By Gerard E. Mullin, MD; Laura K. Turnbull; S. Devi Rampertab, MD, Director of Integrative GI Nutrition Services; Johns Hopkins; Johns Hopkins University School of Nursing; Milton Hershey Penn State School of Medicine.
The use of nutraceutical supplements by patients with gastrointestinal disorders is widespread and growing. Most studies cite that 50% of patients with inflammatory bowel disease use nutraceutical supplements. There is an abundance of clinical trials demonstrating efficacy of nutraceutical supplements for IBD. Probiotics, prebiotics, butyric acid enemas, Curcuma longa, Boswellia serrata and fish oils have been shown to be superior to placebo and in some cases equal to standard medical therapy in randomized trials. Thus the nutraceutical supplements that have been shown to have established efficacy for inflammatory bowel disease are reviewed.
Inflammatory Bowel Disease (IBD): The Gut on Fire
Inflammatory bowel disease is a chronic condition characterized by frequent relapses, hospitalizations, diminished quality of life (QOL), complications that require surgery and intestinal cancer . The pathophysiology of IBD involves an unremitting intestinal inflammation, proinflammatory cytokines, increased reactive oxygen species and tissue injury that is oftentimes triggered by luminal bacteria . Opportunities for natural product therapy include the modulation of mediators involved in the inflammatory process, altering luminal bacteria, modifying the immune response and rejuvenation of intestinal healing.
Usage of supplements for IBD
Surveys of complementary and alternative approaches by patients with gastrointestinal complaints have reported rates of utilization well over 50% [2-16]. Of all digestive disorders, usage appears to be most common in patients with IBD and IBS ,,. Table 1 summarizes the latest research on the utilization patterns of complementary and alternative medicine (CAM) use in IBD. Surveys have also addressed the reasons why patients used nutraceutical supplements for IBD and which ones they felt to be the most effective ,  (Table 1). Given their widespread usage, healthcare practitioners now need to be familiar with the potential benefits of nutraceutical supplements for IBD in an effort to offer superior care to their patients.
a. Aloe vera
A randomized, double-blind, controlled study showed that aloe vera gel, given for 4 weeks to patients with moderately active UC was superior to placebo  . Clinical remission, improvement and response occurred in nine (30%), 11 (37%) and 14 (47%), respectively, of 30 patients given Aloe vera, compared with one (7%), one (7%) two (14%; P < 0.05), respectively, of 14 patients taking placebo (using a 2:1 A. vera: placebo randomization schedule). The Simple Clinical Colitis Activity Index and histological scores decreased during treatment with A. vera but not with placebo.
b. Wheat grass juice
In a randomized, double-blind, controlled trial, 23 patients with active distal UC were given oral wheat grass juice or placebo for 4 weeks .Treatment with wheat grass juice was associated with greater reductions in a composite clinical disease activity index, severity of rectal bleeding and physician’s global assessment than occurred in the placebo group. No side-effects were reported.
c. Germinated barley foodstuff
Two open-label Japanese trials suggested efficacy in UC for a germinated barley foodstuff (GBF), which consists mainly of dietary ﬁber and glutamine-rich protein. The authors believe this substance acts primarily as a prebiotic [29-32]. In the ﬁrst report, 11 patients given GBF for 4 weeks as adjunctive treatment showed a greater fall in clinical disease activity than nine patients given conventional therapy alone. In a follow-up study, 24 weeks of treatment of 21 patients with GBF together with continuing 5-ASA and steroid therapy reduced rectal bleeding and nocturnal diarrhea. Adjunctive GBF also produced a lower relapse rate over 12 months when given to 22 patients with UC in remission than did conventional therapy in 37 such patients . GBF was well tolerated and appeared to be safe in all three reports.
Polyphenols are phytochemicals that are found in food substances produced from plants. Polyphenols are separated from essential micronutrients in that a deficiency state has not been identified; nevertheless, these chemicals are believed to play a biologically-active role and have been shown to be potentially immune-modulating . For IBD, downregulation of inflammatory mediators and nuclear factor kappa beta (NFkB) are broad mechanisms of action for polyphenols’ therapeutic effects.
