Probiotic Strategies for the treatment of Inflammatory Bowel Disorders

Donal Coakley 3rd Year Pharmacy Pharmacology Student Number 104423275

Contents
Page Abstract Introduction History Nowadays Current Treatments Clinical Trials Ulcerative Colitis Pouchitis Crohns Disease Irritable Bowel Syndrome Conclusions References 3 3 3 4 4 5 5 6 7 8 9 10

Probiotic Strategies for the treatment of Inflammatory Bowel Disorders

Abstract
The use of probiotics in the treatment of Inflammatory Bowel Disorders like Crohns Disease and Crohns disease is an unresolved issue. The use of probiotics is often down to anecdotal evidence and rarely in a standardised form. Probiotics are freely available in many yogurts and food supplements. The effectiveness of probiotics as a treatment has not been conclusively proven by any study. Most studies are of limited numbers (less than 50 in many cases) also only one dose of the probiotic is often tried. Despite these limitations many of the trials have yielded positive results which should be examined carefully and more extensive trials carried out. Probiotics need to be investigated especially when current treatments are not totally effective. Probiotics represent a possible simple solution to a highly complex category of disorders.

Introduction
The term inflammatory bowel disorder encompasses a number of clinical conditions. These include ulcerative colitis, crohns disease, pouchitis and irritable bowel syndrome. The precise causes of these conditions remain unknown (Fiocchi C 1998) however studies on mice have shown that mice deficient in the anti-inflammatory interleukin-10 spontaneously develop colonic inflammation if raised under specific pathogen free conditions (Kuhn et al 1993). However when the mice were treated with the probiotic L.plantarum the induced colitis was attenuated (Schultz et al 1998).

History
Probiotics have long been touted as having health benefits. Probiotics are defined by the Joint Food and Agriculture Organisation (FAO) of the U.N and WHO as live micro organisms which when administered confer a health benefit on the host. Elias Metchnikoff was one of the first people to suggest that the presence of bacteria in the human gut could prolong life. In 1917 Alfred Nissle was the first person to use probiotics in the treatment of inflammatory bowel disease. Nissle isolated bacteria from the stools of soldiers who did not suffer diarrhoea when their comrades did. He used one isolated bacteria to treat a 20 year old women with chronic active ulcerative colitis. This strain was E.coli Nissle 1917. She received 200mg per day for 7 weeks. She entered remission of ulcerative colitis after 5 weeks. This was almost certainly the first clinical trial of probiotics. However despite this success it was not until the late 1990s that the first clinical trials were carried out.

Nowadays
Probiotics are widely available and are actively promoted by food companies like Danone as immunity boosting (Actimel L.casei immunitas) and digestion aids (Activia Bifidus Digestum). There are preparations of probiotics which have been successfully used in clinical trials. One of these is VSL#3 which is manufactured by VSL Pharmaceuticals Inc Florida. It contains 4 strains of Lactobacilli (L.casei, L.plantarum, L.acidophilus and L.delbrueckii) 3 strains of Bifidobacterium (B.longum, B.breve and B.infantis) and S.thermophilus. Most clinical trials tend to use individual strains of probiotics instead of multi-spectrum probiotics like VSL#3. At the moment probiotics are considered an alternative medicine for the treatment of IBD. A recent German study (Joos et al 2006) found that 43% of a study group (246 with Crohn's disease and 164 with ulcerative colitis) had used probiotics. This was second only to acupuncture. Patients using probiotics also reported more positive therapeutic results than other therapies. However 77% of the participants felt poorly informed about alternative therapies.

Current Treatments
Current treatments for Crohns disease include aminosalyicates, glucocorticoids, antibiotics and a new drug infliximab (which is an antibody to tumour necrosis factor). Infliximab does however have its risks as demonstrated by a recent study at Harvard Medical School. In two cohorts of 100,000 patients with active Crohns Disease there were 201 more lymphomas and 249 more deaths related to complications from infliximab than in the cohort on standard treatment. The infliximab was however significantly more effective, leading to 12,216 more patients in remission (Corey et al 2006).This demonstrates that the problem with Inflammatory Bowel Disease has not been solved by Infliximab as well as this infliximab comes with a high economic cost. Glucocorticoids remain the main treatment for the induction of remission of moderate to severe Ulcerative colitis (Domenech 2006). However in many cases removal of the colon is necessary. Pouchitis can be treated using antibiotics. Infliximab and aminosalyicates can be used in more severe cases. An interesting strategy that has emerged is the use of probiotics as adjuvants to current therapy. Irritable bowel syndrome has no universally effective therapy. Standard treatment for IBS is to treat the symptoms e.g. laxatives for constipation and smooth muscle relaxants for associated pain. A new treatment Tegaserod acts on 5HT4 receptors and is used in some cases of IBS to relieve constipation. Probiotics have shown some promise in the treatment of IBS.

