        • et al.
        Germinated barley foodstuff prolongs remission in patients with ulcerative colitis.
        Int J Mol Med. 2004; 13: 643-647
        • Russel M.G.
        • Dorant E.
        • Volovics A.
        • Brummer R.J.
        • Pop P.
        • Muris J.W.
        • et al.
        High incidence of inflammatory bowel disease in The Netherlands: results of a prospective study. The South Limburg IBD Study Group.
        Dis Colon Rectum. 1998; 41: 33-40
        • van der Heide H.
        • van den Brandt-Gradel V.
        • Tytgat G.N.
        • Endert E.
        • Wiltink E.H.
        • Schipper M.E.
        • et al.
        Comparison of beclomethasone dipropionate and prednisolone 21-phosphate enemas in the treatment of ulcerative proctitis.
        J Clin Gastroenterol. 1988; 10: 169-172
        • O’Donnell L.J.
        • Virjee J.
        • Heaton K.W.
        Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate.
        BMJ. 1990; 300: 439-440
        • Lichtiger S.
        • Present D.H.
        • Kornbluth A.
        • Gelernt I.
        • Bauer J.
        • Galler G.
        • et al.
        Cyclosporine in severe ulcerative colitis refractory to steroid therapy.
        N Engl J Med. 1994; 330: 1841-1845
        • Saverymuttu S.H.
        • Camilleri M.
        • Rees H.
        • Lavender J.P.
        • Hodgson H.J.
        • Chadwick V.S.
        Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease. A comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion.
        Gastroenterology. 1986; 90: 1121-1128
        • de Jager W.
        • te Velthuis H.
        • Prakken B.J.
        • Kuis W.
        • Rijkers G.T.
        Simultaneous detection of 15 human cytokines in a single sample of stimulated peripheral blood mononuclear cells.
        Clin Diagn Lab Immunol. 2003; 10: 133-139
        • Vandeputte C.
        • Guizon I.
        • Genestie-Denis I.
        • Vannier B.
        • Lorenzon G.
        A microtiter plate assay for total glutathione and glutathione disulfide contents in cultured/isolated cells: performance study of a new miniaturized protocol.
        Cell Biol Toxicol. 1994; 10: 415-421
        • van der Sluijs Veer G.
        • van den Hoven B.
        • Russel M.G.
        • van den Bergh F.A.
        Time-resolved fluorimetric immunoassay of calprotectin: technical and clinical aspects in diagnosis of inflammatory bowel diseases.
        Clin Chem Lab Med. 2006; 44: 292-298
        • Vernia P.
        • Annese V.
        • Bresci G.
        • d’Albasio G.
        • D’Inca R.
        • Giaccari S.
        • et al.
        Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial.
        Eur J Clin Invest. 2003; 33: 244-248
        • Saemann M.D.
        • Bohmig G.A.
        • Osterreicher C.H.
        • Burtscher H.
        • Parolini O.
        • Diakos C.
        • et al.
        Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production.
        Faseb J. 2000; 14: 2380-2382
        • Fusunyan R.D.
        • Quinn J.J.
        • Ohno Y.
        • MacDermott R.P.
        • Sanderson I.R.
        Butyrate enhances interleukin (IL)-8 secretion by intestinal epithelial cells in response to IL-1beta and lipopolysaccharide.
        Pediatr Res. 1998; 43: 84-90
        • 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
        • Malago J.J.
        • Koninkx J.F.
        • Tooten P.C.
        • van Liere E.A.
        • van Dijk J.E.
        Anti-inflammatory properties of heat shock protein 70 and butyrate on Salmonella-induced interleukin-8 secretion in enterocyte-like Caco-2 cells.
        Clin Exp Immunol. 2005; 141: 62-71
        • Weng M.
        • Walker W.A.
        • Sanderson I.R.
        Butyrate regulates the expression of pathogen-triggered IL-8 in intestinal epithelia.
        Pediatr Res. 2007; 62
        • Nelson P.J.
        • Ortiz B.D.
        • Pattison J.M.
        • Krensky A.M.
        Identification of a novel regulatory region critical for expression of the RANTES chemokine in activated T lymphocytes.
        J Immunol. 1996; 157: 1139-1148
        • Sanderson I.R.
        Dietary modulation of GALT.
        J Nutr. 2007; 137: 2557S-2562S
        • Luhrs H.
        • Gerke T.
        • Muller J.G.
        • Melcher R.
        • Schauber J.
        • Boxberge F.
        • et al.
        Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis.
        Scand J Gastroenterol. 2002; 37: 458-466
        • Senagore A.J.
        • MacKeigan J.M.
        • Scheider M.
        • Ebrom J.S.
        Short-chain fatty acid enemas: a cost-effective alternative in the treatment of nonspecific proctosigmoiditis.
        Dis Colon Rectum. 1992; 35: 923-927
        • Steinhart A.H.
        • Hiruki T.
        • Brzezinski A.
        • Baker J.P.
        Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial.
        Aliment Pharmacol Ther. 1996; 10: 729-736
        • Breuer R.I.
        • Soergel K.H.
        • Lashner B.A.
        • Christ M.L.
        • Hanauer S.B.
        • Vanagunas A.
        • et al.
        Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial.
        Gut. 1997; 40: 485-491
        • Scheppach W.
        Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebo-controlled trial. German-Austrian SCFA Study Group.
        Dig Dis Sci. 1996; 41: 2254-2259
        • Scheppach W.
        • Muller J.G.
        • Boxberger F.
        • Dusel G.
        • Richter F.
        • Bartram H.P.
        • et al.
        Histological changes in the colonic mucosa following irrigation with short-chain fatty acids.
        Eur J Gastroenterol Hepatol. 1997; 9: 163-168
        • Martensson J.
        • Jain A.
        • Meister A.
        Glutathione is required for intestinal function.
        Proc Natl Acad Sci U S A. 1990; 87: 1715-1719
        • Aw T.Y.
        Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility.
        Toxicol Appl Pharmacol. 2005; 204: 320-328
        • Loguercio C.
        • D’Argenio G.
        • Delle Cave M.
        • Cosenza V.
        • Della Valle N.
        • Mazzacca G.
        • et al.
        Glutathione supplementation improves oxidative damage in experimental colitis.
        Dig Liver Dis. 2003; 35: 635-641
        • Nieto N.
        • Torres M.I.
        • Fernandez M.I.
        • Giron M.D.
        • Rios A.
        • Suarez M.D.
        • et al.
        Experimental ulcerative colitis impairs antioxidant defense system in rat intestine.
        Dig Dis Sci. 2000; 45: 1820-1827
        • Den Hond E.
        • Hiele M.
        • Evenepoel P.
        • Peeters M.
        • Ghoos Y.
        • Rutgeerts P.
        In vivo butyrate metabolism and colonic permeability in extensive ulcerative colitis.
        Gastroenterology. 1998; 115: 584-590
        • Santhanam S.
        • Venkatraman A.
        • Ramakrishna B.S.
        Impairment of mitochondrial acetoacetyl CoA thiolase activity in the colonic mucosa of patients with ulcerative colitis.
        Gut. 2007; 56: 1543-1549
        • Pitcher M.C.
        • Beatty E.R.
        • Cummings J.H.
        The contribution of sulphate reducing bacteria and 5-aminosalicylic acid to faecal sulphide in patients with ulcerative colitis.
        Gut. 2000; 46: 64-72
        • Thibault R.
        • De Coppet P.
        • Daly K.
        • Bourreille A.
        • Cuff M.
        • Bonnet C.
        • et al.
        Down-regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation.
        Gastroenterology. 2007; 133: 1916-1927