Although numerous polyphenols have been identified, five in particular have evidence of benefit for animal and human studies in IBD including: resveratrol, epigallocatechin, curcumin, quercetin and Boswellia. Resveratrol, epigallocatechin, curcumin and quercetin have been demonstrated to display both prophylactic and therapeutic effects for colitis in animals; however quercetin was the least effective of the polyphenols studied. In humans, clinical studies of polyphenols for the treatment of IBD are limited to Boswelia serrata and Curcuma longa.
Boswellia serrata (‘frankincense’) is a traditional Ayurvedic remedy and a component of incense. In India, the effect of the gum resin from B. serrata in moderately active UC was compared with sulfasalazine. Remission rate in the Boswellia group (82%) resembled that occurring in patients given conventional therapy (75%) . The same authors reported a similar study in 2001 resulting in a 70% remission rate in 20 patients taking Boswellia for 6 weeks compared with 40% in 10 on sulfasalazine . In a randomized, double-blind, controlled 8 week trial, the B. serrata extract, H15, was compared with mesalamine for active CD . The study included 102 patients and was powered to show non-inferiority. The mean Crohn’s Disease Activity Index (CDAI) fell in both groups and H15 was well tolerated. This result was similar to those in previous trials with 5-ASA preparations [38, 39].
Curcumin is the yellow pigment of turmeric (Curcuma longa), a major ingredient of curry: in animal and in vitro studies, it has a range of immunomodulatory and anti-inﬂammatory effects [40-43]. In a recent pilot study, curcumin, when given orally, was reported to benefit ﬁve patients with proctitis and ﬁve with Crohn’s disease . Hanai and colleagues recently published the results of the first randomized, multicenter, double-blind, placebo-controlled trial from Japan to study the effect of Curcumin on maintenance of UC . All of ninety-seven patients who enrolled and eighty-nine patients who completed the study took a standard dose of mesalamine or sulfasalazine and either 1 gm of Curcumin or placebo twice daily for 6 months and then were followed or another 6 months off study medications. The relapse rate at 6 months on therapy was greater for the placebo group than for those who took Curcumin (p=049). Thus, Curcumin may confer some additional therapeutic advantages when used in combination with conventional anti-inflammatory medications in UC.
Prebiotics and Probiotics
As the microbial environment has been shown to play a role in the development and perpetuation of IBD, targeting of the microbiota presents an option for therapeutic intervention ([46-48]. One potential method to manipulate the intestinal microbiota in an attempt to reduce the inflammatory response is via the administration of friendly live bacteria.
Probiotics have been described as, “live micro-organisms which, when consumed in adequate quantities, confer a health benefit on the host” [49-52]). They have been used in the treatment of a number of inflammatory conditions including UC, CD and experimental colitis [53-64]. The mode of action of probiotics is complex and not completely understood, however multiple mechanisms have been described in vitro.
Based on the success of preventing and treating experimental colitis with VSL#3, Lactobacillus GG and other strains, a number of clinical trials have been executed for both CD and UC. Overall, the data for CD has shown mixed results regarding benefit as either an induction or maintenance adjunct to standard medical therapy. In contrast, probiotics have been shown to benefit UC for both induction and for continued remission of disease. Table 2 [65-73].
As the intestinal microbiota has been linked to the pathogenesis of IBD, probiotic treatment is an avenue for therapeutic intervention. Another method is via the administration of prebiotics. Prebiotics are described as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one, or a limited number of bacteria in the colon, thus improving host health” [74, 75].
The rationale behind prebiotic use is to elevate the endogenous numbers of beneficial bacterial strains including lactobacillus and bifidobacterium [76, 77]. This increase then imparts the beneficial effects seen by probiotic administration, including an increase in short chain fatty acid (SCFA) production, particularly butyrate, which is deficient in the colonic mucosa of UC patients. Butyrate provides fuel for enterocytes, prevents pathogenic adherence and production of anti-bacterial substances, and decreases luminal pH [32, 78-81]. Based on these protective mechanisms, administration of SCFA enemas have been shown to be effective for left-sided UC that is refractory to medical therapy [78-81] .
