Whats New in The Understanding Of The Immunology Of Ulcerative Colitis?

IBD’s are characterised by wasting and chronic intestinal inflammation induced by many different cytokine-mediated pathways. It is clearly recognised that medical and surgical interventions do not cure Crohn’s disease because relapse is the rule after remission.

Until a few years ago, IBD was classified into Th1-dependent, that is, Crohn’s disease, and Th2-dependent, that is, ulcerative colitis, phenotypes. However, in recent years, it has been shown that new T-cell subclasses, that is, Th17 and regulatory T cells (T_R), exist independently of Th1 and Th2 and that they play a central role in modulating IBD.

Comment

The role of alternative interventions – non pharmacological – are reviewed in terms of their likelihood of success in relation to ulcerative colitis

Ulcerative colitis (UC)

Is a disease of unknown aetiology characterised by inflammation of the mucosa and occasionally the submucosa of the colon. Conventional drug therapy for ulcerative colitis involves use of aminosalicylates, corticosteroids, azathioprine/6-mercaptopurine, cyclosporine and anti-tumour necrosis factor therapy. Alternative therapies include probiotics, nicotine and fish oil. Absence of enteric parasites in the developed world and defective mucosal defence mechanisms are some of the hypotheses behind the pathogenesis.

Probiotics

Modulate the immune system in the gut by inducing protective cytokines and suppressing proinflammatory cytokines. Trials have shown their benefit in preventing relapse in UC. E. coli 1917 Nissle was as effective as 5-ASA in preventing relapse.[1] A combination of eight species of bacteria called VSL#3, in combination with balsalazide, was slightly more effective than balsalazide or mesalamine alone in mild-to-moderate ulcerative colitis.[2] Lactobacillus GG was shown to be more effective then mesalamine in prolonging relapse free time in ulcerative colitis.[3]

Saccharomyces Boulardii

In ulcerative colitis, a preliminary trial showed Saccharomyces Boulardii to be effective in treatment.[4] A group of 25 patients with a mild to moderate clinical flare-up of ulcerative colitis received additional treatment with S. boulardii 250 mg three times a day for 4 weeks during maintenance treatment with mesalazine. These patients were unsuitable for steroid therapy.

Before and after treatment, Rachmilewitz’s clinical activity index was calculated. The probiotic treatment was considered a therapeutic success only when the final score was lower than 6. Of the 24 patients who completed the study, 17 attained clinical remission; this was confirmed endoscopically.

These preliminary results suggest that S. boulardii can be effective in the treatment of ulcerative colitis.

Fish Oil

Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa. Eicosapentaenoic acid (EPA) derived from fish oil inhibits leukotriene activity. One study showed that fish oil dietary supplementation results in clinical improvement of active mild-to-moderate ulcerative colitis but is not associated with a significant reduction in mucosal leukotriene B4 production, compared with placebo therapy.[5]

A double blind placebo controlled crossover trial of 24 patients with active ulcerative colitis showed reductions in rectal dialysate leukotriene B4 levels, improvements in histologic findings, and weight gain.[6],[7]

Another randomised controlled trial showed that a fish oil-enriched oral supplement significantly decreased the dose of prednisone required to control clinical symptoms.[8] The dose of fish oil 2.7gms (0.18 g EPA/capsule) is 15-18 capsules per day. The large number of capsules in this study as well as the development of a fishy odour in the breath might reduce patient compliance. Nordic Naturals produce fish oils supplements that are designed to prevent the risk of odour and repeating, and are of higher concentration – requiring less capsules, making compliance much easier.

Trichuris Suis

Ulcerative colitis is rare in developing countries. A higher rate of helminth infections and colonisation is thought to be a potential reason for this. Chronic helminthic infections cause persistent immune activation that results in hyporesponsiveness and anergy.[9] This impaired immune function may diminish the capacity of these individuals to mount an immune response and hence decrease the risk of ulcerative colitis.

One study looked at 54 patients with active Ulcerative Colitis who were randomly assigned to ingestion of Trichuris suis ova or placebo for 12 weeks. Improvement in disease activity occurred in 43.3% patients with ova treatment compared with 16.7% patients given placebo.[10] Additional studies are needed to further evaluate this option. Other groups are also looking at worm therapy as a viable alternative to immunosuppressive medication.

