ARBOR CLINICAL NUTRITION: Probiotics in inflammatory bowel disorders

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ARBOR CLINICAL NUTRITION UPDATES ©

This week focuses on the application of probiotics in inflammatory bowel

disorders (e.g. irritable bowel syndrome, ulcerative colitis, Crohn's

disease etc.).

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Arbor Clinical Nutrition Updates

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NUTRITION RESEARCH REVIEW

Study 1: Probiotics as adjunct in ulcerative colitis

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A recent Chinese trial tested probiotics alongside conventional

ulcerative colitis (UC) treatment.

Subjects and method: Randomised controlled trial comparing 8 weeks of

sulphasalazine/glucocorticoid therapy with or without a probiotic (three

Bifidobacteria) in 30 UC patients. Colonic tissue was biopsied before

and after.

Results: Compared with placebo, the probiotic group had a major

improvement in 2 month follow-up relapse rate (20% in probiotic vs 93%

in placebo, p<0.01), along with reduced expression of transcriptional

factor NFB (a regulator of gut inflammatory reactions), lower levels of

pro-inflammatory cytokines, and higher levels of anti-inflammatory

cytokine IL-10. See Graph (in Acrobat edition).

Ref.: World J Gastroenterol. 2004 May 15;10(10):1521-5.

Study 2: Probiotics and IBS

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A new US trial tested probiotics in treatment of irritable bowel

syndrome (IBS).

Subjects and method: RCT of 48 subjects with chronic symptoms indicative

of IBS given placebo or a combination probiotic (various Bifidobacteria,

Lactobacilli and Streptococcus species) for 4-8 wks.

Results: Compared with placebo, probiotics resulted in significant

improvement in subjective flatulence score (25% less than placebo,

p=0.01) and colonic transit time (25% more than placebo, p=0.05) but not

other symptoms or stool characteristics.

Ref.: Neurogastroenterol Motil. 2005 Oct;17(5):687-96.

Study 3: Probiotics and ileal pouchitis

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A new Swedish trial employed probiotics to counter the side-effect of

ileal pouchitis after colonic resection.

Subjects and method: For 4 weeks fermented milk with live probiotic

organisms (Lactobacilli and Bifidobacteria) was given to patients who

had had ileal-pouch-anal-anastomosis, 51 due to ulcerative colitis, 10

due to familial polyposis.

Results: A range of symptoms (e.g. from involuntary defaecation to

abdominal cramps) and need to use napkins significantly decreased in

probiotic patients, with more response in the UC than polyposis patients.

Ref.: Scand J Gastroenterol. 2005 Jan;40(1):43-51.

COMMENTARY

These three new trials highlight important aspects of the current

research on probiotics in inflammatory bowel diseases (IBD), including

Crohn’s disease, ulcerative colitis and irritable bowel syndrome. We

will consider the evidence on whether probiotics can actually help in

treating IBD, what probiotic research tells us about underlying causes,

and briefly consider the safety of probiotics.

Clinical efficacy

The Table (in Acrobat edition) shows that the human trial evidence of

clinical benefit in IBD is mixed. Although it includes over two dozen

studies involving more than 1500 patients (ref.1-28), we have to

discount those that are open trials, to the extent that these disorders

have a highly variable natural course and are susceptible to

psychological influence. For Crohn’s disease this leaves us with just

one small trial reporting benefit (ref.4), and three others which did

not (ref.1, 2, 5).

For ulcerative colitis, on the other hand, the evidence base is broader

and generally encouraging. Three placebo-controlled RCTs showed

significant clinical improvement (ref.18, 20, 23), and other studies

reported that probiotics (or prebiotics) were at least as effective as

conventional treatment in reducing symptoms, obtaining remission and

preventing relapse (ref.19, 21, 22, 24-26).

Probiotics may be useful in ileal pouchitis (which can be a complication

of surgical colectomy, performed, amongst other things, for severe IBD),

although only one trial in the Table was a placebo-controlled RCT (ref.15).

The remaining trials were on the more `non-specific’ IBS. That data was

hopeful but is not conclusive. Two studies did not find a significant

benefit (in part because of a strong placebo effect) (ref.7, 10), but

others did (ref.6, 8, 9, 11).

Mechanisms

Although the causes of IBD are still something of a mystery, in order to

understand the role of probiotics we need to delve a little bit into

this background.

In the complex aetiology of IBD, a strong genetic influence interacts

with abnormalities in the development and function of intestinal mucosal

immunity, mainly involving T-cells. (Crohn’s disease and UC affect

different types of helper T-cell). The development and functioning of

this gut immunity requires a delicate balance of pro- and

anti-inflammatory cytokines (such as the various interleukins, TNF-a

etc.), apparently interacting through physiological elements such as

toll receptors and dendritic cells (ref.29-31).