Common prebiotics include inulin, resistant maltodextrin, oligosaccharides such as fructooligosaccharide (FOS) and galactooligosaccharide (GOS). The body of research involving the use of prebiotics to treat IBD is not currently as extensive as that regarding probiotic therapy. Overall, the four published studies to date all support the use of prebiotics in the treatment of active UC.
n–3 Fatty acids have been promoted as conferring broad health benefits by preventing and treating a wide variety of diseases . In cell culture and animal studies, these essential fatty acids have potent immunomodulatory effects that appear to be mediated both through modulation of eicosanoid synthesis and through an eicosanoid-independent inhibitory effect on the proinflammatory cytokines. Thus, it has been proposed that supplemental n–3 fatty acids might be beneficial in treating or preventing relapse in chronic inflammatory diseases.
For IBD, there are animal in vivo and in vitro studies which all show that n-3 fatty acids can effectively prevent and treat mice-models of colitis [85-90]. An early report on the use of enteric coated formulation for CD found a markedly lower relapse rate for the fish oil group than for the control group (28% compared with 69%; P < 0.001) . However, on the basis of a comprehensive literature review, the available data are insufficient to draw conclusions about the effects of n–3 fatty acids on clinical, endoscopic, or histologic scores or induced remission or relapse rates[88, 90, 92-101].
The data that pertain to the effects of n–3 fatty acids on steroid requirements suggest that n–3 fatty acids may reduce the need for or effective dose of corticosteroids among patients with IBD. Future studies should assess the effects of pharmaceutical grade enteric-coated n–3 fatty acids on clinical outcomes in IBD, including requirements for corticosteroids.
Vitamin D from sunlight exposure is lower in areas where IBD occurs most often, as IBD is most prevalent in northern climates, such as North America and Northern Europe [102, 103]. Vitamin D deficiency is common in patients with IBD even when the disease is in remission . Several observations in animal models of colitis provide strong evidence that establishes vitamin D and vitamin D receptor (VDR) as a physiologic regulator of intestinal inflammation in IBD .
It is unclear why vitamin D deficiency occurs more frequently in both forms of IBD. It is probably due to the combined effects of low vitamin D intake, malabsorption of many nutrients including vitamin D, and decreased outdoor activities in climates that are not optimal for vitamin D synthesis in the skin.
Since the risk of osteoporosis and Vitamin D deficiency is higher in IBD, every patient should be tested for 25-OH vitamin D3 levels . The accumulating evidence for the immunomodulatory effects of VDR ligands certainly provides a rationale for further investigation of their potential in the treatment of IBD.
There is a further need for clinical trials evaluating the potential efficacy of natural approaches in combination with conventional therapy to achieve better outcomes in IBD. Continued education of health care practitioners about the potential benefits of nutraceutical supplements is essential since these therapies are being increasingly employed by patients with IBD.
1. Baumgart DC, Sandborn WJ: Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007, 369(9573):1641-1657.
2. Rawsthorne P, Shanahan F, Cronin NC, Anton PA, Lofberg R, Bohman L, Bernstein CN: An international survey of the use and attitudes regarding alternative medicine by patients with inflammatory bowel disease. The American journal of gastroenterology 1999, 94(5):1298-1303.
3. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC: Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. Jama 1998, 280(18):1569-1575.
4. Garcia-Planella E, Marin L, Domenech E, Bernal I, Manosa M, Zabana Y, Gassull MA: [Use of complementary and alternative medicine and drug abuse in patients with inflammatory bowel disease]. Medicina clinica 2007, 128(2):45-48.
5. Joos S, Rosemann T, Szecsenyi J, Hahn EG, Willich SN, Brinkhaus B: Use of complementary and alternative medicine in Germany - a survey of patients with inflammatory bowel disease. BMC complementary and alternative medicine 2006, 6:19.
6. Bensoussan M, Jovenin N, Garcia B, Vandromme L, Jolly D, Bouche O, Thiefin G, Cadiot G: Complementary and alternative medicine use by patients with inflammatory bowel disease: results from a postal survey. Gastroenterologie clinique et biologique 2006, 30(1):14-23.
7. McCann LJ, Newell SJ: Survey of paediatric complementary and alternative medicine use in health and chronic illness. Archives of disease in childhood 2006, 91(2):173-174.
8. Li FX, Verhoef MJ, Best A, Otley A, Hilsden RJ: Why patients with inflammatory bowel disease use or do not use complementary and alternative medicine: a Canadian national survey. Canadian journal of gastroenterology = Journal canadien de gastroenterologie 2005, 19(9):567-573.
