Modifying the intestinal ecosystem

Criteria for designating a bacterial strain as a probiotic include human origin, acid and bile resistance, survival of gastrointestinal transit, non-pathogenic, production of anti-microbial substances, and immune modulatory activity (Dunne et al., 2001). The most commonly used probiotics include lactobacilli and bifidobacteria species that lack inflammatory activity. However, other bacteria including non-pathogenic Escherichia coli, and multi-strain cocktails such as VSL#3 have been used for probiotic effect also. VSL#3 comprises Lactobacillus casei, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus delbrueckii subspecies bulgaricus, Bifidobacterium infantis,

Table 5.1 Commensal bacteria play a role in IBD - the evidence Experimental evidence from animal models of IBD

Commensal bacteria influence mucosal immune development and function Bacterial colonisation is a pre-requisite for an inflammatory phenotype Germ-free animals do not develop IBD-like lesions Alteration of the microbiota with antibiotics can be beneficial

Disease can be propagated by adoptive transfer of T cells reactive with enteric bacteria but not dietary or epithelial antigens

Administration of probiotics can delay onset of disease and attenuate the inflammatory process

Experimental evidence from human studies

Cellular and humoral immune reactivity against components of the microbiota is evident in patients with IBD

Linkage of the CARD15 polymorphisms and other PRR polymorphisms with a subset of human Crohn's disease incriminates defective interpretation of the local microenvironment

Observational evidence from patient-related studies

Bacterial numbers within the mucosa of IBD patients are increased compared with that of non-inflamed and inflammatory disease controls

Lesions occur in areas of the bowel with highest bacterial counts

Faecal stream diversion has a beneficial effect on the clinical course of disease

Relapse occurs consistently with restoration of faecal stream

Administration of antibiotics has therapeutic efficacy in IBD patients

Administration of probiotics has therapeutic efficacy in IBD patients

Enteroadherent and intramucosal bacteria are increased in Crohn's disease

Metabolic diseases involving defective phagocytic microbicidal function tend to develop

Crohn's-like lesions that respond to antibiotics or correction of immune defect

Bifidobacterium breve, Bifidobacterium longum, and Streptococcus salivarius subspecies thermophilus. It is noteworthy that the potential for targeting host-microbial interactions for therapeutic effects in IBD is not limited to prokaryotes. Non-bacterial organisms such as Saccharomyces boulardii have demonstrated probiotic properties, and helminths and helminthic antigens are under investigation with encouraging results in animal models of inflammation and in humans (Elliott et al., 2005; Guslandi et al., 2003; Summers et al., 2005).

5.4.1 Mechanisms of probiotic action

Increasing evidence supports a therapeutic role for probiotic strategies for treating enteric infections, post-antibiotic syndromes, necrotising enterocolitis, and irritable bowel syndrome (Allen et al., 2004; D'Souza et al., 2002; Lin et al., 2005; O'Mahony et al., 2005). Although an early report described the use of a retention enema containing exogenous bacterial microbiota to induce remission in a patient with ulcerative colitis (Bennet and Brinkman, 1989), the use of microbial therapy for IBD has only recently attracted serious interest from clinicians.

Multiple microbe-microbe and host-microbe interactions probably account for the versatility of probiotic action. The beneficial effects of probiotics may be either direct, or indirect through modification of the intestinal ecosystem, epithelial barrier function, or the immune response. Figure 5.2 illustrates several mechanisms of probiotic action that are relevant to IBD therapy: (1) competition with pathogenic bacteria for receptors and essential nutrients; (2) secretion of antimicrobial factors that suppress pathogen overgrowth or pro-inflammatory activity; (3) inhibition of apoptosis in epithelial cells; (4) enhancement of mucosal barrier function; (5) priming and stimulation of humoral and cell-mediated immunity; (6) modulation of immune responses and cytokine secretion; and (7) induction of T cell apoptosis in the lamina propria. Oral consumption of probiotics is associated with immune engagement and demonstrable systemic immunologic changes (McCarthy et al., 2003), and it appears that probiotics serve to mimic the commensal microbiota and exploit host-microbial signalling pathways. It remains to be established which potential probiotic mechanism(s) relate to various clinical diseases. Experimental models have revealed that probiotic strains differ greatly in their mechanisms of action; any singular mechanism is unlikely to account for all of their clinical effects.