Clinical Trials
One of the major problems with clinical trials in this area is the differing probiotic strains, doses and formulations used. This leads to a lot of variables. The efficacy of one strain of probiotics does not mean that all probiotics are effective. The term probiotic tends to be used instead of the genus and strain of probiotic. This needs to be clarified and the doses used standardised. An interesting aspect of the clinical trials studied is the use of prebiotics in combination with probiotics. Interestingly the trials that used the combination yielded positive results. Pre-biotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating growth or activity, or both of one or a restricted number of bacteria in the colon (Lim C et al 2005). The use of probiotics in combination with prebiotics warrants further research.

Probiotics in Inflammatory Bowel Disease Ulcerative Colitis

Ulcerative Colitis is a disease of the lining of the large bowel. It is chronic and has frequent relapses. A recent study showed that treatment with Lactobacillus GG seems to be more effective than standard treatment with mesalazine in prolonging the relapse free time (Zocco et al 2003). The patients were treated with 18x10^9 viable bacteria/day either with or without 2400mg daily of mesalazine. Another group just received 2400mg daily of mesalazine. LGG alone was just as effective as mesalazine and provided significantly better efficacy in delaying relapses of UC. Two studies showed that E.coli Nissle 1917 is as effective as mesalazine in maintaining remission of UC (Kruis et al 2001 and Rembracken et al 1999). One randomised controlled pilot trial used symbiotic therapy (Bifidobacterium longum/Synergy) in 18 patients with active UC for one month. Biological markers for UC like TNFalpha and Interleukin 1alpha were significantly reduced. Biopsies also revealed reduced inflammation (Furrie et al 2005). A six week study by Bilboni et al found that the probiotic mixture VSL#3 induced remission of active ulcerative colitis in 53% of the 32 patients treated. Only 9% of the patients had worsened symptoms (Bibloni et al 2005).

One study investigated the use of 3g/day of VSL#3 probiotic in combination with 2.25g/day of balsalazide. It was found to be significantly superior to balsalazide alone and mesalazine alone in obtaining remission of mild to moderate UC (Tursi et al 2004). The evidence from the above trials supports the strategy of using probiotics in the treatment of acute mild to moderate UC and in the maintenance of remission in chronic UC. The use of probiotics as an adjuvant to existing treatment seems particularly promising. However the small numbers of patients and the short trial period limit the importance of the results. They do however warrant further extensive investigation as the current therapy is not entirely successful at treating ulcerative colitis. Many patients require surgery like ileal ouch anal anastomosis for Ulcerative Colitis and following surgery complications like Pouchitis can develop.

Pouchitis
The probiotic combination VSL#3 has been shown to be effective in preventing Pouchitis onset in patients who underwent ileal pouch-anal anastomosis for UC. Pouchitis is a non-specific, idiopathic inflammation of the ileal reservoir. It is the most frequent long term complication following pouch surgery for UC (Sandborn 1994). In the study using VSL#3 two of the twenty patients treated with VSL#3 for one year had an episode of acute Pouchitis compared to 8 of the 20 patients treated with placebo. Also treatment with VSL#3 showed a significant improvement in an inflammatory bowel disease questionnaire when compared to placebo (Gionchetti et al 2003) . In contrast a study on the effect of LGG on Pouchitis yielded less positive results. Twenty patients with a history of Pouchitis took part in the randomised double blind placebo controlled trial. Only 40% of the patients receiving LGG were colonised with LGG and no differences were observed with regard to disease symptoms between the groups (Kuisma et al 20030. Trials of probiotics on Pouchitis are extremely limited and the numbers involved in both trials were very small. Conclusions cannot be made on the basis of two trials.