9. Langhorst J, Anthonisen IB, Steder-Neukamm U, Ludtke R, Spahn G, Michalsen A, Dobos GJ: Amount of systemic steroid medication is a strong predictor for the use of complementary and alternative medicine in patients with inflammatory bowel disease: results from a German national survey. Inflammatory bowel diseases 2005, 11(3):287-295.
10. Kong SC, Hurlstone DP, Pocock CY, Walkington LA, Farquharson NR, Bramble MG, McAlindon ME, Sanders DS: The Incidence of self-prescribed oral complementary and alternative medicine use by patients with gastrointestinal diseases. Journal of clinical gastroenterology 2005, 39(2):138-141.
11. Day AS, Whitten KE, Bohane TD: Use of complementary and alternative medicines by children and adolescents with inflammatory bowel disease. Journal of paediatrics and child health 2004, 40(12):681-684.
12. Hilsden RJ, Verhoef MJ, Best A, Pocobelli G: Complementary and alternative medicine use by Canadian patients with inflammatory bowel disease: results from a national survey. The American journal of gastroenterology 2003, 98(7):1563-1568.
13. Quattropani C, Ausfeld B, Straumann A, Heer P, Seibold F: Complementary alternative medicine in patients with inflammatory bowel disease: use and attitudes. Scandinavian journal of gastroenterology 2003, 38(3):277-282.
14. Langmead L, Chitnis M, Rampton DS: Use of complementary therapies by patients with IBD may indicate psychosocial distress. Inflammatory bowel diseases 2002, 8(3):174-179.
15. Hilsden RJ, Meddings JB, Verhoef MJ: Complementary and alternative medicine use by patients with inflammatory bowel disease: An Internet survey. Canadian journal of gastroenterology = Journal canadien de gastroenterologie 1999, 13(4):327-332.
16. Sutherland LR, Verhoef MJ: Why do patients seek a second opinion or alternative medicine? Journal of clinical gastroenterology 1994, 19(3):194-197.
17. Moody GA, Eaden JA, Bhakta P, Sher K, Mayberry JF: The role of complementary medicine in European and Asian patients with inflammatory bowel disease. Public health 1998, 112(4):269-271.
18. Hilsden RJ, Scott CM, Verhoef MJ: Complementary medicine use by patients with inflammatory bowel disease. The American journal of gastroenterology 1998, 93(5):697-701.
19. Hilsden RJ, Verhoef MJ: Complementary and alternative medicine: evaluating its effectiveness in inflammatory bowel disease. Inflammatory bowel diseases 1998, 4(4):318-323.
20. Verhoef MJ, Scott CM, Hilsden RJ: A multimethod research study on the use of complementary therapies among patients with inflammatory bowel disease. Alternative therapies in health and medicine 1998, 4(4):68-71.
21. Moser G, Tillinger W, Sachs G, Maier-Dobersberger T, Wyatt J, Vogelsang H, Lochs H, Gangl A: Relationship between the use of unconventional therapies and disease-related concerns: a study of patients with inflammatory bowel disease. Journal of psychosomatic research 1996, 40(5):503-509.
22. Leong RW, Lawrance IC, Ching JY, Cheung CM, Fung SS, Ho JN, Philpott J, Wallace AR, Sung JJ: Knowledge, quality of life, and use of complementary and alternative medicine and therapies in inflammatory bowel disease: a comparison of Chinese and Caucasian patients. Digestive diseases and sciences 2004, 49(10):1672-1676.
23. Burgmann T, Rawsthorne P, Bernstein CN: Predictors of alternative and complementary medicine use in inflammatory bowel disease: do measures of conventional health care utilization relate to use? The American journal of gastroenterology 2004, 99(5):889-893.
24. Chen ZS, Nie ZW, Sun QL: [Clinical study in treating intractable ulcerative colitis with traditional Chinese medicine]. Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban 1994, 14(7):400-402.
25. Wang B, Ren S, Feng W, Zhong Z, Qin C: Kui jie qing in the treatment of chronic non-specific ulcerative colitis. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan / sponsored by All-China Association of Traditional Chinese Medicine, Academy of Traditional Chinese Medicine 1997, 17(1):10-13.
26. Chen Q, Zhang H: Clinical study on 118 cases of ulcerative colitis treated by integration of traditional Chinese and Western medicine. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan / sponsored by All-China Association of Traditional Chinese Medicine, Academy of Traditional Chinese Medicine 1999, 19(3):163-165.