Mechanisms of probiotic action

Nutrient competition

Receptor competition

Antimicrobial activity e.g., bacteriocins lactic acid

Stimulate humoral immunity ■ Increased secretory IgA

Inhibition of epithelial cell apoptosis enterocyte lumen

Enhanced barrier function

Increased mucus secretion Enhanced tight junctions

Stimulate cellmediated immunity Induce regulatory T cells lamina propria

Immunomodulatory activity

Decreased pro-inflammatory cytokine secretion Increased anti-inflammatory cytokine secretion Modulation of dendritic cells

Induction of T cell apoptosis

Fig. 5.2 Mechanisms of probiotic action in inflammatory bowel disease (IBD).

5.4.2 Probiotic and prebiotic studies in animal models

Encouraging results of some probiotic therapies have been observed in various animal models of experimental colitis. The reported beneficial effects range from protection against the severity of intestinal inflammation or the recurrence of colitis, or the enhancement of disease resolution. These effects are associated with a reduction in pro-inflammatory cytokines and an induction of regulatory cytokines (McCarthy et al., 2003; Schultz et al., 2002).

Administration of Lactobacillus reuteri R2LC, but not Lactobacillus rhamnosus GG, significantly attenuated inflammation in acetic acid- or methotrexate-induced colitis in rats (Fabia et al., 1993; Holma et al., 2001; Mao et al., 1996). Conversely, L. rhamnosus GG and VSL#3 demonstrated a protective effect in the iodoacetamide model of colitis (Shibolet et al., 2002). Bifidobacterium infantis 35624 also limited inflammation, and its protective effects were evident outside the context of established inflammation and at the pre-inflammatory stage (McCarthy et al., 2003; Sheil et al., 2006). In the IL-10 deficient model of spontaneous colitis, VSL#3, Lactobacillus reuteri and Lactobacillus plantarum 299v have demonstrated therapeutic effects (Madsen et al., 2001, 1999; Schultz et al., 2002). VSL#3 also enhanced epithelial barrier function in this model. L. rhamnosus GG, but not L. plantarum 299v, prevented the recurrence of colitis in gnotobiotic transgenic rats (Dieleman et al., 2003). It is noteworthy that although not all probiotic preparations have a beneficial effect in all models, they do not appear to be harmful to any model.

Interestingly, non-viable irradiated probiotic bacteria and the subcutaneous administration of DNA derived from the VSL#3 cocktail have demonstrated protective effects in a number of animal models of colitis (Rachmilewitz et al., 2004). The effects were shown to be mediated not by bacterial metabolites or ability to colonise the colon, but by the DNA through TLR9 (Rachmilewitz et al., 2002; Rachmilewitz et al., 2004). These findings in particular, as well as the supportive finding that DNA from VSL#3 can attenuate NF-kB-mediated signalling in intestinal enterocytes (Jijon et al., 2004), challenge the traditional assumption that probiotic bacteria must be live and intact.

A number of prebiotic combinations have been tested in animal models of intestinal inflammation. Lactulose, germinated barley foodstuff, inulin, and fructo-oligosaccharide are some of the prebiotic preparations that have been shown to reduce inflammation in dextran sodium sulphate, IL-10 knockout mice, and trinitrobenzene sulphonic acid models of colitis (Cherbut et al., 2003; Fukuda et al., 2002; Madsen et al., 1999; Videla et al., 2001). Further investigation of the potential synergistic effects of co-administration of prebiotics with probiotics would also be of interest.

5.4.3 Probiotic and prebiotic studies in pouchitis

Despite the encouraging data from probiotic studies in animal models of colitis, the role of probiotics in human IBD has proven more complex. The most impressive studies have been in patients with pouchitis (Table 5.2). Pouchitis is a common complication, an estimated 24-46% of patients experience at least one episode following pouch surgery for ulcerative colitis.

