Final Progress Report
Proposal No. IBD-0166R
Principal Investigator: James O. Lindsay, BM BCh, Ph.D.
Applicant Organization: King's College London (United Kingdom)
Project Title: Fructo-oligosaccharides and Crohn’s disease: a prospective, randomized, double-blind controlled trial
Period of Award: August 7, 2006 – December 31, 2009
PROJECT AIMS
1) Conduct an appropriately powered double blind placebo controlled trial of prebiotic fructo-oligosaccharides in patients with
moderately active Crohn’s disease with predefined clinical microbiological and immunological endpoints
2) Assess the demographic, clinical and genetic factors associated with dysbiosis in patients with active Crohn’s disease
3) Assess the impact of the dysbiosis in patients with moderately active Crohn’s disease on dendritic cell phenotype.
PROJECT ACCOMPLISHMENTS
217 patients were screened and 103 patients with moderately active Crohn’s disease and one other marker of disease activity (CRP / PLT / ESR) were recruited to a clinical trial of 15g FOS vs placebo. This equated to complete accrual according to the power calculation specified in the protocol. Demographic features were reocrded. Baseline investigations included routine biochemistry and haematology, faecal calprotectin, disease activity assessed by CDAI, Quality of life assessed by IBDQ, baseline prebiotic consumption assessed by FFQ, faecal microbiology assessed by FISH, a subgroup had dendritic cell phenotype assessed in mucosal biopsies harvested at flexible sigmoidoscopy. All patients were genotyped for common Crohn’s disease polymorphisms. The ITT group consisted of 103 patients. The primary endpoint was clinical response at week 4. At this point all patients who continued in the trial had a repeat of the baseline investigations. Side effects were monitored as was adherence.
SUMMARY OF IMPORTANT RESULTS
1) More patients randomised to FOS withdrew from the trial than randomised to placebo
2) There was no significant difference between groups in the number of patients who achieved the primary endpoint (a fall in CDAI of greater
than 70 points in the ITT group.
3) There was no significant difference between groups in the number of patients who achieved any of the pre-specified secondary endpoints
(clinical response in the per protocol group, clinical remission in the ITT or per protocol group, absolute CDAI between groups, CRP
between groups or faecal calprotectin.
4) Dendritic cell IL-10 release increased significantly over the trial period in patients taking FOS but not placebo. There was also a reduction
the percentage of dendritic cells that stained positive for IL-6 in patients taking FOS but not placebo. There was no change in IL-12 release
over the trial period in either FOS or placebo patients.
5) Despite multiple previous reports suggesting that FOS results in an increase in faecal and mucosal bifidobacteria and F. prausnitzii, there
was no alteration in faecal concentrations or proportions of either in patients receiving FOS or placebo over the trial period.
6) Assessment of demographic factors that impact upon the luminal microbiota in patients with active Crohn’s disease revealed that
smokers and patients with ileal involvement have luminal microbiota consisting of significantly higher bacteroides and lower
immuno-regulatory F. prausnitzii. This may indicate a potential mechanism through which the negative effects of smoking on Crohn’s
disease are mediated.
7) Assessment of dendritic cell phenotype in patients with moderately active Crohn’s disease showed that IL-6 production and TLR
expression was increased and correlated with disease activity.
8) The balance of pro-inflammatory and immuno-regulatory luminal microbiota is associated with altered mucosal DC function in patients
with CD, supporting the concept that intestinal DC function is influenced by the composition of the commensal microbiota.
LAY SUMMARY
Crohn’s disease is a chronic inflammatory condition of the bowel that leads to a range of unpleasant symptoms including bloody diarrhoea, abdominal pain and abscess formation. Approximately 50% of patients require surgery to remove an affected part of bowel in the first 5 years of their disease. Current medical treatments that aim to control flares of the disease and prevent recurrence after surgery by suppressing the immune system are associated with a wide range of side effects. Recent research into the cause of Crohn’s disease has focussed on the relationship between the bacteria in the bowel and the gut immune system. There is strong evidence that certain strains of these bacteria prolong the inflammation associated with Crohn’s disease. However, it has been discovered recently that bacteria such as bifidobacteria and F prausnitzii may reduce bowel inflammation and increase protective mechanisms in the bowel lining. Also, studies have shown differences in the numbers of bacteria between healthy people and patients with Crohn’s disease as well as between patients with active and inactive disease. This has led to attempts to modify the gut bacterial balance as a treatment for Crohn’s disease. We are interested in the role of a prebiotic called fructo-oligosaccharide (FOS), which is a type of carbohydrate that is resistant to digestion by humans, but can be fermented by bifidobacteria and F. prausnitzii. We had performed an initial study in 10 patients with Crohn’s disease which showed that adding 3 spoonfuls of FOS to the regular diet each day was well tolerated, led to an increase in the number of bifidobacteria in the stool, increased the production of anti-inflammatory proteins, and most importantly, improved the Crohn’s disease activity.
This project set out to investigate the factors that influence the gut bacteria in Crohn’s disease and what effect these differences had on the intestinal immune system. We also assessed the clinical benefit of attempting to alter the gut bacteria using FOS in a carefully conducted placebo controlled clinical trial. We calculated that we would need to recruit 100 patients to have a good chance of detecting a meaningful difference between FOS and placebo.
Over the course of the research period we screened 217 and recruited 103 patients with active Crohn’s disease that met our stringent inclusion criteria. Patients underwent a series of baseline investigations to assess their disease activity, intestinal bacterial and immune cell function. They were then randomised to receive 3 teaspoons /day of FOS or placebo and reassessed after 4 weeks. During the trial we recorded any side effects and disease activity.
Our results clearly show that FOS does not improve either objective or subjective markers of disease activity in this patient group even though it did shift the balance in the intestinal immune system to a less inflammatory state. Surprisingly FOS did not change the gut bacteria in the way we expected, suggesting that it does not have the same effect in patients with gut inflammation as it does in healthy people. Our study of the factors that affect the intestinal bacteria showed that smoking (a known risk factor for developing Crohn’s disease) increased the number of inflammatory bacteria. Interestingly the balance of bacteria within an individuals gut seemed to influence the function of the intestinal immune system
In summary, our results have highlighted the link between smoking and alterations in gut bacteria and the impact that has on the intestinal immune system in patients with active Crohn’s disease. The clinical trial of FOS had no impact on disease activity at all and did not alter the gut bacteria in the way we expected although it did lead to changes in intestinal immune function.