27. Langmead L, Feakins RM, Goldthorpe S, Holt H, Tsironi E, De Silva A, Jewell DP, Rampton DS: Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis. Alimentary pharmacology & therapeutics 2004, 19(7):739-747.
28. Ben-Arye E, Goldin E, Wengrower D, Stamper A, Kohn R, Berry E: Wheat grass juice in the treatment of active distal ulcerative colitis: a randomized double-blind placebo-controlled trial. Scandinavian journal of gastroenterology 2002, 37(4):444-449.
29. Araki Y, Andoh A, Fujiyama Y, Kanauchi O, Takenaka K, Higuchi A, Bamba T: Germinated barley foodstuff exhibits different adsorption properties for hydrophilic versus hydrophobic bile acids. Digestion 2001, 64(4):248-254.
30. Bamba T, Kanauchi O, Andoh A, Fujiyama Y: A new prebiotic from germinated barley for nutraceutical treatment of ulcerative colitis. Journal of gastroenterology and hepatology 2002, 17(8):818-824.
31. Fukuda M, Kanauchi O, Araki Y, Andoh A, Mitsuyama K, Takagi K, Toyonaga A, Sata M, Fujiyama Y, Fukuoka M et al: Prebiotic treatment of experimental colitis with germinated barley foodstuff: a comparison with probiotic or antibiotic treatment. International journal of molecular medicine 2002, 9(1):65-70.
32. Kanauchi O, Suga T, Tochihara M, Hibi T, Naganuma M, Homma T, Asakura H, Nakano H, Takahama K, Fujiyama Y et al: Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial. Journal of gastroenterology 2002, 37 Suppl 14:67-72.
33. Hanai H, Kanauchi O, Mitsuyama K, Andoh A, Takeuchi K, Takayuki I, Araki Y, Fujiyama Y, Toyonaga A, Sata M et al: Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. International journal of molecular medicine 2004, 13(5):643-647.
34. Shapiro H, Singer P, Halpern Z, Bruck R: Polyphenols in the treatment of inflammatory bowel disease and acute pancreatitis. Gut 2007, 56(3):426-435.
35. Gupta I, Parihar A, Malhotra P, Singh GB, Ludtke R, Safayhi H, Ammon HP: Effects of Boswellia serrata gum resin in patients with ulcerative colitis. European journal of medical research 1997, 2(1):37-43.
36. Gupta I, Parihar A, Malhotra P, Gupta S, Ludtke R, Safayhi H, Ammon HP: Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta medica 2001, 67(5):391-395.
37. Gerhardt H, Seifert F, Buvari P, Vogelsang H, Repges R: [Therapy of active Crohn disease with Boswellia serrata extract H 15]. Zeitschrift fur Gastroenterologie 2001, 39(1):11-17.
38. Hanauer SB: The case for using 5-aminosalicyclates in Crohn's disease: pro. Inflammatory bowel diseases 2005, 11(6):609-612.
39. Hanauer SB: Supplemental evidence. Nature clinical practice 2005, 2(9):375.
40. Gautam SC, Gao X, Dulchavsky S: Immunomodulation by curcumin. Advances in experimental medicine and biology 2007, 595:321-341.
41. Camacho-Barquero L, Villegas I, Sanchez-Calvo JM, Talero E, Sanchez-Fidalgo S, Motilva V, Alarcon de la Lastra C: Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. International immunopharmacology 2007, 7(3):333-342.
42. Kurup VP, Barrios CS, Raju R, Johnson BD, Levy MB, Fink JN: Immune response modulation by curcumin in a latex allergy model. Clin Mol Allergy 2007, 5:1.
43. Sharma S, Chopra K, Kulkarni SK, Agrewala JN: Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway. Clinical and experimental immunology 2007, 147(1):155-163.
44. Holt PR, Katz S, Kirshoff R: Curcumin therapy in inflammatory bowel disease: a pilot study. Digestive diseases and sciences 2005, 50(11):2191-2193.
45. Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Andoh A, Tsujikawa T, Fujiyama Y, Mitsuyama K, Sata M et al: Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006, 4(12):1502-1506.
