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Beneficial Microbes, 2015; 6(2): 209-217 SPECIAL ISSUE: Prebiotics and probiotics in paediatrics

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Prebiotics and probiotics in irritable bowel syndrome and inflammatory bowel disease in children S. Guandalini*, E. Cernat and D. Moscoso Section of Gastroenterology, Hepatology and Nutrition Department of Pediatrics. University of Chicago, 5841 S. Maryland Ave., MC 4065, Chicago, IL 60637, USA; [email protected] Received: 18 May 2014 / Accepted: 18 July 2014 © 2014 Wageningen Academic Publishers

REVIEW ARTICLE Abstract Underlying pathophysiological mechanisms of irritable bowel syndrome (IBS), a common disorder characterized by abdominal pain associated to a change in stool consistency or frequency, include low-grade inflammation and intestinal microbiota changes. Few and disappointing data are available for prebiotics. A few controlled trials (RCTs) of probiotics are instead available with favourable effects, although most are limited by suboptimal design and small sample size. A recent report from the Rome foundation group included 32 RCTs of probiotics, most of which showed an overall modest improvement in symptoms, with the patients most benefitting from probiotics being those with predominant diarrhoea and those having a post-infectious IBS. A review focusing only on children with functional gastrointestinal disorders concluded that probiotics are more effective than placebo in the treatment of patients with abdominal pain-related functional gastrointestinal disorders, although no effect on constipation was evident. The role for probiotics in inflammatory bowel disease (IBD) appears logical: the endogenous intestinal microbiota plays a central role in their development, and various probiotics have been found effective in animal models of IBD. However, research in humans has been overall quite limited, and it would seem that after a phase of intense research in the first decade of this century, the pace has slowed down, with fewer clinical trials been published in the past 2-3 years. To summarize current evidence: no probiotic has proven successful in Crohn’s disease. In ulcerative colitis, on the other hand, data are more promising, and a very recent meta-analysis, that included 23 randomized controlled trials, concluded that there is evidence of efficacy for the probiotic mixture VSL#3 in helping inducing and maintaining remission, as well as in maintaining remission in patients with pouchitis. It is fair to state that for both IBD and IBS, more well-designed, rigorous, randomized clinical trials must be performed. Keywords: irritable bowel syndrome, functional gastrointestinal disorders, inflammatory bowel disease, Crohn’s disease, ulcerative colitis

1. Introduction Among the most promising areas of utilization of preparations that could beneficially affect the microbiome are two separate, but equally important conditions: irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Theoretically one could influence the microbiome either indirectly by providing the metabolic fuel (prebiotics) needed for the growth and expansion of beneficial microorganisms or by directly administering to the host such microorganisms (probiotics). We will thus examine the current status of the utilization of both,

prebiotics and probiotics, in both disorders with a special emphasis on children.

2. Prebiotics in irritable bowel syndrome IBS is a very common functional gastrointestinal disorder (FGID), affecting up to 50% of the children and teenagers seen by a gastroenterology practice (Bausserman and Michail, 2005; Everhart and Renault, 1991). In addition to involve significant health care costs, IBS has a relevant negative impact on quality of life and social functioning (Spiller et al., 2007). The so-called Rome III criteria (Rasquin

ISSN 1876-2833 print, ISSN 1876-2891 online, DOI 10.3920/BM2014.0067209

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S. Guandalini et al.