Pouchitis is characterised by non-specific inflammation of the ileal reservoir.

Although many patients respond to antibiotics, approximately 10% of patients develop chronic pouchitis (Fazio et al., 1995; Sandborn et al., 1994). Altered luminal microbiota may be a risk factor for pouchitis. Reduced numbers of bifidobacteria and lactobacilli, as well as increased counts of Clostridium perfringens and other species have been recorded in stool samples of patients with pouchitis (Ruseler-van Embden et al., 1994).

A number of studies have indicated that altering the microbiota in the pouch by administering probiotic bacteria can be effective in maintaining remission in chronic pouchitis, or preventing the development of pouchitis in the first place (Gionchetti et al., 2000, 2003; Mimura et al., 2004) (Table 5.2). Two randomised controlled trials involving a total of 76 patients evaluated VSL#3 as a maintenance therapy. In both studies the relapse rate was 15% in the VSL#3 group compared to 100% (Gionchetti et al., 2000) or 94% (Mimura et al., 2004) in the placebo group. In one of these studies all those in remission following probiotic treatment relapsed on completion of the trial (Gionchetti et al., 2000). An uncontrolled open-label study of the effectiveness of VSL#3 in clinical practice was less encouraging. Of 31 patients with antibiotic-dependent pouchitis, <20% maintained remission on VSL#3 during 8 months of follow up (Shen et al., 2005). There were some inherent problems with this study. Patients had to purchase and bear the cost of medication, and although the medication was self-administered, adherence was not monitored.

In a randomised controlled trial, VSL#3 was shown to reduce the risk of post-surgical prevention of pouchitis, and also reduce the stool frequency of patients without clinical pouchitis (Gionchetti et al., 2003). A recent study reported that the diversity of the bacterial microbiota was increased, whereas fungal diversity was repressed, in patients in VSL#3-maintained remission compared to placebo treatment (Kuhbacher et al., 2006). These findings support a therapeutic role of probiotic bacteria in the restoration or maintenance of a protective intestinal microbiota.

Lactobacillus rhamnosus GG did not demonstrate efficacy for the treatment of active acute pouchitis, although in a case controlled study, a decreased cumulative risk of pouchitis was observed in patients taking L. rhamnosus GG (Gosselink et al., 2004; Kuisma et al., 2003). Trials using a fermented milk product, Cultura®, which contains Lactobacillus acidophilus La-5 and Bifidobacterium animalis subspecies lactis Bb-12, have also shown some benefit in the prevention and treatment of active pouchitis (Laake et al., 2003, 2004, 2005). Several of these studies are encouraging. However, the wider, open clinical experience with probiotics in pouchitis patients is inconsistent. Whether this relates to variability in patients populations, or the quality and choice of probiotic preparation, is unclear. Further studies should

Table 5.2 Clinical trials of probiotics in pouchitis

Study

n

Duration

Probiotic

Response to probiotic

Reference

RCT; maintenance of antibiotic-

40

9 months

VSL#3

85% response vs 0% in

Gionchetti et al., 2000

induced remission

placebo group

Open-label; treatment of acute

10

1 month

Cultura®

50% endoscopic improvement;

Laake et al., 2003

active pouchitis

0% histologic improvement

RCT; treatment of active acute

20

3 months

Lactobacillus

No benefit on clinical or endoscopic

Kuisma et al., 2003

pouchitis

rhamnosus GG

response

RCT; post-operative prevention

40

12 months

VSL#3

90% response vs 60% in placebo group

Gionchetti et al., 2003

RCT; maintenance of antibiotic-

36

12 months

VSL#3

85% response vs 6% in placebo group

Mimura et al., 2004

induced remission

Case control study; post-

117

3 years

Lactobacillus

Decreased risk of pouchitis;

Gosselink et al., 2004

operative prevention

rhamnosus GG

cumulative risk at 3 years 7% vs 29%

Controlled clinical trial;

