A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn’s disease

New medical treatments are emerging for the treatment of the inflammatory bowel disease (IBD) ulcerative colitis (UC) and Crohn’s disease (CD) and the positioning of established medication is continuously being refined. Most of the new treatments are for severe disease, but patients continue to experiment with non-drug related remedies in the hope of improving wellbeing. Accordingly many people with IBD seek means of altering lifestyle issues including complementary alternative treatment (Hilsden et al. 1999, 2003; Quattropani et al. 2003) and they frequently do so without consulting their doctors (Bensoussan et al. 2006). The most common alternative treatments are homeopathy, acupuncture, traditional Chinese medicine and increasingly the use of probiotics (Joos et al. 2006).

The interest in probiotics has been fueled by new technologies that demonstrate that the intestinal microbiome is significantly altered in a number of intestinal and extra-intestinal diseases, suggesting that bacterial dysbiosis may have an etiological or pathogenic role in some of these disorders (Ni et al. 2017). This is of particular relevance in UC and CD as it offers the possibility that probiotics might be useful as an adjuvant treatment.

Antimicrobials have an established albeit limited place in the treatment of IBD, but the use of other regimes intended to interact with the intestinal flora, such as colonic lavage, dietary modifications (Obih et al. 2016), faecal microbiota transplants (Cohen and Maharshak 2017) and probiotics (Weizman et al. 2012) are much more controversial (Cheifetz et al. 2017). The main problem for acceptance of some of these studies is that the trials have lacked controls, etc. Indeed there are no regulatory requirements for randomized controlled trials when it comes to food supplements (probiotics), dietary management and similar interventions (Gallinger et al. 2014; Cheifetz et al. 2017).

Prebiotics have nevertheless been assessed in IBD in order to reduce symptoms in active disease and to prolong clinical remission. The perception from Cochrane and other reviews are that some probiotics [E. coli (Nissle 1917)], VSL-3, Bifidobacterium longum (along with a pre-biotic fructo-oigosaccharide/inulin mix), Bifidobacteria fermented milk) reduce clinical disease activity modestly, using a variety of comparators and outcome measures (Mallon et al. 2007). Some [VSL-3 (2 studies), Lactobacillus GG, E. coli (Nissle 1917) (5 studies), Bifidobacterium, Bifidobacterium longum, Bifidobacterium breve and bifidum with Lactobacillus, Bifidobacterium breve and longum (Yakoult with Lactobacillus)] may prolong remission (Zigra et al. 2007; Sang et al. 2010) in patients with mild to moderately severe UC (when added to standard therapy), compared with a variety of comparators and outcome measures. However, probiotics [Lactobacillus GG (4 studies) Lactobacillus johnsonii (2 studies), VSL-3 and E. coli (Nissle 1917)] do not prolong remission significantly in CD (Rolfe et al. 2006; Rahimi et al. 2008; Doherty et al. 2009; Shen et al. 2009), again using various outcome measures.

Probiotics differ in their formulation including bacteriological composition so that the effect of a particular brand cannot be extrapolated over to another one. Symprove is a liquid based probiotic containing live bacteria that survive a simulated gastrointestinal environment (Fredua-Agyeman and Gaisford 2015). Previous trials using Symprove show a significant improvement in the overall irritable bowel syndrome (IBS) symptom severity score (mostly abdominal pain and bowel habits) in patients with IBS (Sisson et al. 2014) and some symptoms associated with diverticular disease (constipation, diarrhoea, mucorrhoea and back pain) (Kvasnovsky et al. 2017). Symprove had a tendency to reduce intestinal inflammation in IBS and may prevent inflammation in diverticular disease.

Our purpose was to assess the short-term effects of Symprove on quality of life and intestinal inflammation in a cohort of asymptomatic patients with IBD as compared with placebo.

This was a single-centre, randomized, double-blind, placebo-controlled trial designed to assess the short-term efficacy of the probiotic Symprove to improve quality of life and alter intestinal inflammation in patients with quiescent or mild symptoms of UC and CD (IORAS: 183662). The trial took place at King’s College Hospital, London, between November 2010 and October 2014.