et al., 2006) define IBS as characterized by the association of abdominal pain with a change in stool pattern in the absence of an organic cause. Altered gastrointestinal motility, altered brain/gut function, low-grade inflammation, psychosocial disturbance, visceral hypersensitivity, and intestinal microbiota all appear to contribute substantially (Kruis et al., 2012; Quigley and Flourie, 2007). It is however likely that IBS, whose pathophysiology remains elusive, is the end result of different pathogenetic factors contributing in various degrees in different patients to the final syndrome (Longstreth et al., 2006). To date there have only been four RCTs investigating the use and efficacy of prebiotics to treat IBS symptoms, all of them in adult patients. The first RCT was a cross over trial where 21 patients with IBS were given 6 g/day of oligofructose (Hunter et al., 1999). There were no significant deviations in symptoms for the treated or control group. The second study conducted by Olesen and Gudmand-Hoyer (2000) involved 96 patients with IBS who were given either 20 g/day of fructose-olygosaccharides (FOS) or placebo throughout a period of 12 weeks. This high dose increased symptoms at 4-6 weeks, thereby suggesting high dosage of prebiotics, such as FOS, would be ineffective and potentially even dangerous for treatment of IBS. The third study involved 105 patients with functional bowel disorders who were administered 5 g/day of oligofructose (Paineau et al., 2008). Although improvements in global symptoms and bloating were noted, only 50 patients could be included in the final analysis due to withdrawal or violation of protocol. The most recent, and at present last, study was conducted over a period of four weeks and involved random administration of 3.5 g/day of galacto-olygosaccharide (GOS), 7 g/day of GOS, or placebo to 44 IBS patients (Silk et al., 2009). The administration of GOS at both doses resulted in an increased predominance of bifidobacteria in faecal samples; and the lowest dose also resulted in significant improvement in bloating, flatulence, and global relief of IBS symptoms. However, higher dosage of GOS caused worse bloating symptoms. All in all, if general conclusions can be drawn based on these 4 RCTs, since low dosage of GOS prebiotics appeared

to have therapeutic effects on IBS, it is quite conceivable that the key to improvement may lie in the dosage: a low to moderate dose might provide some symptom relief, while higher doses may end up causing worsening symptoms. This negative effect may be related to increased luminal gas production following fermentation. In fact, it has been shown that a diet high in fermentable carbohydrates elevated hydrogen gas in 15 patients with IBS as well as 15 health control patients (Ong et al., 2010). This resulted in increased abdominal pain, bloating, and flatulence among IBS patients, as well as flatulence among healthy controls. To further support this concept, a recent study showed that a diet low in fermentable oligosaccharides, disaccharides, monosaccharaides and polyols is beneficial in improving IBS symptoms (Staudacher et al., 2014).

3. Prebiotics in inflammatory bowel disease The introduction of biological agents has markedly improved our ability to treat patients with the chronic, incurable inflammatory disorders grouped under the name of IBD, namely Crohn’s disease (CD), ulcerative colitis (UC) and indeterminate colitis. However, improved clinical efficacy has come at the cost of increased risks, including malignancies (Biancone et al., 2007; De Vries et al., 2008). Thus, it is not surprising that the use of ‘alternative’ remedies is very frequent in patients with IBD, and especially in children (Wong et al., 2009). In this regard, the possible use of prebiotics, agents that could beneficially influence the microbiota, appears enticing. With the immune system development as well as gut microbiota establishment occurring during early life, it is not surprising that children often have a more severe and extensive presentation of disease (De Greef et al., 2013). However, and quite surprisingly, in the face of a substantial amount of promising data obtained in animal systems (Araki et al., 2007; Bovee-Oudenhoven et al., 2003; Fukuda et al., 2002; Hoentjen et al., 2005; Kanauchi et al., 2002) there are no studies investigating the efficacy of prebiotics in children with IBD. Some prebiotics have, however, been tested in RCTs involving adult patients with UC and CD (Table 1; Scaldaferri et al., 2013).

Table 1. Prebiotics in adult inflammable bowel disease (Scaldaferri et al., 2013). Prebiotic

Endpoint

Outcome

Reference

Fructooligosaccharides

Reduction of disease activity index

controversial

Germinated barley foodstuff

Remission in patients with mild-to-moderate active ulcerative colitis

effective

Ispaghula husk Oligofructose with inulin Inulin

Remission in patients with mild-to-moderate active ulcerative colitis Reduction of inflammation in ulcerative colitis Reduction of inflammation in pouchitis

effective effective effective

Benjamin et al., 2011; Lindsay et al., 2006 Bamba et al., 2002; Kanauchi et al., 2002 Hallert et al., 1991 Casellas et al., 2007 Welters et al., 2002

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Beneficial Microbes 6(2)