Crohns Disease
The strategy of using probiotics in Crohns disease has not been tested widely. Crohns disease is very difficult to treat. 70% of people suffering from Crohns disease are operated on and the rate of occurrence within one year of the operation is between 70 and 90% (Rutgeerts et al 1990 and Olaison et al 1992) For this reason three trials studied the effectiveness of probiotics in preventing the reoccurrence of Crohns disease. In one study patients were given 12 billion cfu of Lactobacillus GG in a randomised placebo controlled trial. Clinical reoccurrence was observed in three (16.6%) patients on LGG and in two (10.5%) who received placebo. The rate of endoscopic reoccurrence was also higher in those on LGG versus those on placebo (35.3%). The study reported that there were no significant differences in the severity of the lesions (Prantera et al 2000). One other study showed that probiotics in combination with antibiotics was more effective than mesalazine alone. The study used the probiotic preparation VSL#3 (Rizzello et al 2000). Endoscopic reoccurrence was lower in the probiotic group (20%) than in the mesalazine group (40%) Saccharomyces Boulardi was successfully used in combination with mesalazine in reducing reoccurrence of Crohns disease. When compared to mesalazine alone the combination was found to be superior (1 in 16 relapses versus 6 in 16 relapses) (Guslandi et al 2000). Increased mucosal TNF-alpha production in Crohns disease was shown to be reduced by lactobacilli in another study. This however was an in-vitro study. ( Borruel et al 2001) The problem with the trials carried out using probiotics to treat Crohns disease is that the trials are not of sufficient size. Despite this it does seem that probiotics are best used in combination with existing therapies to prevent the reoccurrence following surgery. The use of probiotics alone to induce remission has not been properly tested.

Irritable Bowel Syndrome

Studies on the effect of probiotic treatment on Irritable Bowel Syndrome have yielded contrasting results. One of the main problems with studies in this area is the varying doses of probiotics given. A recent study highlighted this problem by giving three different doses of the probiotic Bifidobacterium infantis 35624 to women with IBS. The study found that B.infantis at a dose of 1x10^8 cfu was significantly superior to placebo and all other Bifidobacterium doses in alleviating the symptoms of IBS. The two other doses of probiotic (1x10^6 cfu and 1x10^10 cfu) were not significantly different from placebo (Whorwell et al 2006). Another study on Bifidobacterium infantis 35624 found that the symptomatic alleviation of IBS was associated with normalisation of the ratio of an anti-inflammatory to a pro-inflammatory cytokine (OMahony et al 20050. The use of a probiotic-prebiotic combination Prescript assist in IBS was investigated. Prescriptassist is a broad spectrum probiotic consisting of 29 soil based pH resistant micro flora with a probiotic. The double blind placebo controlled clinical study included 25 people. Treatment with prescript-assist was associated with significant reductions in IBS symptoms (Bittner et al 2005). Studies on VSL#3 found that VSL#3 did reduce abdominal bloating and flatulence in patients with irritable bowel syndrome. However the overall symptoms of IBS were not significantly reduced (Kim et al 2005).

An early study by Niedzielin found that Lactobacillus plantarum 299v was effective at alleviating abdominal pain in 20 IBS patients when compared to placebo. The trial however was only four weeks long. This probiotics warrants further research as the results were promising (Niedzielin et al 2001). In a trial on the probiotic Lactobacillus reuteri ATCC 55730 IBS symptoms didnt improve after six months of receiving 1x10^8 cfu of Lactobacillus reuteri ATCC 55730. Constipation and flatulence was marginally improved in the L.reuteri ATCC 55730 group over placebo (Niv et al 2005).

Conclusions
The trials that have been carried out on probiotics suggest that probiotics can be an effective strategy in the treatment of IBD. The use of probiotics as a strategy in the treatment of IBD has to be examined especially when existing treatments are not very effective at alleviating the symptoms of IBD. Newer therapies like infliximab have shown promise but there is still a huge untapped market for a proven cure to IBD or even a proven inducer of remission. However more work needs to be done to investigate the relationship between the dose of probiotics and the effectiveness of probiotic. The importance of the dose of probiotics was well demonstrated in the study using B.infantis 35624 to treat IBS in women. Only one of the doses effectively alleviated the symptoms of IBS and importantly it wasnt the highest dose. This demonstrates the possibility that like most other drugs probiotics are dose dependent. The clinical trials also demonstrate that different strains of bacteria are more effective at treating particularly disorders. The statement that probiotics are effective at treating a particular disorder is a very general statement. The genus and strain of bacteria used should be stated instead of the general term probiotics as this is misleading. The issue of the use of prebiotics also warrants extensive further investigation as their use in small clinical trials has been promising. A prebiotic is a nondigestible food ingredient whose beneficial effects on the host result from the selective stimulation of growth and/or activity of members of the bacterial community that inhabits the human bowel (the gut micro biota). Prebiotics could be an important strategy in enhancing the effectiveness of probiotics. A promising strategy appears to be the use of probiotics as adjuvants to current drugs. Probiotics combined with existing drugs like aminosalyicates have been used efficaciously in maintaining remission of UC and in inducing remission in Crohns disease. A trial using probiotics as adjuvants to infliximab would be of interest as it has already been demonstrated that infliximab is efficacious in the treatment of Crohns disease. (Corey et al 2006) The fact remains that probiotics have neither been proven nor disproved as an effective strategy for the treatment of IBD. A lot of work still needs to be done especially with regards to increased participation in clinical trials as current trials are simply too small.

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