The study was conducted in accordance with the guidelines for Good Clinical Practice (CPMP ICH 135 95), the principles of the Declaration of Helsinki and with all relevant local and national guidelines including the archiving of records. All patients were provided with written and verbal information about the study and subsequently gave informed written consent before study entry.

The Medicines and Healthcare products Regulatory Agency was consulted prior to starting this study and concluded that Symprove is classified as a food supplement rather than an investigational medicinal product.

The National Research Ethics Service approved the study protocol. Further review was undertaken locally by the Research and Development Committee of King's College Hospital who acted as Sponsors for the study.

Patients with UC and CD were recruited from King’s College Hospital Gastroenterology outpatients. The main inclusion criteria were patients attending routine clinical review with established UC and CD, age 18–70 years, diagnosed at least 6 months prior to the trial. Patients were required to have stabile inactive clinical disease, as defined by < 5 points on Harvey Bradshaw score (Harvey and Bradshaw 1980) (which corresponded to a score of ≤ 4 on the Truelove-Witts criteria (Truelove and Witts 1955) for ulcerative colitis, without a change in medication for 4 months. Patients on no treatment, maintenance treatment with a 5-aminosalicylic preparation or low dose Azathioprine (1 mg/kg) were eligible for inclusion in the trial, but those on steroids (prednisolone > 4 mg/day) and biologics were excluded from the study.

Exclusion criteria included patients having undergone intestinal resection, patients with serious co-morbidity including neurological, rheumatological, respiratory, nephrological, cardiovascular, psychiatric disease, patients with alcohol or drug addiction or dependency problems (within the last 5 years) and pregnant or lactating women. Patients with previous intolerances or adverse reactions to probiotics or the use of these products within the preceding 3 months were excluded.

Between November 2010 and October 2014 over 300 patients with UC and 250 patients with CD were considered for participation in these studies. The trial was terminated in November 2014 when no patient with CD had been recruited for 5 months.

No significant side effects were reported, and the probiotic was well tolerated by everyone.

Table 1 shows the Demographic details of the whole study group.

This short-term, double-blind, randomized placebo-controlled clinical trial included patients with UC and CD that were in clinical remission and on minimal treatment. There were no significant changes in any of the measured outcome parameters, but there was a clear signal that the probiotic might be anti-inflammatory in patients with quiescent UC. This was supported by post-hoc analyses of the sequential changes of FCAL.

The medical management of IBD can be separated into two phases: induction and maintenance treatment (with a view to prolong the time to the next clinical relapse and reduce its severity). Maintenance treatment is advocated for most patients and this involves the administration of sulphasalazine or one of the 5-ASA preparations and at times azathioprine. The study group in the present study were predominantly clinically asymptomatic patients on 5 amino salicylic acid preparations and minimal other therapies, which might account for the uniformly good IBD QOL scores and the relatively normal laboratory parameters, apart from the FCAL levels. These did not change significantly during the treatments.

It is of note that, in patients otherwise in clinical remission, FCAL levels were increased in both UC and CD on entry to the trial, indicative of ongoing intestinal inflammation. This is a recognized finding in patients with IBD, but more importantly FCAL in excess of fivefold for the upper normal limit (e.g. 250 µg/g) confers a significant risk of clinical relapse of the disease in the next 6–12 months (Tibble et al. 2000).

Similar analyses in the CD patients showed no significant differences between probiotic and placebo treated patients and none of the patients experienced a clinical relapse.

The shortcomings of this study are that it was exploratory i.e. there was no preliminary study carried out in order to enable a robust power calculation for sample sizes and the fact that it took to a selected group of asymptomatic IBD patients that are on minimal medical treatment and such patients probably represent less that 10% of IBD patients and hence not representative of the whole group of patients with IBD.

In summary this study suggests that the probiotic Symprove may be associated with reduced intestinal inflammation in patients with UC. Further studies are however required to see if long-term ingestion of this probiotic maintains its anti-inflammatory action and whether it prevents clinical relapse of those patients that are at significant risk of clinical relapse.