Supplements for IBD — The Inside Tract on Treatment
By Gerard E. Mullin, MD, MHS, FACN, CNSP, CNS, AGAF,
and Kathie M. Swift, MS, RD, LDN
Vol. 8 No. 10 P. 76
Mary flew from San Francisco to our integrative medical center (UltraWellness) in Lenox, Mass. She had seen at least a dozen practitioners in the past two years for help in managing Crohn’s disease (CD). Mary had consulted with gastroenterologists, acupuncturists, naturopaths, nutritionists, and herbalists and had traveled to our center for another opinion.
George was diagnosed with ulcerative colitis (UC) and didn’t wait long before seeking a second opinion at Johns Hopkins division of gastroenterology, hoping that a gastroenterologist with specialized training in nutrition may offer him some hope and help.
Mary and George shared more than the pain and frustration common in patients with inflammatory bowel disease (IBD). Both, like many patients who dietitians encounter today, are treating digestive disorders such as CD and UC with nutraceuticals. In many cases, patients have concocted their own formulary of supplements with the help of Google, while others have been prescribed a laundry list of products that various practitioners have recommended.
The use of nutraceutical supplements by patients with gastrointestinal disorders is widespread and growing. Most studies cite that 50% of patients with digestive disorders use supplements. Given that there are more than 90 million Americans who have diagnosed gastrointestinal conditions and may rely on the expert advice of an RD in choosing supplements, we need to be familiar with the evidence supporting their use.
Many clinical trials demonstrate the 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.
IBD: The Fire Within
IBD is a chronic condition characterized by frequent relapses, hospitalizations, diminished quality of life, complications that require surgery, and intestinal cancer.1 The pathophysiology of IBD involves an unremitting intestinal inflammation, proinflammatory cytokines, increased reactive oxygen species, and tissue injury oftentimes triggered by luminal bacteria.1 Opportunities for natural product therapy include modulation of mediators involved in the inflammatory process, altering luminal bacteria, modifying the immune response, and rejuvenation of intestinal healing.
Supplement Use in Digestive Health and Disease
Surveys of complementary and alternative approaches by patients with gastrointestinal complaints have reported usage rates ranging from 21% to 68%.2-16 The use of complementary and alternative medicine (CAM) for all digestive indications appears to be more prevalent in North America than Europe, although the growth of the industry in Europe is now probably faster. As in other contexts, the single most used type of CAM for gastrointestinal disorders is herbal therapy.17-20 Usage appears to be most common in patients with IBD and irritable bowel syndrome.2,9,16 This may be related to the chronic and refractory nature of these disorders, as well as to psychological factors.20,21
Indeed, recent surveys in the United Kingdom and Hong Kong have shown that the use of CAM by patients with IBD is most common in those with poor quality of life.14,22 In a national survey from Germany, 51% of IBD patients had experience with CAM, with the use of homeopathy and herbal therapy being the most popular. Patients’ total systemic steroid intake, suggesting poorly controlled disease, was a strong predictor of CAM use.5 Table 1 summarizes the latest research on the utilization patterns of CAM use in IBD. Surveys have also addressed the reasons why patients used nutraceutical supplements for IBD and which ones they felt were the most effective (see Table 1).5,23 Doctors, dietitians, and gastroenterologists can no longer ignore the widespread usage and potential benefits of nutraceutical supplements for IBD.
Traditional Chinese Medicine (TCM)
Numerous reports in Chinese literature concern the treatment of UC with herbal remedies. However, only three clinical trials have compared combination herbs in both the oral and enema form with conventional medical therapy for UC. In all studies, TCM was superior to both placebo and conventional medical therapy.24-26 Interpreting the results of these comparative studies is compromised by a lack of randomization, standardization of extracts, and blinding.
A randomized, double-blind, controlled study showed that aloe vera gel given for four weeks to patients with moderately active UC was superior to placebo.27 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%), and two (14%; P < 0.05), respectively, of 14 patients taking placebo (using a 2:1 ratio of aloe vera to placebo randomization schedule). The Simple Clinical Colitis Activity Index and histological scores decreased during treatment with aloe vera but not with placebo.
In a randomized, double-blind, controlled trial, 23 patients with active distal UC were given oral wheatgrass juice or placebo for four weeks.28 Treatment with wheatgrass juice was associated with greater reductions in a composite clinical disease activity index, the severity of rectal bleeding, and the doctor’s global assessment than occurred in the placebo group. No side effects were reported.
