A Role for Probiotics in Pediatric Inflammatory Bowel Disease—Is there Evidence to Support It?
IBD patients,9 could be high.
suggesting that adherence to therapies such as probiotics
Probiotics—Modulating Gut Flora to Decrease Inflammation?
Modulation of the gut flora through probiotics has been suggested as a way to maintain the balance and integrity of the intestinal flora. Potential mechanisms of action of probiotics to promote gastrointestinal health are presented in Figure 1. Evidence regarding a beneficial effect of probiotics in IBD remains equivocal. Furthermore, there is still controversy as to which type of probiotics is more suitable for IBD. Many strains are available on the market and the amount of probiotics varies from one formulation to another. Also, even though probiotics seem reasonably safe (as most studies have not reported significant side effects), probiotics are not marketed under the same rigorous process as the one used to evaluate new drugs by governmental organizations such as the US Food and Drug Administration (FDA). Looking at current studies and evidence, two formulations of probiotics seem to be standing out: VSL#3 (composed of four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus salivarius) and Escherichia coli Nissle 1917 (EcN), the latter only available in Europe.
Probiotics have been proposed as a way to affect the epithelial barrier function.10
Looking at Evidence—Are Probiotics Effective in Inflammatory Bowel Disease? Most of the evidence regarding the use of probiotics in IBD comes from adult data. We will summarize available adult data and mostly focus on pediatric data for both UC and CD.
Ulcerative Colitis
Data in adult UC are considerable. The earliest published trial on the use of probiotics in maintenance therapy in UC came in 1997. Kruis et al.11 showed that a non-pathogenic strain of E. coli Nissle 1917 (EcN) was as effective as mesalamine. Even though this study was limited by its small size and short duration, it did open the way to more studies. A meta-analysis looking at remission induction and maintenance effects of probiotics on UC was published in 2010.12
Thirteen randomized
controlled trials were analyzed. The use of probiotics in the induction of remission was not shown to be beneficial, but probiotics as an adjunct treatment were more effective than placebo in maintaining remission in UC. Recently, Tursi et al.13
published a multicenter, double-
blind, randomized, placebo-controlled, parallel study looking at treatment relapse of mild to moderate UC using VSL#3 for eight weeks as an adjunctive therapy to standard treatment (5-aminosalicylic acid [5-ASA] and/or immunosuppressants). These results showed a decrease in UC disease activity index (UCDAI) in patients treated with probiotics. However, they found no statistical difference in stool frequency, physician’s rate of disease activity, and endoscopic scores. Remission was higher in the VSL#3 group than in the placebo group: 47 versus 32% (p=0.069). Therefore, we could summarize that current adult data for the treatment of UC with probiotics do not support their use in induction therapy. However, they may have a role as an adjunct therapy in maintenance therapy. As outlined in a recent review, there are still unanswered questions in terms of dosage, duration and specific type of probiotics to use.14
US GASTROENTEROLOGY & HEPATOLOGY REVIEW
Figure 1: Potential Mechanisms of Action of Probiotics to Promote Gastrointestinal Health
Colonization resistance
Competitive exclusion
slp PB G P Reduce
macromolecular permeability and bacterial translocation
Maintain barrier function
Maintain tight junctions (ZO-1, claudin1)
Metabolic effects
Bacteriocins Decrease pH Quorum sensing
Modulation of signal transduction Probiotics Enhance microbial flora
Enhance cytokines (IL-10, TGFβ)
NF-κB IFNγ MAPK TC Source: Sherman et al., 2009.30 DC Reprinted with permission from SAGE Publications.
IFN = interferon; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor kappa B; TGF = transforming growth factor.
In pediatrics, UC is also the one area where most research has been conducted. This is largely due to the fact that evidence has shown some benefits in this condition. Henker et al.15
Innate/adaptive immunomodulation IgA, IgG, IgM
Increase mucin
production PC
reported an open-label
pilot study on the use of EcN for remission maintenance of UC in children and adolescents. Thirty-four children (aged between 11 and 18 years) with UC in remission were either given EcN (two capsules/day) or 5-ASA (median dose 1.5g/day) and then followed for one year. Both relapse rates were similar and maintenance with EcN was reported as effective compared with standard therapy with 5-ASA. However, usual recommendations for 5-ASA suggest treatment dose significantly higher than a median dose of 1.5g/day. In 2009, Miele et al.16
published
Also, the 36.4% remission rate reported at one month in the placebo group is quite low compared with known data for UC therapy induction with steroids and 5-ASA. Huynh et al.17
reported a pilot study 55
a randomized, placebo-controlled, double-blind study on the role of VSL#3 in induction and maintenance of remission in children with active UC. Twenty-nine patients (mean age of 9.8 years) with newly diagnosed UC were randomized to receive VSL#3 (dose based on weight) or placebo along with oral steroid induction and oral mesalamine maintenance. Patients had follow-up at one, two, six, and 12 months. Endoscopy was performed at baseline, six and 12 months and at anytime if relapse occurred. Lichtiger colitis activity index (LCAI) and a physician’s global assessment were used to measure the disease activity. The mean LCAI at time of diagnosis, the mean length of steroid exposure as well as the mean endoscopic scores performed at diagnosis were similar in both groups. However, remission was achieved in 92.8% of patients treated with VSL#3 compared with 36.4% treated with placebo. Endoscopic scores were also significantly lower in the probiotics group at six and 12 months and at time of relapse. The authors concluded that a highly concentrated mixture of probiotics bacterial strains was effective in active UC and to maintain remission. However, some limitations have to be underlined. First, a minority of patients had pancolitis. This goes against epidemiological studies performed in North America showing that most children present with pancolitis.6
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