51

1 month

Cultura®

Improvement in PDAI, but not

Laake et al., 2004

prevention of acute pouchitis

histology

Clinical trial; prevention of

61

1 month

Cultura®

Improved symptoms and endoscopic

Laake et al., 2005

acute pouchitis

response

Open-label; management of

31

8 months

VSL#3

Only 6 completed trial; no

Shen et al., 2005

antibiotic-dependent pouchitis

differences in PDAI vs placebo

RCT; role of the microbiota in

15

12 months

VSL#3

Increased bacterial diversity, reduced

Kuhbacher et al., 2006

maintenance of remission

fungal diversity in probiotic group

VSL#3 comprises Lactobacillus casei, Lactobacillusplantarum, Lactobacillus acidophilus, Lactobacillus delbrueckii subspecies bulgaricus, Bifidobacterium infantis, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus salivarius subspecies thermophilus. Cultura® contains Lactobacillus acidophilus La-5 and Bifidobacterium animalis subspecies lactis Bb-12. n, total number of patients; PDAI, pouchitis disease activity index; RCT, randomised controlled trial.

VSL#3 comprises Lactobacillus casei, Lactobacillusplantarum, Lactobacillus acidophilus, Lactobacillus delbrueckii subspecies bulgaricus, Bifidobacterium infantis, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus salivarius subspecies thermophilus. Cultura® contains Lactobacillus acidophilus La-5 and Bifidobacterium animalis subspecies lactis Bb-12. n, total number of patients; PDAI, pouchitis disease activity index; RCT, randomised controlled trial.

uc o also address whether there is a need for antibiotic pre-treatment to induce remission prior to administration of probiotic therapy.

5.4.4 Probiotic and prebiotic studies in ulcerative colitis

The results of the published clinical trials with pharmabiotics in the treatment of ulcerative colitis are shown in Table 5.3. In earlier trials, VSL#3 and Esherichia coli Nissle 1917 were shown to reduce remission of acute ulcerative colitis (Kruis et al., 1997; Rembacken et al., 1999). However, these studies were not adequately powered for equivalence, but the observed efficacy was similar to that of mesalazine in the maintenance of remission. Mesalazine is the standard treatment used to prevent ulcerative colitis relapses. In a later and larger study involving 327 patients with inactive ulcerative colitis, E. coli Nissle 1917 was deemed statistically equivalent to mesalazine in the maintenance of remission (Kruis et al., 2004). Lactobacillus rhamnosus GG has also shown the same efficacy as mesalazine in maintaining remission of ulcerative colitis (Zocco et al., 2006).VSL#3 has demonstrated efficacy in the induction and maintenance of remission, and significant concentrations of the probiotics present in VSL#3 were identified in faecal cultures (Bibiloni et al., 2005; Venturi et al., 1999).

One randomised control trial of a bifidobacteria-fermented milk administered as maintenance therapy over one year recorded fewer relapses in the treatment arm (27% vs 90% in control group), but no difference in the endoscopic score (Ishikawa et al., 2003). This milk product contained Bifidobacterium breve (Yakult Co. Ltd., Tokyo, Japan), Bifidobacterium bifidum (Yakult), and Lactobacillus acidophilus YIT 0168. However, the study was limited by the absence of blinding among the investigators and patients and a lack of correlation in the outcome measures. Similarly, following the administration of BIFICO® (Shanghai Sine Pharmaceutical Corp. Ltd., Shanghai, China), a capsule containing Bifidobacterium, Enterococcus, and Lactobacillus acidophilus, the relapse rate in the probiotic group was 20% compared with 93% in the placebo group. Furthermore, NF-kB activation was significantly attenuated and IL-10 expression was elevated in the probiotic group (Cui et al., 2004). More recently, in an in vitro model, treatment with Bifidobacterium longum was shown to inhibit NF-kB activation and downregulate inflammatory cytokine secretion from inflamed tissues of active ulcerative colitis (Bai et al., 2006). In combination with inulin-oligofructose, this species was used as a synbiotic in a randomised controlled trial of 18 patients with active ulcerative colitis (Bifidobacterium longum/Synergy I, Orafti, Tienen, Belgium). Although endoscopic differences were not significant, there was a significant reduction in inflammatory cytokines in the synbiotic group that was accompanied by reduced inflammation and regeneration of epithelial tissue (Furrie et al., 2005).