46. Fedorak RN, Madsen KL: Probiotics and prebiotics in gastrointestinal disorders. Current opinion in gastroenterology 2004, 20(2):146-155.
47. Fedorak RN, Madsen KL: Probiotics and the management of inflammatory bowel disease. Inflammatory bowel diseases 2004, 10(3):286-299.
48. Rioux KP, Fedorak RN: Probiotics in the treatment of inflammatory bowel disease. Journal of clinical gastroenterology 2006, 40(3):260-263.
49. Shanahan F: Host-flora interactions in inflammatory bowel disease. Inflammatory bowel diseases 2004, 10 Suppl 1:S16-24.
50. Shanahan F: Probiotics and the immune response: how much can we expect? Journal of pediatric gastroenterology and nutrition 2004, 39 Suppl 3:S748-749.
51. Shanahan F: Probiotics in inflammatory bowel disease--therapeutic rationale and role. Advanced drug delivery reviews 2004, 56(6):809-818.
52. Sheil B, McCarthy J, O'Mahony L, Bennett MW, Ryan P, Fitzgibbon JJ, Kiely B, Collins JK, Shanahan F: Is the mucosal route of administration essential for probiotic function? Subcutaneous administration is associated with attenuation of murine colitis and arthritis. Gut 2004, 53(5):694-700.
53. Madsen KL, Doyle JS, Jewell LD, Tavernini MM, Fedorak RN: Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology 1999, 116(5):1107-1114.
54. Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E: Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science (New York, NY 2000, 289(5483):1352-1355.
55. O'Mahony L, Feeney M, O'Halloran S, Murphy L, Kiely B, Fitzgibbon J, Lee G, O'Sullivan G, Shanahan F, Collins JK: Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Alimentary pharmacology & therapeutics 2001, 15(8):1219-1225.
56. Shibolet O, Karmeli F, Eliakim R, Swennen E, Brigidi P, Gionchetti P, Campieri M, Morgenstern S, Rachmilewitz D: Variable response to probiotics in two models of experimental colitis in rats. Inflammatory bowel diseases 2002, 8(6):399-406.
57. Dieleman LA, Goerres MS, Arends A, Sprengers D, Torrice C, Hoentjen F, Grenther WB, Sartor RB: Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment. Gut 2003, 52(3):370-376.
58. McCarthy J, O'Mahony L, O'Callaghan L, Sheil B, Vaughan EE, Fitzsimons N, Fitzgibbon J, O'Sullivan GC, Kiely B, Collins JK et al: Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut 2003, 52(7):975-980.
59. Shiba T, Aiba Y, Ishikawa H, Ushiyama A, Takagi A, Mine T, Koga Y: The suppressive effect of bifidobacteria on Bacteroides vulgatus, a putative pathogenic microbe in inflammatory bowel disease. Microbiology and immunology 2003, 47(6):371-378.
60. Moon G, Myung SJ, Jeong JY, Yang SK, Cho YK, Lee SM, Chang HS, Byeon JS, Lee YJ, Lee GH et al: [Prophylactic effect of Lactobacillus GG in animal colitis and its effect on cytokine secretion and mucin gene expressions]. The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi 2004, 43(4):234-245.
61. Rachmilewitz D, Katakura K, Karmeli F, Hayashi T, Reinus C, Rudensky B, Akira S, Takeda K, Lee J, Takabayashi K et al: Toll-like receptor 9 signaling mediates the anti-inflammatory effects of probiotics in murine experimental colitis. Gastroenterology 2004, 126(2):520-528.
62. Gaudier E, Michel C, Segain JP, Cherbut C, Hoebler C: The VSL# 3 probiotic mixture modifies microflora but does not heal chronic dextran-sodium sulfate-induced colitis or reinforce the mucus barrier in mice. The Journal of nutrition 2005, 135(12):2753-2761.
63. Herias MV, Koninkx JF, Vos JG, Huis in't Veld JH, van Dijk JE: Probiotic effects of Lactobacillus casei on DSS-induced ulcerative colitis in mice. International journal of food microbiology 2005, 103(2):143-155.
64. Moller PL, Paerregaard A, Gad M, Kristensen NN, Claesson MH: Colitic scid mice fed Lactobacillus spp. show an ameliorated gut histopathology and an altered cytokine profile by local T cells. Inflammatory bowel diseases 2005, 11(9):814-819.
