Keywords

1 Introduction

Crohn’s disease (CD), ulcerative colitis (UC), and undetermined colitis, grouped under the name of inflammatory bowel diseases (IBD), are chronic, currently incurable inflammatory diseases of the gastrointestinal tract of largely unknown causes. While IBD can arise at any age, approximately 10% of cases occur in children and teenagers, with Crohn’s disease more commonly affecting girls and UC boys (Loftus 2004). IBD appears to be increasing in prevalence worldwide (Duricova et al. 2014).

The balance between beneficial and harmful intestinal microorganisms leads to either mucosal homeostasis or chronic inflammation, and it is known that endogenous intestinal microbiota is involved in the onset of IBD (Scharl and Rogler 2012), as extensively recently reviewed in Basson et al. (2017) and Zuo and Ng (2018). Additionally, it has been shown that microbiota in IBD patients differs from healthy individuals, as it is characterized by a reduced diversity, reduced abundance of Firmicutes and Bacteroidetes, and increased abundance of Enterobacteriaceae (Gosiewski et al. 2012).

The possible mechanisms of probiotic efficacy have been explored in a variety of experimental conditions both in vitro and in vivo (reviewed in (Abraham and Quigley 2017)). The effects of any probiotic depend on a number of factors, including its metabolism, the molecules expressed on its surface, as well as the metabolites they produce (Oelschlaeger 2010).

In fact, a widely accepted theory on the pathogenesis of IBD calls for a complex interaction between genes (NOD2 and ATG16L1 variants being the best known) and a number of abnormalities like an imbalance between pro-inflammatory and anti-inflammatory T cell responses (including TNF-alfa and nitric oxide), an impaired epithelial barrier function, and more in general, as mentioned above, a condition of dysbiosis (Ganji-Arjenaki and Rafieian-Kopaei 2018).

However, despite the valid conceptual basis for the use of probiotics in IBD, well supported by encouraging experimental data in animal models, there is a paucity of published clinical trials in humans. We will examine randomized clinical trials (RCTs) that have used a comparator, either a placebo or an accepted standard therapy. The possible utilization of probiotics for the prevention of IBD is discussed elsewhere in this book (see Chapter 6).

2 Gut Microbiota in IBD

As mentioned, the different composition of microbiota in IBD patients in respect to healthy individuals has been well documented in the past several years (Sokol et al. 2006) to the point that a dysbiotic microbiome is considered to be a critical factor for the onset of IBD (Prosberg et al. 2016; Nishida et al. 2018), in spite of uncertainties about the fact that the dysbiosis could be the consequence, and not the cause, of the intestinal inflammation per se (Mack 2011) as well described in a thorough recent review by Ni et al. (Ni et al. 2017).

In addition, an altered intestinal permeability has been found in patients with IBD, especially CD, and this may involve alterations in the mucosal barrier eventually promoting bacterial translocation (Chassaing and Darfeuille-Michaud 2011).

Whether the environmental trigger for IBD responsible for these changes in a condition of dysbiosis is a single bacterium or, more likely, a number of microorganisms is still unclear. Furthermore, also unclear is if the role played by an abnormal immune reaction of the commensal microorganisms is important (Orel and Kamhi Trop 2014).

In fact, it appears that individuals who are genetically predisposed at some point lose the tolerance to commensal bacteria, thereby developing an inflammatory process chronically triggered and maintained by the microbiota (Fiorucci et al. 2002).

To further stress the role of the endogenous microbiota, it was found that the vast majority of IBD patients’ intestinal mucosal biopsies showed evidence of bacterial invasion, while control samples were devoid of bacteria (Seksik et al. 2003; Swidsinski et al. 2002).

An imbalance between beneficial and pathogenic bacteria as a contributory element in the development of IBD is further suggested by the reduction in mucosa-associated Bifidobacteria and a concomitant increase in E. coli and Clostridia (Ott et al. 2004; Ott and Schreiber 2006; Manichanh et al. 2006).

Further changes in the IBD microbiome were found using a metagenomic approach that revealed fewer Bacteroidetes and Firmicutes, bacteria that are known to possess an important butyrate-generating and anti-inflammatory activity (Sokol et al. 2006; Frank et al. 2011; Martinez et al. 2008).