Germinated barley foodstuff containing glutamine-rich protein and hemicellulose-rich fibres have alleviated symptoms in patients with ulcerative

Table 5.3 Clinical trials of probiotics in ulcerative colitis

Study

Duration Probiotic

RCT; maintenance of 120

remission

RCT; maintenance of 116

remission

RCT; acute active disease 116

Open-label; maintenance 20 of remission

RCT; maintenance of 21

remission

Open-label; acute active 25 disease

Open-label; treatment of 6 chronic active disease

4 months Escherichia coli Nissle 1917

12 months Escherichia coli Nissle 1917

3 months Escherichia coli Nissle 1917

12 months VSL#3

12 months Bifidobacteria-fermented milk

1 month Saccharomyces boulardii

1 week Faecal enemas derived from healthy donors

RCT; maintenance of remission

RCT; maintenance of remission

Open-label; induction of remission

RCT; treatment of active disease

327 12 months

30 8 weeks

34 6 weeks

18 1 month

Escherichia coli Nissle 1917

BIFICO VSL#3

Bifidobacterium longum with inulin-oligofructose

Response to probiotic

Reference

84% response to probiotic vi 89% response to mesalazine

26% response to probiotic vi 25% to mesalazine

68% response to probiotic vi 75% to mesalazine

75% in remission

73% response to probiotic vi 10% response in control group

Kruis et al., 1997

Rembacken et al., 1999

Rembacken et al., 1999

Venturi et al., 1999

Ishikawa et al., 2003

68% in clinical remission Guslandi et al., 2003

100% remission; off standard medications by 4 months; disease-free during follow-up

Statistically equivalent to mesalazine

80% remission rate vs 7% in placebo group

53% remission rate

Significant reduction in inflammatory cytokines

Borody et al., 2003

Kruis et al., 2004 Cui et al., 2004 Bibiloni et al., 2005 Furrie et al., 2005

"C

Table 5.3 Continued

Study n

Duration

Probiotic

Response to probiotic

Reference

Open-label; treatment of 12

4 weeks

Bifidogenic growth

Statistically significant

Suzuki et al., 2006

ulcerative colitis

stimulator (prebiotic)

improvement in clinical

activity index score

Open-label; maintenance 187

12 months

Lactobacillus

No difference compared to

Zocco et al., 2006

of remission

rhamnosus GG

mesalazine

VSL#3 comprises Lactobacillus casei, Lactobacillusplantarum, Lactobacillus acidophilus, Lactobacillus delbrueckii subspecies bulgaricus, Bifidobacterium infantis, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus salivarius subspecies thermophilus. The bifidobacteria-fermented milk product contains Bifidobacterium breve (Yakult Co. Ltd., Tokyo, Japan), Bifidobacterium bifidum (Yakult), and Lactobacillus acidophilus YIT 0168. BIFICO® (Shanghai Sine Pharmaceutical Corp. Ltd., Shanghai, China) capsules contain Bifidobacterium, Enterococcus, and Lactobacillus acidophilus. n, total number of patients; RCT, randomised controlled trial.

1 CD

CD sa o colitis (Bamba et al., 2002). These prebiotics are thought to work by decreasing stool frequency, increasing local butyrate levels, and increasing the numbers of bifidobacteria and eubacteria. An example of a bifidogenic growth stimulator is a prebiotic preparation produced by Propionibacterium freudenreichii isolated from Swiss cheese. Oral administration of this prebiotic to 12 patients over one month resulted in a significant improvement in the clinical activity index scores of the patients (Suzuki et al., 2006). Interestingly, the yeast, Saccharoymces boulardii (Biocodex Laboratories, Montrouge, France) has been shown to induce remission rates similar to those reported for VSL#3, E. coli Nissle 1917, and mesalazine (Guslandi et al., 2003). To further define the role of probiotics, prebiotics, or synbiotics in ulcerative colitis there is a need for larger placebo controlled trials to be performed.