Germinated Barley Foodstuff (GBF)
Two open-label Japanese trials suggested efficacy in UC for a GBF, consisting mainly of dietary ?ber and glutamine-rich protein that the authors believe to act primarily as a prebiotic.29-32 In the ?rst report, 11 patients given GBF for four weeks as an 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-aminosalicylic acid (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 patients.33 GBF was well tolerated and appeared safe in all three reports.
Polyphenols are phytochemicals found in food substances produced from plants. They 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.34 For IBD, downregulation of inflammatory mediators and nuclear factor kappa beta 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: resveratrol, epigallocatechin, curcumin, quercetin, and Boswellia. Resveratrol, epigallocatechin, curcumin, and quercetin have been demonstrated to display 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 Boswellia serrata and Curcuma longa.
Boswellia serrata, more commonly known as frankincense, is a traditional Ayurvedic remedy and a component of incense. In India, the effect of the gum resin from Boswellia 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%).35 The same authors reported a similar study in 2001 that resulted in a 70% remission rate in 20 patients taking Boswellia for six weeks compared with 40% in 10 patients on sulfasalazine.36 In a randomized, double-blind, controlled eight-week trial, the Boswellia serrata extract H15 was compared with mesalamine for active CD.37 The study included 102 patients and was powered to show noninferiority. The mean Crohn’s Disease Activity Index fell in both groups, and H15 was well tolerated. This result was similar to results 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-in?ammatory effects.40-43 In a recent pilot study, curcumin, when given orally, was reported to benefit ?ve patients with proctitis and ?ve with CD.44 Hanai and colleagues recently published the results of the first randomized, multicenter, double-blind, placebo-controlled trial from Japan to study curcumin’s effect on UC maintenance.45 All 97 patients who enrolled and 89 patients who completed the study took a standard dose of mesalamine or sulfasalazine and either 1 gram of curcumin or placebo twice daily for six months and then were followed for another six months off study medications. The relapse rate at six 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.
Probiotics, Prebiotics, and Synbiotics
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 microorganisms that, when consumed in adequate quantities, confer a health benefit on the host.”49-52 They have been used in the treatment of numerous 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 have shown mixed results for benefiting as either an induction or maintenance adjunct to standard medical therapy. In contrast, probiotics have been shown to benefit UC for both induction and continued remission of disease (see 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 is the administration of prebiotics, which are described as “nondigestible 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 will impart 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 and can provide fuel for enterocytes, prevention of pathogenic adherence, production of antibacterial substances, and decreased luminal pH.32,78-81 Administration of SCFA enemas have been shown effective for left-sided UC that is refractory to medical therapy.78-82
Common prebiotics include inulin, resistant maltodextrin, and oligosaccharides such as fructooligosaccharide and galactooligosaccharide. The body of research involving the use of prebiotics to treat IBD is not currently as extensive as that underlying probiotic therapy. Overall, the four published studies to date all support prebiotic use in the treatment of active UC.
In addition to probiotic and prebiotic administration, another viable option is to use both prebiotic and probiotic administration in conjunction, referred to as synbiotics.74,83 The rationale behind synbiotic treatment is that the desired probiotic and prebiotic (presumably with demonstrated efficacy on their own) would exert a beneficial effect greater than would be observed when administered individually. However, it may be the case that a prebiotic not efficacious when administered alone stimulates the probiotic species, significantly elevating its beneficial effects.
There are few studies demonstrating the positive effects of synbiotic therapy, but it is becoming a more logical and viable treatment option for future IBD studies.
Omega-3 fatty acids have been promoted as conferring broad health benefits by preventing and treating a wide variety of diseases.84 In cell culture and animal studies, these essential fatty acids have potent immunomodulatory effects that appear to be mediated through both modulation of eicosanoid synthesis and an eicosanoid-independent inhibitory effect on the proinflammatory cytokines. Thus, it has been proposed that supplemental omega-3 fatty acids may be beneficial in treating or preventing relapse in chronic inflammatory diseases.
For IBD, there are animal in vivo and in vitro studies that show omega-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 the control group (28% compared with 69%; P < 0.001).91 However, on the basis of a comprehensive literature review, the available data are insufficient to draw conclusions about the effects of omega-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 omega-3 fatty acids on steroid requirements suggest that omega-3 fatty acids may reduce the dosage of corticosteroids needed among patients with IBD. Future studies should assess the effects of pharmaceutical-grade enteric-coated omega-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.104 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.105
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.106 The accumulating evidence for the immunomodulatory effects of VDR ligands provides a rationale for further investigation of their potential in IBD treatment.107
There is a further need for clinical trials of the potential efficacy of natural approaches in combination with conventional therapy to achieve better outcomes in IBD. Continued education of dietitians, physicians, and other healthcare practitioners on the potential benefits of nutraceutical supplements is essential if we are to give well-informed advice to patients like Mary and George who are considering or already using alternative therapies for IBD.