Mucous Support

In the active phase of the disease, Ulcerative Colitis patients exhibit reductions in the thickness of the colonic mucous layer, in the number of mucus-containing goblet cells, and in ex vivo analysed MUC2 production (the main secreted-colonic mucin).[11] The probiotic Bifido Bifidus a colon dominating strain has been shown to increase mucous production, and may represent a strategy for improved inflammation control in these patients.[12]

Safety

Cases of infection due to lactobacilli and bifidobacteria are extremely rare, and are estimated to occur at a rate of approximately 0.05%–0.4% of all cases of infective endocarditis and bacteraemia.[13]

Comment

This complex interplay of genetic, microbial and environmental factors culminates in a sustained activation of the mucosal immune and non-immune response, probably facilitated by defects in the intestinal epithelial barrier and mucosal immune system, resulting in active inflammation and tissue destruction. Therefore clinical therapy needs to be directed against a number of events simultaneously, each persons genetic, environmental and socal background will also impact on outcomes, so be prepared to add or extract interventions as needed.

References

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[1] Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative col itis: a randomised trial. Lancet. 1999 Aug 21;354(9179):635-9. View Abstract

[2] Tursi A, Brandimarte G, Giorgetti GM, Forti G, Modeo ME, Gigliobianco A. Low-dose balsalazide plus a high-potency probiotic preparation is more effective than balsalazide alone or mesalazine in the treatment of acute mild-to-moderate ulcerative colitis. Med Sci Monit. 2004 Nov;10(11):PI126-31. View Abstract

[3] Zocco MA, dal Verme LZ, Cremonini F, Piscaglia AC, Nista EC, Candelli M, Novi M, Rigante D, Cazzato IA, Ojetti V, Armuzzi A, Gasbarrini G, Gasbarrini A. Efficacy of Lactobacillus GG in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther. 2006 Jun 1;23(11):1567-74.View Abstract

[4] Guslandi M, Giollo P, Testoni PA. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur J Gastroenterol Hepatol. 2003 Jun;15(6):697-8. View Abstract

[5] Aslan A, Triadafilopoulos G. Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. Am J Gastroenterol. 1992 Apr;87(4):432-7. View Abstract

[6] Seidner DL, Lashner BA, Brzezinski A, Banks PL, Goldblum J, Fiocchi C, Katz J, Lichtenstein GR, Anton PA, Kam LY, Garleb KA, Demichele SJ.  An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: a randomized, controlled trial. Gastroenterol Hepatol. 2005 Apr;3(4):358-69. View Abstract

[7] Stenson WF, Cort D, Rodgers J, Burakoff R, DeSchryver-Kecskemeti K, Gramlich TL, Beeken W. Dietary supplementation with fish oil in ulcerative colitis. Ann Intern Med. 1992 Apr 15;116(8):609-14. View Abstract

[8] Seidner DL, Lashner BA, Brzezinski A, Banks PL, Goldblum J, Fiocchi C, Katz J, Lichtenstein GR, Anton PA, Kam LY, Garleb KA, Demichele SJ.An oral supplement enriched with fish oil, soluble fiber, and antioxidants for corticosteroid sparing in ulcerative colitis: a randomized, controlled trial. Clin Gastroenterol Hepatol. 2005 Apr;3(4):358-69. View Abstract

[9] Borkow G, Leng Q, Weisman Z, Stein M, Galai N, Kalinkovich A, Bentwich Z.Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy. J Clin Invest. 2000 Oct;106(8):1053-60. View Abstract

[10] Summers RW, Elliott DE, Weinstock JV.  Why Trichuris suis should prove safe for use in inflammatory bowel diseases. Inflamm Bowel Dis.  2005 Aug;11(8):783-4. No Abstract

[11] Faure M, Moënnoz D, Montigon F, Mettraux C, Breuillé D, Ballèvre O.J Nutr. Dietary threonine restriction specifically reduces intestinal mucin synthesis in rats. 2005 Mar;135(3):486-91. View Abstract

[12] Khailova L, Dvorak K, Arganbright KM, Halpern MD, Kinouchi T, Yajima M, Dvorak B.Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol. 2009 Nov;297(5):G940-9. View Abstract

[13] Borriello SP, Hammes WP, Holzapfel W, Marteau P, Schrezenmeir J, Vaara M, Valtonen V. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 2003 Mar 15;36(6):775-80. Epub 2003 Mar 5. View Abstract