An alternative pharmabiotic strategy, faecal bacteriotherapy, was employed with interesting outcomes in a study by Borody et al. (2003). Faecal enemas were prepared from healthy adult donors, and administered once daily for five consecutive days as enemas to six ulcerative colitis patients on high-fibre diets. The bacteriotherapy achieved 100% remission, all patients were off standard medications within 4 months, and were disease-free for 1-13 years follow-up despite the fact that no maintenance therapy was used. These reports are striking, and clearly worthy of further investigation both from a pathogenesis as well as a therapeutic perspective.

5.4.5 Probiotic and prebiotic studies in Crohn's disease

The evidence for therapeutic efficacy of probiotics in Crohn's disease is varied and inconclusive (Table 5.4). There have been very few randomised controlled clinical trials. Small patient numbers, differences in disease activity and variations in disease distribution have confounded most trials. One of the earliest studies examined the use of Saccharomyces boulardii (Biocodex Laboratories) in patients with moderately active Crohn's disease. There was a significant decrease in the Crohn's disease activity index (CDAI) compared with the control group (Plein and Hotz, 1993). S. boulardii has been used also in combination with mesalazine in the maintenance of remission. There was a significant difference in the relapse rate after one year between the probiotic and placebo groups (Guslandi et al., 2000). Despite this encouraging result, no further Crohn's disease studies with S. boulardii have been published.

In a randomised, double-blind, placebo-controlled pilot study involving 28 patients with active colonic Crohn's disease, 70% of patients who received Escherichia coli Nissle 1917 daily for one year remained in remission compared with 30% in the placebo-treated group (Malchow, 1997). Lactobacillus salivarius UCC118 has yielded encouraging results in treating acute active Crohn's disease also (McCarthy et al., 2001). Furthermore, Campieri et al. reported that a combination of antibiotic and VSL#3 treatment was efficacious in preventing post-operative recurrence of Crohn's disease when compared with mesalazine (Campieri et al., 2000).

Table 5.4 Clinical trials of probiotics in Crohn's disease

Study

n

Duration

Probiotic

Response to probiotic

Reference

RCT; treatment of

20

2 weeks

Saccharomyces boulardii

Decreased diarrhoea and CDAI

Plein et al., 1993

acute disease

index in probiotic group

Open-label; treatment of

14

10 days

Lactobacillus rhamnosus GG

Increased secretion of

Malin et al., 1996

paediatric Crohn's disease

immunoglobulin A, enhanced barrier function

RCT; maintenance of

28

12 months

Escherichia coli Nissle 1917

Relapse rate of 30% in probiotic

Malchow et al., 1997

remission

group vi 70% in placebo (not significant)

Open-label; treatment

4

6 months

Lactobacillus rhamnosus GG

Improved intestinal

Gupta et al., 2000

of active disease

permeability and CDAI

RCT; maintenance of

40

12 months

VSL#3

Endoscopic remission of 80%

Campieri et al., 2000

remission

vs 60% in melalazine group

RCT; maintenance of

32

6 months

Saccharomyces boulardii

94% remission in probiotic group

Guslandi et al., 2000

remission

compared to 38% mesalazine group

Open-label; treatment of

25

3 months

Lactobacillus salivarius

Reduction in CDAI and steroid use

McCarthy et al., 2001

active disease

UCC118

RCT; maintenance of

45

12 months

Lactobacillus rhamnosus GG

No difference between two

Prantera et al., 2002

remission

groups at 1 year

RCT; induction and

11

6 months

Lactobacillus rhamnosus GG

No benefit in induction or

Schultz et al., 2004

maintenance of remission

maintenance of remission

RCT; maintenance of

39

2 years

Lactobacillus rhamnosus GG

No difference in the median time

Bousvaros et al., 2005

remission in children

to relapse compared to placebo

RCT; maintenance of

48

6 months

Lactobacillus johnsonii LA1

No benefit in preventing

Marteau et al., 2006

remission

recurrence of disease

VSL#3 comprises Lactobacillus casei, Lactobacillusplantarum, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus salivarius subspecies patients; RCT, randomised controlled trial.