65. Venturi A, Gionchetti P, Rizzello F, Johansson R, Zucconi E, Brigidi P, Matteuzzi D, Campieri M: Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis. Alimentary pharmacology & therapeutics 1999, 13(8):1103-1108.
66. Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT: Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet 1999, 354(9179):635-639.
67. Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M: Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Alimentary pharmacology & therapeutics 1997, 11(5):853-858.
68. Guslandi M, Giollo P, Testoni PA: A pilot trial of Saccharomyces boulardii in ulcerative colitis. European journal of gastroenterology & hepatology 2003, 15(6):697-698.
69. Ishikawa H, Akedo I, Umesaki Y, Tanaka R, Imaoka A, Otani T: Randomized controlled trial of the effect of bifidobacteria-fermented milk on ulcerative colitis. Journal of the American College of Nutrition 2003, 22(1):56-63.
70. Borody TJ, Warren EF, Leis S, Surace R, Ashman O: Treatment of ulcerative colitis using fecal bacteriotherapy. Journal of clinical gastroenterology 2003, 37(1):42-47.
71. Kruis W, Fric P, Pokrotnieks J, Lukas M, Fixa B, Kascak M, Kamm MA, Weismueller J, Beglinger C, Stolte M et al: Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004, 53(11):1617-1623.
72. Kato K, Mizuno S, Umesaki Y, Ishii Y, Sugitani M, Imaoka A, Otsuka M, Hasunuma O, Kurihara R, Iwasaki A et al: Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermented milk on active ulcerative colitis. Alimentary pharmacology & therapeutics 2004, 20(10):1133-1141.
73. Furrie E, Macfarlane S, Kennedy A, Cummings JH, Walsh SV, O'Neil D A, Macfarlane GT: Synbiotic therapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with active ulcerative colitis: a randomised controlled pilot trial. Gut 2005, 54(2):242-249.
74. Bengmark S, Martindale R: Prebiotics and synbiotics in clinical medicine. Nutr Clin Pract 2005, 20(2):244-261.
75. Lim CC, Ferguson LR, Tannock GW: Dietary fibres as "prebiotics": implications for colorectal cancer. Molecular nutrition & food research 2005, 49(6):609-619.
76. Roberfroid MB: Prebiotics and synbiotics: concepts and nutritional properties. The British journal of nutrition 1998, 80(4):S197-202.
77. Salminen S, Bouley C, Boutron-Ruault MC, Cummings JH, Franck A, Gibson GR, Isolauri E, Moreau MC, Roberfroid M, Rowland I: Functional food science and gastrointestinal physiology and function. The British journal of nutrition 1998, 80 Suppl 1:S147-171.
78. Hallert C, Bjorck I, Nyman M, Pousette A, Granno C, Svensson H: Increasing fecal butyrate in ulcerative colitis patients by diet: controlled pilot study. Inflammatory bowel diseases 2003, 9(2):116-121.
79. Sartor RB: Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology 2004, 126(6):1620-1633.
80. Fernandez-Banares F, Hinojosa J, Sanchez-Lombrana JL, Navarro E, Martinez-Salmeron JF, Garcia-Puges A, Gonzalez-Huix F, Riera J, Gonzalez-Lara V, Dominguez-Abascal F 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). The American journal of gastroenterology 1999, 94(2):427-433.
81. Kanauchi O, Serizawa I, Araki Y, Suzuki A, Andoh A, Fujiyama Y, Mitsuyama K, Takaki K, Toyonaga A, Sata M et al: Germinated barley foodstuff, a prebiotic product, ameliorates inflammation of colitis through modulation of the enteric environment. Journal of gastroenterology 2003, 38(2):134-141.
82. Welters CF, Heineman E, Thunnissen FB, van den Bogaard AE, Soeters PB, Baeten CG: Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Diseases of the colon and rectum 2002, 45(5):621-627.
83. Bengmark S: Synbiotics and the mucosal barrier in critically ill patients. Current opinion in gastroenterology 2005, 21(6):712-716.
84. Ruxton CH, Reed SC, Simpson MJ, Millington KJ: The health benefits of omega-3 polyunsaturated fatty acids: a review of the evidence. J Hum Nutr Diet 2007, 20(3):275-285.