— Gerard E. Mullin, MD, MHS, FACN, CNSP, CNS, AGAF, is director of integrative gastrointestinal nutrition services at Johns Hopkins Hospital.
— Kathie M. Swift, MS, RD, LDN, is nutrition director at the UltraWellness Center in Lenox, Mass.
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, et al. An international survey of the use and attitudes regarding alternative medicine by patients with inflammatory bowel disease. Am J Gastroenterol. 1999;94(5):1298-1303.
3. Eisenberg DM, Davis RB, Ettner SL, et al. 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, Domènech E, et al: [Use of complementary and alternative medicine and drug abuse in patients with inflammatory bowel disease]. Med Clin (Barc). 2007;128(2):45-48.
5. Joos S, Rosemann T, Szecsenyi J, et al. Use of complementary and alternative medicine in Germany - a survey of patients with inflammatory bowel disease. BMC Complement Altern Med. 2006;6:19.
6. Bensoussan M, Jovenin N, Garcia B, et al. Complementary and alternative medicine use by patients with inflammatory bowel disease: results from a postal survey. Gastroenterol Clin Bio. 2006;30(1):14-23.
7. McCann LJ, Newell SJ. Survey of paediatric complementary and alternative medicine use in health and chronic illness. Arch Dis Child. 2006;91(2):173-174.
8. Li FX, Verhoef MJ, Best A, et al. Why patients with inflammatory bowel disease use or do not use complementary and alternative medicine: A Canadian national survey. Can J Gastroenterol. 2005;19(9):567-573.
9. Langhorst J, Anthonisen IB, Steder-Neukamm U, et al. 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. Inflamm Bowel Dis. 2005;11(3):287-295.
10. Kong SC, Hurlstone DP, Pocock CY, et al. The incidence of self-prescribed oral complementary and alternative medicine use by patients with gastrointestinal diseases. J Clin Gastroenterol. 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. J Paediatr Child Health. 2004;40(12):681-684.
12. Hilsden RJ, Verhoef MJ, Best A, et al. Complementary and alternative medicine use by Canadian patients with inflammatory bowel disease: results from a national survey. Am J Gastroenterol. 2003;98(7):1563-1568.
13. Quattropani C, Ausfeld B, Straumann A, et al. Complementary alternative medicine in patients with inflammatory bowel disease: use and attitudes. Scand J Gastroenterol. 2003;38(3):277-282.
14. Langmead L, Chitnis M, Rampton DS. Use of complementary therapies by patients with IBD may indicate psychosocial distress. Inflamm Bowel Dis. 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. Can J Gastroenterol. 1999;13(4):327-332.
16. Sutherland LR, Verhoef MJ. Why do patients seek a second opinion or alternative medicine? J Clin Gastroenterol. 1994;19(3):194-197.
17. Moody GA, Eaden JA, Bhakta P, et al. 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. Am J Gastroenterol. 1998;93(5):697-701.
19. Hilsden RJ, Verhoef MJ. Complementary and alternative medicine: evaluating its effectiveness in inflammatory bowel disease. Inflamm Bowel Dis. 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. Altern Ther Health Med. 1998;4(4):68-71.
21. Moser G, Tillinger W, Sachs G, et al. Relationship between the use of unconventional therapies and disease-related concerns: A study of patients with inflammatory bowel disease. J Psychosom Res. 1996;40(5):503-509.
22. Leong RW, Lawrance IC, Ching JY, et al. Knowledge, quality of life, and use of complementary and alternative medicine and therapies in inflammatory bowel disease: A comparison of Chinese and Caucasian patients. Dig Dis Sci. 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? Am J Gastroenterol. 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. 1994;14(7):400-402.
25. Wang B, Ren S, Feng W, et al: Kui jie qing in the treatment of chronic non-specific ulcerative colitis. J Tradit Chin Med. 1997;17(1):10-13.
27. Langmead L, Feakins RM, Goldthorpe S, et al. Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis. Aliment Pharmacol Ther. 2004;19(7):739-747.
28. Ben-Arye E, Goldin E, Wengrower D, et al. Wheat grass juice in the treatment of active distal ulcerative colitis: a randomized double-blind placebo-controlled trial. Scan J Gastroenterol. 2002;37(4):444-449.
29. Araki Y, Andoh A, Fujiyama Y, et al. 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, et al. A new prebiotic from germinated barley for nutraceutical treatment of ulcerative colitis. J Gastroenterol Hepatol. 2002;17(8):818-824.