To support the possible utilization of probiotics in IBD, Kim et al. (Kim et al. 2018) recently showed that Lactobacillus acidophilus (LA1) significantly interferes with endoplasmic reticulum stress, suppresses NF-κB activation (a major step in the pathogenesis of IBD), and thus possesses a potential to be utilized as an immunomodulator in the treatment of IBD.

Focusing now on data available in children, the first large investigation on pediatric microbiota (Conte et al. 2006) showed a higher number of mucosa-associated bacteria in the small and large intestine of patients with IBD than in healthy controls. Of note, the highest concentrations of mucosa-associated bacteria were found in children with CD and with undeterminate colitis (Conte et al. 2006).

Kellermayer et al. (Kellermayer et al. 2012) reported in an investigation on still untreated pediatric patients with CD that those patients who had granulomatous CD had a higher number of genera and species, significantly differentiating them from controls and from patients with CD with no granulomas (Kellermayer et al. 2012).

3 Probiotic Treatment of Pediatric IBD

As properly stated in a recent position paper by an ESPGHAN task force (Miele et al. 2018), high-quality studies on the effect of probiotics in pediatric IBD are extremely limited: only two RCTs in UC (Miele et al. 2009; Oliva et al. 2012) and one in CD (Bousvaros et al. 2005). Thus, while certainly one can extrapolate conclusions from data obtained in adults, briefly summarized below, caution must be exerted.

3.1 Crohn’s Disease

Most studies on testing the efficacy of probiotic interventions in CD (either in children or in adults) have assessed their role in maintaining remission achieved with standard medical therapy or surgical resection.

The probiotic yeast S. boulardii in addition to mesalamine proved effective in an initial study in adults with CD in reducing the rates of relapses (Guslandi et al. 2000); subsequently, however, a RCT with this probiotic failed to show significant differences in the frequency of relapses that occurred in 47.5% of the S. boulardii arm compared to 53.2% in the placebo arm (Bourreille et al. 2013). A recent systematic review on the use of S. boulardii in IBD (Sivananthan and Petersen 2018) confirms the current lack of evidence of its efficacy in these disorders.

A multicenter RCT on 75 children with CD testing the efficacy to maintain remission of the probiotic Lactobacillus rhamnosus GG (LGG) in addition to standard therapy (Bousvaros et al. 2005) also failed to demonstrate any additional benefit of the probiotic. Indeed, the children receiving LGG even relapsed sooner, though not significantly so, than those who were on placebo.

Similarly disappointing data have been recently reported for adults in a systematic review and meta-analysis on the efficacy of probiotics in CD (Derwa et al. 2017). The meta-analysis included 22 RCTs on IBD, and of these 8 tested the efficacy of probiotics either in inducing remission, maintaining remission, or preventing relapses after surgery in patients with CD: none of these studies showed any significant benefit of probiotics.

Thus, at present it seems clear that there is no evidence of any beneficial effects of probiotics in the treatment of CD either in adults or in children, and this conclusion has been recently reiterated by a consensus paper of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) that does not recommend probiotics in the induction or maintenance of remission of pediatric CD (Miele et al. 2018). However, one needs to remain mindful of the very limited number of RCTs performed, especially in children, and of the various genotypes and phenotypes of this condition, that are likely to require a more personalized therapeutic approach.

3.2 Ulcerative Colitis

While probiotics in CD have so far failed to show any clinical usefulness, the same is not true for ulcerative colitis (UC), where some of the many RCTs have indeed shown promising results, both in adults and in children, as reviewed recently in Derwa et al. (2017).

Among the most studied probiotics in animal models of colitis (Rodriguez-Nogales et al. 2018), E. coli Nissle 1917, widely used in Europe, showed encouraging results in an open-label trial in children in 2008 (Henker et al. 2008); however, this initial unblinded study was not followed by any RCT in children. In adults, five studies conducted between 1997 and 2014, reviewed by Scaldaferri et al. (Scaldaferri et al. 2016), showed essentially a “non-inferiority” as compared to treatment with mesalazine in maintaining clinical remission. In the most recently published RFCT on 100 patients, no additional benefit of Nissle 1917 when administered with mesalazine was shown compared to mesalazine alone (Petersen et al. 2014).

