Probiotic Strategies for the Treatment of Inflammatory Bowel Disorders

8/3/2019 Probiotic Strategies for the Treatment of Inflammatory Bowel Disorders

1/13

Probiotic Strategies for

the treatment ofInflammatory BowelDisorders

Donal Coakley

3rd Year Pharmacy

Pharmacology

Student Number104423275


2/13

Contents

Page

Abstract 3

Introduction 3

History 3

Nowadays 4

Current Treatments 4

Clinical Trials 5

Ulcerative Colitis 5

Pouchitis 6

Crohns Disease 7

Irritable Bowel Syndrome 8

Conclusions 9

References 10


3/13

Probiotic Strategies for the treatment ofInflammatory Bowel Disorders

AbstractThe 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 foodsupplements. 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 resultswhich 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.

IntroductionThe 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 shownthat 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 probioticL.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 peopleto 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 usedone isolated bacteria to treat a 20 year old women with chronic active ulcerative colitis. This strain

wasE.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 carriedout.


4/13

Nowadays

Probiotics are widely available and are actively promoted by food companies like Danone asimmunity boosting (ActimelL.casei immunitas) and digestion aids (ActiviaBifidus 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 ofLactobacilli (L.casei, L.plantarum, L.acidophilus andL.delbrueckii) 3 strains ofBifidobacterium

(B.longum, B.breve andB.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 diseaseand 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 relatedto 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 byInfliximab 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 (Domenech2006). However in many cases removal of the colon is necessary. Pouchitis can be treated usingantibiotics. 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.
http://images.google.com/imgres?imgurl=http://www.spesaonline.com/SOL/images/products/big/80649502.jpg&imgrefurl=http://www.fonzito.com/catalogo/id_89/960/Cido%2Be%2BBevande.html&h=170&w=170&sz=9&hl=en&start=1&tbnid=0a8ufMfgquiR2M:&tbnh=99&tbnw=99&prev=/images%3Fq%3DDanone%2BActivia%26svnum%3D10%26hl%3Den%26lr%3D%26rls%3Dcom.microsoft:en-UShttp://images.google.com/imgres?imgurl=http://www.spesaonline.com/SOL/images/products/big/270267.jpg&imgrefurl=http://www.fonzito.com/catalogo/id_89/990/Cido%2Be%2BBevande.html&h=170&w=170&sz=11&hl=en&start=1&tbnid=aTAc0ZLG66sPjM:&tbnh=99&tbnw=99&prev=/images%3Fq%3DDanone%2BActimel%26svnum%3D10%26hl%3Den%26lr%3D%26rls%3Dcom.microsoft:en-US%26sa%3DN


5/13

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 doesnot 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 non-digestible 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 withLactobacillus 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 ofmesalazine. 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 thatE.coli Nissle 1917is as effective as mesalazine in maintaining remissionof 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).


6/13


7/13

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 ofoccurrence 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 ofLactobacillus GG in arandomised 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 onLGG versus those on placebo (35.3%). The study reported that there were no significantdifferences 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 arenot 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.


8/13

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 probioticBifidobacterium infantis 35624 to women with IBS. The study found that B.infantis at a dose of1x10^8 cfu was significantly superior to placebo and all otherBifidobacterium 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 onBifidobacterium 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. Prescript-assist 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 withprescript-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 thatLactobacillus plantarum 299v was effective at alleviatingabdominal 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 probioticLactobacillus reuteri ATCC 55730 IBS symptoms didnt improve aftersix months of receiving 1x10^8 cfu ofLactobacillus reuteri ATCC 55730. Constipation and

flatulence was marginally improved in theL.reuteri ATCC 55730 group over placebo (Niv et al

2005).


9/13

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 ofIBD. 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 usingB.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 drugsprobiotics are dose dependent. The clinical trials also demonstrate that different strains of bacteriaare 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 thebacterial 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 maintainingremission 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.


10/13

References

Bibiloni R ; Fedorak RN ; Tannock GW ; Madsen KL ; Gionchetti P ; Campieri M ; De Simone C ; Sartor RBVSL#3 probiotic-mixture induces remission in patients with active ulcerative colitis

The American journal of gastroenterology. (Am J Gastroenterol) 2005 Jul; 100(7): 1539-46

Bittner Alvah C, Croffut Robert M. and Stranahan Mary C

Prescript-assist probiotic-prebiotic treatment for irritable bowel syndrome: A methodologically oriented, 2-

week, randomized, placebo-controlled, double-blind clinical studyClinical Therapeutics, Volume 27, Issue 6, June 2005, Pages 755-761

Borruel N, Casellas F, Antolin M, Carol M, De Lara F, Espin E, Guarner F and Malagelada J R

Increased mucosal TNF- production in Crohn's disease can be modulated locally by probioticsGastroenterology, Volume 120, Issue 5, Supplement 1, April 2001, Pages A278-A279

Corey A. Siegel, Chin Hur, Joshua R. Korzenik, G. Scott Gazelle and Bruce E. Sands

Risks and Benefits of Infliximab for the Treatment of Crohns DiseaseClinical Gastroenterology and Hepatology, Volume 4, Issue 8, August 2006, Pages 1017-1024

Domnech, Eugeni

Inflammatory Bowel Disease: Current Therapeutic OptionsDigestion, 2006 Supplement, Vol. 73, p67-76, 10p, 4 charts

Fiocchi Claudio

Inflammatory Bowel Disease: Etiology and PathogenesisGastroenterology 1998 115:182-205

Furrie E, Macfarlane S, Kennedy A, Cummings J H, Walsh S V, ONeil D A and Macfarlane G T Synbiotictherapy (Bifidobacterium longum/Synergy 1) initiates resolution of inflammation in patients with activeulcerative colitis: a randomized controlled pilot trial

Gut 2005; 54:242-249

Gionchetti P ; Rizzello F ; Helwig U ; Venturi A ; Lammers KM ; Brigidi P ; Vitali B ; Poggioli G ; MiglioliM ; Campieri M

Prophylaxis of Pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial.Gastroenterology. (Gastroenterology) 2003 May; 124(5): 1202-9

Guslandi M., Mezzi G., Viaggi P. and Testoni P. A.