31. Fukuda M, Kanauchi O, Araki Y, et al. Prebiotic treatment of experimental colitis with germinated barley foodstuff: a comparison with probiotic or antibiotic treatment. Int J Mol Med. 2002;9(1):65-70.
32. Kanauchi O, Suga T, Tochihara M, et al. Treatment of ulcerative colitis by feeding with germinated barley foodstuff: first report of a multicenter open control trial. J Gastroenterol. 2002;(37 Suppl)14:67-72.
33. Hanai H, Kanauchi O, Mitsuyama K, et al. Germinated barley foodstuff prolongs remission in patients with ulcerative colitis. Int J Mol Med. 2004;13(5):643-647.
34. Shapiro H, Singer P, Halpern Z, et al. Polyphenols in the treatment of inflammatory bowel disease and acute pancreatitis. Gut. 2007;56(3):426-435.
35. Gupta I, Parihar A, Malhotra P, et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res. 1997;2(1):37-43.
36. Gupta I, Parihar A, Malhotra P, et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med. 2001;67(5):391-395.
37. Gerhardt H, Seifert F, Buvari P, et al. [Therapy of active Crohn disease with Boswellia serrata extract H 15]. Z Gastroenterol. 2001, 39(1):11-17.
38. Hanauer SB: The case for using 5-aminosalicyclates in Crohn’s disease: pro. Inflamm Bowel Dis. 2005;11(6):609-612.
39. Hanauer SB. Supplemental evidence. Nat Clin Pract Gastroenterol Hepatol. 2005;2(9):375.
40. Gautam SC, Gao X, Dulchavsky S. Immunomodulation by curcumin. Adv Exp Med Biol. 2007;595:321-341.
41. Camacho-Barquero L, Villegas I, Sanchez-Calvo JM, et al. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmocol. 2007;7(3):333-342.
42. Kurup VP, Barrios CS, Raju R, et al. Immune response modulation by curcumin in a latex allergy model. Clin Mol Allergy. 2007;5:1.
43. Sharma S, Chopra K, Kulkarni SK, et al. Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway. Clin Exp Immunol. 2007;147(1):155-163.
44. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005;50(11):2191-2193.
45. Hanai H, Iida T, Takeuchi K, 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. Curr Opin Gastroenterol. 2004;20(2):146-155.
47. Fedorak RN, Madsen KL. Probiotics and the management of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10(3):286-299.
48. Rioux KP, Fedorak RN. Probiotics in the treatment of inflammatory bowel disease. J Clin Gastroenterol. 2006;40(3):260-263.
49. Shanahan F: Host-flora interactions in inflammatory bowel disease. Inflamm Bowel Dis. 2004;(10 Suppl)1:S16-S24.
50. Shanahan F. Probiotics and the immune response: how much can we expect? J Pediat Gastroenterol Nutr. 2004;(39 Suppl)3:S748-749.
51. Shanahan F. Probiotics in inflammatory bowel disease--therapeutic rationale and role. Adv Drug Deliv Rev. 2004;56(6):809-818.
52. Sheil B, McCarthy J, O’Mahony L, et al. 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, et al. Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology. 1999;116(5):1107-1114.
54. Steidler L, Hans W, Schotte L, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289(5483):1352-1355.
55. O’Mahony L, Feeney M, O’Halloran S, et al. Probiotic impact on microbial flora, inflammation and tumour development in IL-10 knockout mice. Aliment Pharmacol Ther. 2001;15(8):1219-1225.
56. Shibolet O, Karmeli F, Eliakim R, et al: Variable response to probiotics in two models of experimental colitis in rats. Inflamm Bowel Dis. 2002;8(6):399-406.
57. Dieleman LA, Goerres MS, Arends A, et al. 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, 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, et al. The suppressive effect of bifidobacteria on Bacteroides vulgatus, a putative pathogenic microbe in inflammatory bowel disease. Microbiol Immunol. 2003;47(6):371-378.
60. Moon G, Myung SJ, Jeong JY, et al. [Prophylactic effect of Lactobacillus GG in animal colitis and its effect on cytokine secretion and mucin gene expressions]. Korean J Gastroenterol. 2004;43(4):234-245.
61. Rachmilewitz D, Katakura K, Karmeli F, 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, et al. The VSL#3 probiotic mixture modifies microflora but does not heal chronic dextran-sodium sulfate-induced colitis or reinforce the mucus barrier in mice. J Nutr. 2005;135(12):2753-2761.
63. Herias MV, Koninkx JF, Vos JG, et al. Probiotic effects of Lactobacillus casei on DSS-induced ulcerative colitis in mice. Int J Food Microbiol. 2005;103(2):143-155.
