Scientific Abstract

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

The goal of this proposal is to assess the therapeutic efficacy of fructo-oligosaccharides (FOS) in patients with moderately active Crohn’s disease in a double-blind, placebo controlled trial.

Manipulation of the intestinal microbiota is an attractive therapeutic strategy for patients with Crohn’s disease. FOS have been shown to increase fecal and mucosal bifidobacteria concentrations throughout the colon in healthy subjects. We recently reported a three week open label trial of 15g/day FOS in patients with moderately active Crohn’s disease. In the ten patients studied, disease activity was significantly reduced as measured by the Harvey Bradshaw Index (HBI). There was a significant increase in fecal bifidobacteria after FOS therapy. Furthermore, mucosal bifidobacteria were increased in patients that entered clinical remission compared to those that had persistent disease activity. Finally, there was a significant increase in lamina propria dendritic cell IL-10 production. This was associated with an increase in TLR-4 expression.

The current experimental plan is an appropriately powered double blind placebo controlled trial of four weeks dietary supplementation with15g FOS per day in patients with moderately active Crohn’s disease (CDAI 250-450). The primary endpoint will be disease response at week four (reduction in CDAI by 70 points or more), with secondary endpoints to include disease remission at week four, fall in HBI, fall in CRP, improvement in quality of life (measured by IBDQ) and both response and remission at week twelve. We will assess the tolerability of FOS in this patient group using a validated prebiotic side effect diary. The microbiological affects of FOS will be assessed using fluorescence in situ hybridization of both feces and mucosal biopsies. Finally, the effect of FOS on lamina propria cytokine release and TLR expression will be assessed in a subset of patients.

In conclusion, the hypothesis is that FOS induces immunoregulatory dendritic cell responses via its promotion of mucosal bifidobacteria resulting in a reduction in disease activity in patients with moderately active Crohn’s disease. This novel therapeutic strategy is supported by preliminary open label data and has none of the side effects of conventional immunosuppressive medications. If proven to be effective in the current double-blind, placebo controlled trial, it would have wide application in patients with Crohn’s disease, and thus represent a major advance in the therapy of this disease.