One of the most studied probiotic preparations for UC both in adults and in children is however De Simone Formulation, a proprietary mixture that combines eight strains of lactic acid-producing bacteria (L. plantarum, L. delbrueckii subsp. bulgaricus, L. casei, L. acidophilus, Bifidobacterium breve, B. longum, B. infantis, and Streptococcus salivarius subsp. Thermophilus). In children, Miele et al. performed a 1-year prospective, placebo-controlled, RCT investigation to assess the efficacy on this preparation in the treatment of children with active UC. More than 90% of the children achieved remission when treated with De Simone Formulation and standard therapy, while only 36% of those treated with mesalazine and placebo did (Miele et al. 2009). Of note, De Simone Formulation was also an effective adjuvant in maintaining remission. In fact, children who underwent remission on De Simone Formulation had lower endoscopic and histological scores (p < 0.05) than those on placebo, and only 21% of them experienced a relapse within 1 year, compared to 73% of the children on placebo (p = 0.014).

In the same year, De Simone Formulation was also tested by Huynh et al. (Huynh et al. 2009) in an open-label study in children with UC, mild to moderately active. Remission was achieved in 56%, with no change or worsening in 39% of patients. The probiotic mixture was well tolerated without any clinical adverse effects.

L. reuteri (ATCC 55730) administered in the amount of 1010 CFU by enema was tried against placebo in a small study assessing in children, also treated with oral mesalazine, remission of their mild to moderate ulcerative proctitis (Oliva et al. 2012). Clinical, endoscopic, and histologic scores improved more in the children treated with probiotic.

In their 2017 meta-analysis on probiotics and IBD including 22 RCTs all performed in adults, Derwa et al. (Derwa et al. 2017) concluded that probiotics – when considered overall – did not show benefits over placebo in inducing remission of patients with active UC. However, clumping different strains and different doses of probiotics may end up by masking efficacy of some strains; and indeed, when they restricted the analysis to RCTs using De Simone Formulation, a significant probiotic beneficial effect over placebo was demonstrated with a RR of 0.74. In addition, probiotics also proved to be just as efficacious as aminosalicylic acid in preventing relapses of UC, once in remission. Had the meta-analysis included also the pediatric study by Miele et al. (2009), clearly the case for the usefulness of De Simone Formulation as a potent coadjuvant in the treatment of UC, already supported by a previous meta-analysis (Mardini and Grigorian 2014), would have been even stronger.

4 Conclusions

Modifications of the microbiota in children with IBD are a conceptually logical and exciting means to control in a more “natural” way these aggressive conditions, especially in consideration of the high burden of the medical treatment. Such modifications could theoretically be achieved by several approaches: intervention on nutrition (Miele et al. 2018; Lane et al. 2017), administration of probiotics, and – more recently – also fecal microbial transplant (Jeon et al. 2018). While the use of probiotics may appear to be the “lowest hanging fruit,” unfortunately the evidence so far accumulated is not hard enough, especially in children, to be translated in clinical recommendations. More specifically, in the case of CD, clearly there is at the moment no evidence of any role for probiotics: however, it must be stressed again that CD is a complex condition, extremely heterogeneous in its genetic asset, phenotype presentations, and outcomes. It is therefore conceivable that the trials so far conducted have not yet addressed with the proper probiotic strains and doses the specific patient profiles. In the case of UC, on the other hand, the benefit of De Simone Formulation as an adjunct to medical therapy should be considered demonstrated, especially in cases of mild to moderate activity and including patients who have a post-colectomy pouch to prevent episodes of the fastidious pouchitis (Singh et al. 2015).

Future translational research should focus on creating in the lab better strains, and here the application of metagenomics may help identify specific strains with biologically.

plausible efficacy in inflammatory bowel disease (McIlroy et al. 2018), but also exploring the possibility of identifying and combining various strains each possessing different features that may be synergistic, as in the recent work by Alard et al. (Alard et al. 2018). Combining a nutritional intervention tailored on the patient’s profile (Miele et al. 2018) with the appropriate combination of well-defined probiotic strains may represent an exciting future alternative to the current burden of pharmacological treatment for children with IBD.