Lactobacillus delbrueckii subspecies bulgaricus, Bifidobacterium infantis, thermophilus. CDAI, Crohn's disease activity index; n, total number of r

ot c

1 cd cd sa

O Ui

VSL#3 comprises Lactobacillus casei, Lactobacillusplantarum, Lactobacillus acidophilus, Bifidobacterium breve, Bifidobacterium longum, and Streptococcus salivarius subspecies patients; RCT, randomised controlled trial.

Lactobacillus delbrueckii subspecies bulgaricus, Bifidobacterium infantis, thermophilus. CDAI, Crohn's disease activity index; n, total number of

Lactobacillus rhamnosus GG has been used in two open-label studies in paediatric Crohn's disease. One study reported elevated levels of gut immunoglobulin A following probiotic treatment, but without clinical improvement (Malin et al., 1996). The other study reported improved intestinal permeability and clinical scores in four children with mildly active Crohn's disease (Gupta et al., 2000). Of note, three patients had relapse of their Crohn's disease within 4-12 weeks of discontinuation of the Lactobacillus treatment. In more recent randomised controlled trials, L. rhamnosus GG did not demonstrate significant efficacy as a maintenance therapy in 75 children with Crohn's disease, in 11 patients with moderate to active Crohn's disease, or in 45 patients after curative surgery (Bousvaros et al., 2005; Prantera et al., 2002; Schultz et al., 2004). Similarly, Lactobacillus johnsonii LA1 did not achieve statistical significance in reducing endoscopic recurrence of Crohn's disease post-operatively (Marteau et al., 2006). Collectively, the result of these studies is not encouraging, and at the moment, probiotics as a therapeutic option for Crohn's disease is not scientifically validated.

Crohn's disease is a complex condition, variable in its location as well as its manifestation. Variability in the composition and diversity of the microbiota along and over the cross-sectional axis of the gastrointestinal tract suggests that depending on the topographic distribution of lesions in Crohn's disease, a single probiotic may not be equally suited to different subsets of patients. Colonic location of disease seems to respond better to antibiotics, and may, as a result, be more susceptible to pharmabiotic therapy. Investigators need to determine whether we are dealing with the wrong probiotic, the wrong dose, the wrong indication. Are probiotic combinations or other pharmabiotic approaches needed? There may be a role for probiotics in the enhancement of epithelial barrier function in the very early stages of Crohn's disease. Larger well-powered randomised control trials are clearly needed to conclusively determine whether there is a role for probiotics in Crohn's disease.

5.4.6 Safety of probiotics

Probiotics are not selected among pathogens, and by definition, have a high safety profile and the tolerance is usually excellent. Many of the commercial probiotic products have been officially designated as 'generally regarded as safe', and the deliberate ingestion of lactobacilli or bifidobacteria does not pose a greater risk of infection than that associated with the commensal strains (Borriello et al., 2003). Nonetheless, some reports of infections probably caused by probiotics have been published (De Groote et al., 2005; Riquelme et al., 2003). Probiotic strains adhering to the intestinal mucosa could translocate, inducing bacteraemia and sepsis. However, this is very rare and it is estimated that infection due to probiotics represent between 0.05% and 0.4% of cases of infective endocarditis or bacteraemia (Gasser, 1994). Most of these rare cases have occurred in immunocompromised patients or those with severe underlying disease. Obviously, the administration of probiotics to these patients groups should be approached with caution. Several studies have administered probiotic preparations to children; they are well tolerated and safe (Gupta et al., 2000; Malin et al., 1996; Vanderhoof and Young, 1998).

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