85. Bassaganya-Riera J, Hontecillas R: CLA and n-3 PUFA differentially modulate clinical activity and colonic PPAR-responsive gene expression in a pig model of experimental IBD. Clinical nutrition (Edinburgh, Scotland) 2006, 25(3):454-465.
86. Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, Serhan CN, Kang JX: Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proceedings of the National Academy of Sciences of the United States of America 2006, 103(30):11276-11281.
87. Whiting CV, Bland PW, Tarlton JF: Dietary n-3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis. Inflammatory bowel diseases 2005, 11(4):340-349.
88. Meister D, Ghosh S: Effect of fish oil enriched enteral diet on inflammatory bowel disease tissues in organ culture: differential effects on ulcerative colitis and Crohn's disease. World J Gastroenterol 2005, 11(47):7466-7472.
89. Arita M, Yoshida M, Hong S, Tjonahen E, Glickman JN, Petasis NA, Blumberg RS, Serhan CN: Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proceedings of the National Academy of Sciences of the United States of America 2005, 102(21):7671-7676.
90. Shoda R, Matsueda K, Yamato S, Umeda N: Therapeutic efficacy of N-3 polyunsaturated fatty acid in experimental Crohn's disease. Journal of gastroenterology 1995, 30 Suppl 8:98-101.
91. Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M: Effect of an enteric-coated fish-oil preparation on relapses in Crohn's disease. The New England journal of medicine 1996, 334(24):1557-1560.
92. Arslan G, Brunborg LA, Froyland L, Brun JG, Valen M, Berstad A: Effects of duodenal seal oil administration in patients with inflammatory bowel disease. Lipids 2002, 37(10):935-940.
93. Belluzzi A, Boschi S, Brignola C, Munarini A, Cariani G, Miglio F: Polyunsaturated fatty acids and inflammatory bowel disease. The American journal of clinical nutrition 2000, 71(1 Suppl):339S-342S.
94. Hawkey CJ, Mahida YR, Hawthorne AB: Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators. Agents and actions 1992, Spec No:C22-26.
95. Hillier K, Jewell R, Dorrell L, Smith CL: Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease. Gut 1991, 32(10):1151-1155.
96. Jorquera Plaza F, Espinel Diez J, Olcoz Goni JL: [Inflammatory bowel disease: importance of nutrition today]. Nutr Hosp 1997, 12(6):289-298.
97. Lorenz R, Weber PC, Szimnau P, Heldwein W, Strasser T, Loeschke K: Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease--a randomized, placebo-controlled, double-blind cross-over trial. Journal of internal medicine 1989, 731:225-232.
98. O'Morain C, Tobin A, Suzuki Y, O'Riordan T: Risk factors in inflammatory bowel disease. Scand J Gastroenterol Suppl 1989, 170:58-60; discussion 66-58.
99. Razack R, Seidner DL: Nutrition in inflammatory bowel disease. Current opinion in gastroenterology 2007, 23(4):400-405.
100. Simopoulos AP: Omega-3 fatty acids in inflammation and autoimmune diseases. Journal of the American College of Nutrition 2002, 21(6):495-505.
101. Vilaseca J, Salas A, Guarner F, Rodriguez R, Martinez M, Malagelada JR: Dietary fish oil reduces progression of chronic inflammatory lesions in a rat model of granulomatous colitis. Gut 1990, 31(5):539-544.
102. Podolsky DK: Inflammatory bowel disease (2). The New England journal of medicine 1991, 325(14):1008-1016.
103. Podolsky DK: Inflammatory bowel disease (1). The New England journal of medicine 1991, 325(13):928-937.
104. Pappa HM, Gordon CM, Saslowsky TM, Zholudev A, Horr B, Shih MC, Grand RJ: Vitamin D status in children and young adults with inflammatory bowel disease. Pediatrics 2006, 118(5):1950-1961.
105. Bikle DD: What is new in vitamin D: 2006-2007. Current opinion in rheumatology 2007, 19(4):383-388.
106. Lichtenstein GR, Sands BE, Pazianas M: Prevention and treatment of osteoporosis in inflammatory bowel disease. Inflammatory bowel diseases 2006, 12(8):797-813.
107. Mullin GE, Dobs A: Vitamin d and its role in cancer and immunity: a prescription for sunlight. Nutr Clin Pract 2007, 22(3):305-322.