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In an open trial involving patients with mild to moderate UC who had been unresponsive or intolerant to standard treatment, patients received 20-30 mg of germinated barley food (GBF) in a daily feeding (Bamba et al., 2002). At four weeks the GBF treatment had resulted in clinical and endoscopic improvement regardless of initial extent of disease, and the improvement was linked to elevated butyrate concentration in stool. A study by Kanauchi et al. (2002) found that GBF increased levels of Bifdobacterium and Eubacterium limosum and appeared to prolong remission in UC patients. Casellas et al. (2007) in a placebo controlled RCT on 19 UC patients treated with mesalazine showed that the group who received oligofructose-enriched inulin supplementation had a lower faecal calprotectin than controls (Casellas et al., 2007). As for CD, a small, open-label study with FOS supplementation in 10 CD patients showed that FOS improved disease activity index, increased faecal bifidobacteria concentrations and modified mucosal dendritic cell function (Lindsay et al., 2006). A recent RCT in 103 patients with CD randomized to receive FOS (n=54) or placebo (n=49) failed to show any significant difference in the number of patients achieving a clinical response between the FOS and placebo groups (Benjamin et al., 2011). Taken together, these observations on the use of prebiotics in IBD suggest that they may have some potential. Clearly however, there is still more research to be done and conducting larger double blind placebo controlled clinical trials should be considered.

4. Probiotics in irritable bowel disease The potential role for probiotics in IBS is based on a number of observations. Alterations in the intestinal microbiota have been described in patients with IBS versus nonIBS populations have been reported (Carroll et al., 2012; Kassinen et al., 2007; Saulnier et al., 2011); the development of IBS after a gastro-intestinal infection is well documented (‘post-infectious IBS’) (Saps et al., 2008); colonic faecal microbiota transplantation (DuPont, 2014) has been utilized; and it is quite conceivable that microbiota may interfere with additional factors involved in the pathophysiology of IBS (Collins et al., 2012; Johnson et al., 2011). In adults, several trials have been published, with sometimes conflicting results, although overall the outcomes have been quite promising (Camilleri, 2001; Kruis et al., 2012; McFarland and Dublin, 2008). In children, fewer RCT are available. Earlier investigations were not particularly encouraging: a Cochrane systematic review in 2009 (Huertas-Ceballos et al., 2009) aiming at determining the efficacy of dietary interventions in recurrent abdominal pain and analysing published RCT up to 2007, included two trials comparing supplementation with Lactobacillus GG Beneficial Microbes 6(2)

Probiotics in IBS and IBD

against placebo (Bausserman and Michail, 2005; Gawronska et al., 2007). The authors concluded that there was lack of high quality evidence that the probiotic supplementation could be considered effective in the management of children with recurrent abdominal pain. Since then, new RCT have been published, prompting interest in re-evaluating the role of probiotics in the management of IBS in children. In fact, a very recent systematic review and meta-analysis (Korterink et al., 2014) on the effect of different probiotics as a treatment for FGID in children and adolescents included 9 trials, 5 linked to the abdominal pain-related FGID (Bausserman and Michail, 2005; Francavilla et al., 2012; Gawronska et al., 2007; Guandalini et al., 2010; Romano et al., 2010), and 4 with defecation-related FGID (Banaszkiewicz and Szajewska, 2005; Bu et al., 2007; Guerra et al., 2011; Tabbers et al., 2009). The trials on abdominal pain used Lactobacillus GG, Lactobacillus reuteri DSM 17938 and the probiotic mixture VSL#3. The meta-analysis concluded that the use of such probiotics significantly increased treatment success in children with abdominal pain-related FGID, especially children with IBS. In our double-blinded, placebocontrolled, cross-over RCT (Guandalini et al., 2010), we found that the patients taking VSL#3 compared with placebo experienced a significant (P

Prebiotics and probiotics in irritable bowel syndrome and inflammatory bowel disease in children.

Underlying pathophysiological mechanisms of irritable bowel syndrome (IBS), a common disorder characterized by abdominal pain associated to a change i...
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