Role ofSaccharomyces boulardiiin the prevention of clinical relapses of Crohn's diseaseDigestive and Liver Disease, Volume 32, Supplement 1, May 2000, Page A44

Joos S, Rosemann T, Szecsenyi J, Hahn EG, Willich SN, Brinkhaus BUse of complementary and alternative medicine in Germany - a survey of patients with inflammatory bowel

diseaseBMC Complement Altern Med. 2006 May 22; 6:19


11/13

Kim HJ; Vazquez Roque MI; Camilleri M; Stephens D; Burton DD; Baxter K; Thomforde G; Zinsmeister AR

A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome

with bloatingNeurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society

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

Kruis W, Fric P and Stolte M

Maintenance of remission in ulcerative colitis is equally effective withEscherichia coli Nissle 1917and with

standard mesalazineGastroenterology, Volume 120, Issue 5, Supplement 1, April 2001, Page A127

Khn Ralf, Lhler Jrgen , Rennick Donna, Rajewsky Klaus and Mller Werner

Interleukin-10 deficient mice develop chronic enterocoloitisCell Volume75 Issue 2: 263-274

Kuisma J ; Mentula S ; Jarvinen H ; Kahri A ; Saxelin M ; Farkkila M

Effect ofLactobacillus rhamnosus GG on ileal pouch inflammation and microbial floraAlimentary pharmacology & therapeutics. (Aliment Pharmacol Ther) 2003 Feb 15; 17(4): 509-15

Lim C , Ferguson L, Tannock G W

Dietary fibers prebiotics: implications for colorectal cancer

Molecular Nutrition & Food Research Vol. 49 Issue 6 Pages 609-619

Niedzielin K ; Kordecki H ; Birkenfeld B

A controlled, double-blind, randomized study on the efficacy ofLactobacillus plantarum 299Vin patients

with irritable bowel syndromeEuropean journal of gastroenterology & hepatology. (Eur J Gastroenterol Hepatol) 2001 Oct; 13(10): 1143-7

Niv E ; Naftali T ; Hallak R ; Vaisman NThe efficacy ofLactobacillus reuteri ATCC 55730 in the treatment of patients with irritable bowel syndrome--

a double blind, placebo-controlled, randomized studyClinical nutrition (Edinburgh, Scotland) (Clin Nutr) 2005 Dec; 24(6): 925-31

OMahony L ; McCarthy J ; Kelly P ; Hurley G ; Luo F ; Chen K ; O'Sullivan GC ; Kiely B ; Collins JK ;

Shanahan F ; Quigley EMLactobacillus andBifidobacterium in irritable bowel syndrome: symptom responses and relationship tocytokine profiles

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

Olaison G; Smedh K; Sjdahl R

Natural course of Crohn's disease after ileocolic resection: endoscopically visualized ileal ulcers preceding

symptoms.Gut. (Gut) 1992 Mar; 33(3): 331-5

Prantera C; Scribano ML; Falasco G; Andreoli A; Luzi C

Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn's disease: arandomized controlled trial withLactobacillus GG

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


12/13

Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM and Axon ATR

Non-pathogenicEscherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trialThe Lancet, Volume 354, Issue 9179, 21 August 1999, Pages 635-639

Rizzello F., Gionchetti P., Venturi A., Amadini C., Morselli C., Ugolini F., Palmonari V., Poggioli G. and

Campieri MProphylaxis of postoperative recurrence of Crohn's disease: Combination of antibiotic and probiotic versus

mesalazineDigestive and Liver Disease, Volume 32, Supplement 2, November 2000, Page A69

Rutgeerts P, Geboes K, et al

Predictability of the postoperative course of Crohns diseaseGastroenterology 1990; 99: 956-963

Sandborn WJ

Pouchitis following ilealpouch-anal anastomosis: definition, pathogenesis, and treatmentGastroenterology. (Gastroenterology) 1994 Dec; 107(6): 1856-60

Schultz M, Veltkamp C, Dieleman LA, Wyrick PB, Tonkonogy SL and Sartor RBContinuous feeding ofL.Plantarum attenuates established colitis in interleukin-10 deficient mice

Gastroenterology, Volume 114, Supplement 1, 15 April 1998, Page A1081

Tursi A ; Brandimarte G ; Giorgetti GM ; Forti G ; Modeo ME ; Gigliobianco ALow-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.International medical journal of experimental and clinical research. ( 2004 Nov; 10(11): PI126-31

Whorwell PJ ; Altringer L ; Morel J ; Bond Y ; Charbonneau D ; O'Mahony L ; Kiely B ; Shanahan F ;

Quigley EMEfficacy of an encapsulated probioticBifidobacterium infantis 35624 in women with irritable bowel syndrome

The American journal of gastroenterology. (Am J Gastroenterol) 2006 Jul; 101(7): 1581-90

Zocco M.A, Zileri Dal Verme L, Cremonini F, Piscaglia A C, Nista E C, Candelli M, Novi M, Gigante D,

Cazzato I A, Ojettim V, Armuzzi A, Gasbarrini G

Efficacy ofLactobacillus GG in maintaining remission of ulcerative colitis.

Alimentary Pharmacology Therapeutics 23, 1567-1574


13/13

Documents

Probiotic Strategies for the Treatment of Inflammatory Bowel Disorders