The colonic bacterial population is bound up with the development of

this immune function in ways only partially understood. For one thing,

in animal experiments IBD-like pathology will not occur in a sterile gut

(ref.32). Patients with IBD may have an abnormal microflora, in regard

not only to the composition of organisms that make it up, but also their

adhesion to and penetration through the intestinal cells (ref.31-33).

Probiotics can potentially counter all these abnormalities. By applying

`competitive pressure’ they can reduce the population of abnormal

organisms (antibiotics have been used for this as well). They can

reverse adhesion/penetration abnormalities (ref.33, 34). On the other

hand, the extent to which this abnormal flora is the cause rather than

the effect of IBD is still unclear (ref.33).

`Healthy flora’ also plays a direct and crucial role in the development

of GIT immune balance within the T-cell system. The cytokine elements

that keep inflammatory processes in check (e.g. IL-10) have been found

to be reduced in IBD (ref.29, 32), and probiotics can counter this

imbalance (ref.32, 33), as shown in new Study 1. Indeed one trial found

that probiotics’ effect on cytokines was directly correlated with its

clinical efficacy in IBD (ref.6). Probiotics can also influence the toll

receptors and dendritic cells involved in healthy gut immunity (ref.35).

Other possible therapeutic effects include correction of abnormal

intestinal permeability (`leaky gut’), improved mucus production and

production of short chain fatty acids (ref.29, 32).

Safety

Probiotics do have a long history of apparently safe use (ref.35, 36).

Even so, the fact that they can exert potentially powerful immune

effects should give grounds for some caution until we have more data.

This is particularly relevant when we see probiotics being added to

infant formula or given to seriously immuno-compromised patients, in

whom there have been isolated cases of opportunistic infection from

probiotic species (e.g. Enterococcus and Saccharomyces species - ref.35,

36).

There is much that is still unknown. Long term trials (> 1 yr) would be

welcome. Species- and strain-specificity as well as genetic variations

in host susceptibility remain intriguing uncertainties, as we discussed

in last week’s issue (ref.37). Until we have more data on such

specificity, clinicians might be advised to use the particular

probiotics or mixtures proven in RCTs.

Overall we are optimistic about the potential of probiotics to assist

patients with IBD. Whilst some uncertainties in the practicalities of

prescription remain, this is still a treatment option that clinicians

should definitely consider.

References:

1. Inflamm Bowel Dis. 2005 Sep;11(9):833-9.

2. BMC Gastroenterol. 2004 Mar 15;4:5.

3. Eur J Gastroenterol Hepatol. 2003 Jun;15(6):697-8.

4. Dig Dis Sci. 2000 Jul;45(7):1462-4.

5. Gut. 2002 Sep;51(3):405-9.

6. Gastroenterology. 2005 Mar;128(3):541-51.

7. Clin Nutr. 2005 Dec;24(6):925-31.

8. World J Gastroenterol. 2004 May 15;10(10):1521-5.

9. Aliment Pharmacol Ther. 2005 Sep 1;22(5):387-94.

10. J Pediatr. 2005 Aug;147(2):197-201.

11. Clin Ther. 2005 Jun;27(6):755-61.

12. Aliment Pharmacol Ther. 2005 Oct 15;22(8):721-8.

13. Neurogastroenterol Motil. 2005 Oct;17(5):687-96.

14. Scand J Gastroenterol. 2004 Dec;39(12):1228-35.

15. Gastroenterology. 2003 May;124(5):1202-9.

16. Scand J Gastroenterol. 2003 Apr;38(4):409-14.

17. Am J Gastroenterol. 2005 Jul;100(7):1539-46.

18. Gut. 2005 Feb;54(2):242-9.

19. Aliment Pharmacol Ther. 1997 Oct;11(5):853-8.

20. Aliment Pharmacol Ther. 2004 Nov 15;20(10):1133-41.

21. Gut. 2004 Nov;53(11):1617-23.

22. Med Sci Monit. 2004 Nov;10(11):PI126-31.

23. Scand J Gastroenterol. 2005 Jan;40(1):43-51.

24. Int J Mol Med. 2004 May;13(5):643-7.

25. J Am Coll Nutr. 2003 Feb;22(1):56-63.

26. Lancet. 1999 Aug 21;354(9179):635-9.

27. Aliment Pharmacol Ther. 1999 Aug;13(8):1103-8.

28. Drugs Today (Barc). 2005 Jul;41(7):453-9.

29. Nat Rev Drug Discov. 2006 Mar;5(3):197-209.

35. Nutr Rev. 2006 Jan;64(1):1-14.

34. Appl Environ Microbiol. 2005 Jun;71(6):2880-7.

30. Gut. 2005 Mar;54(3):317-20.

33. Gut. 2004 May;53(5):620-2.

31. J R Soc Med. 2003 Apr;96(4):167-71.

32. Gut. 2001 Jan;48(1):132-5.

36. Clin Microbiol Infect. 2005 Dec;11(12):958-66.

37. Arbor Clin Nutr Updates. 2006;246:1-5.

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