64. Moller PL, Paerregaard A, Gad M, et al. Colitic scid mice fed Lactobacillus spp. show an ameliorated gut histopathology and an altered cytokine profile by local T cells. Inflamm Bowel Dis. 2005;11(9):814-819.
65. Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of the faecal flora by a new probiotic preparation: Preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther. 1999;13(8):1103-1108.
66. Rembacken BJ, Snelling AM, Hawkey PM, et al. 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, et al. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Therapeutics. 1997;11(5):853-858.
68. Guslandi M, Giollo P, Testoni PA. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur J Gastroenterol Hepatol. 2003;15(6):697-698.
69. Ishikawa H, Akedo I, Umesaki Y, et al. Randomized controlled trial of the effect of bifidobacteria-fermented milk on ulcerative colitis. J Am Coll Nutr. 2003;22(1):56-63.
70. Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003;37(1):42-47.
71. Kruis W, Fric P, Pokrotnieks J, 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, et al: Randomized placebo-controlled trial assessing the effect of bifidobacteria-fermented milk on active ulcerative colitis. Aliment Pharmacol Ther. 2004;20(10):1133-1141.
73. Furrie E, Macfarlane S, Kennedy A, et al. 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. Mol Nutr Food Res. 2005;49(6):609-619.
76. Roberfroid MB. Prebiotics and synbiotics: concepts and nutritional properties. The Brit J Nutr. 1998;80(4):S197-202.
77. Salminen S, Bouley C, Boutron-Ruault MC, et al. Functional food science and gastrointestinal physiology and function. Brit J Nutr. 1998;80(Suppl 1):S147-171.
78. Hallert C, Bjorck I, Nyman M, et al. Increasing fecal butyrate in ulcerative colitis patients by diet: controlled pilot study. Inflamm Bowel Dis. 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. Fernández-Bañares F, Hinojosa J, Sánchez-Lombraña JL, 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(2):427-433.
81. Kanauchi O, Serizawa I, Araki Y, et al. Germinated barley foodstuff, a prebiotic product, ameliorates inflammation of colitis through modulation of the enteric environment. J Gastroenterol. 2003;38(2):134-141.
82. Welters CF, Heineman E, Thunnissen FB, et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with an ileal pouch-anal anastomosis. Dis Colon Rectum. 2002;45(5):621-627.
83. Bengmark S. Synbiotics and the mucosal barrier in critically ill patients. Curr Opin Gastroenterol. 2005;21(6):712-716.
84. Ruxton CH, Reed SC, Simpson MJ, et al. 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. Clin Nutr. 2006;25(3):454-465.
86. Hudert CA, Weylandt KH, Lu Y, et al. Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc Natl Acad Sci U S A. 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. Inflamm Bowel Dis. 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, et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Proc Natl Acad Sci U S A. 2005;102(21):7671-7676.
90. Shoda R, Matsueda K, Yamato S, et al. Therapeutic efficacy of N-3 polyunsaturated fatty acid in experimental Crohn’s disease. J Gastroenterol. 1995;30 Suppl 8:98-101.
91. Belluzzi A, Brignola C, Campieri M, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. N Engl J Med. 1996;334(24):1557-1560.
92. Arslan G, Brunborg LA, Froyland L, et al. 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, et al: Polyunsaturated fatty acids and inflammatory bowel disease. Am J Clin Nutr. 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 Actions. 1992;Spec No:C22-26.
95. Hillier K, Jewell R, Dorrell L, et al. 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 Goñi JL. [Inflammatory bowel disease: Importance of nutrition today]. Nutr Hosp. 1997;12(6):289-298.
97. Lorenz R, Weber PC, Szimnau P, et al. Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo-controlled, double-blind cross-over trial. J Intern Med Suppl. 1989;731:225-232.
98. O’Morain C, Tobin A, Suzuki Y, et al. Risk factors in inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:58-60.
99. Razack R, Seidner DL. Nutrition in inflammatory bowel disease. Curr Opin Gastroenterol. 2007;23(4):400-405.
100. Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002;21(6):495-505.
101. Vilaseca J, Salas A, Guarner F, et al. 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). N Engl J Med. 1991;325(14):1008-1016.
103. Podolsky DK. Inflammatory bowel disease (1). N Engl J Med. 1991;325(13):928-937.
104. Pappa HM, Gordon CM, Saslowsky TM, et al. 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. Curr Opin Rheumatology. 2007;19(4):383-388.
106. Lichtenstein GR, Sands BE, Pazianas M. Prevention and treatment of osteoporosis in inflammatory bowel disease. Inflamm Bowel Dis. 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.