Ten to 46% of children 4 - 16 yr. of age around the world have recurrent abdominal pain and up to 66% of these develop irritable bowel syndrome (IBS) as adults. Data from adults suggest that motility disturbances, visceral hypersensitivity, low grade gastrointestinal (GI) mucosal inflammation, and alterations in the enteric bacterial population may interact with each other to produce the symptoms of IBS. Certain probiotics such as VSL#3 may act to improve these factors and thus, reduce the pain and stooling symptoms of IBS. Before we are permitted to carry out a prospective, randomized, double-blind trial of probiotics in children, the FDA requires that we carry out a safety trial of VSL#3 in aduls with IBS under our current IND. We propose that R34 support will enable us to carry out additional measures in the adult safety trial that will facilitate our ability to eventually move forward with a large, randomized trial of VSL#3 in children with IBS by providing information regarding dose/duration pharmacokinetics, gut microbial composition, safety, toxicity, and gut barrier function related to the use of this probiotic. Thus, as part of our current safety trial ofthe probiotic VSL#3 in adult patients with IBS our Specific Aims are to: 1) Quantify the duration of treatment/total cumulative dose response of microbial signatures of the organisms in VSL#3 in stool after administration;2) Determine the effect of VSL#3 administration on the overall composition of the gut microbiome;and 3) Measure GI permeability as a measure of gut barrier function before and after the administration of different durations of treatments/total cumulative dose of VSL#3. The study will be carried out in accordance with our FDA mandated safety trial (IND# 13728). Adults with IBS as defined by the adult Rome III criteria will be recruited. Patients will keep a diary of their pain and stooling habits for 1 week during which time they will collect baseline stool sample for microbial analysis and undergo a GI permeability urine sugar test. They then will be randomized to receive in an open-label fashion the probiotic VSL#3 containing 900 billion bacteria for either 4 wk (n=10) or 8 wk (n=10). The microbial analysis of stool and GI permeability test will be repeated after completion of probiotic administration. During administration of the probiotic patients will keep a daily pain and stooling diary as well as recor any adverse events. Four weeks after they have finished the treatment they will complete the Rome III questionnaire. The proposed study addresses priority areas identified by PAR-10-163 as well as NCCAM in general. Our proposal will provide preliminary data on the effects of different durations of treatment/cumulative doses of VSL#3 on colonization of the gut by the bacteria in VSL#3 and their effect on GI barrier function (permeability) that will be crucial in planning and carrying out a large, randomized trial of the probiotic in children with IBS. Further, our results will provide critical information regarding the safety and potential toxicity of VSL#3 that will be vital to satisfying FDA requirements for an IND for the study of VSL#3 in children.
Irritable bowel syndrome affects 10-15% of adults and children and is associated with significant physical, emotional, and economic burdens. There is a critical need for effective therapies. The results of this proposal will provide key information required to design and carry out in children a randomized double-blind trial of VSL#3, a probiotic that has shown promise in the treatment of this often debilitating disorder.