A)Overview and Specific Aims:
Higher than normal levels of hydrogen sulfide (H2S) in the colon plays an important role in the etiology of ulcerative colitis (UC). Increased H2S impairs the colonic cell's ability to oxidize butyrate and other short-chain fatty acids required for cell nutrition. Sulfur in the human body is largely provided by diet; high intakes of sulfur and sulfate-containing foods have been found to be associated with an increased risk of recurrence of UC. Hence, it is only rational to identify whether foods high in sulfur or sulfate increase the risk of poor outcomes in UC. To our knowledge, there have been no studies investigating the impact of a reduced sulfur diet compared to conventional management on disease severity in patients with UC. Our main objectives are to identify if a reduced sulfur diet added to conventional management results in 1. improved disease severity, 2. reduced exposure of the host to sulfur-containing compounds, and 3. alterations in the microbiome of the patients. To achieve these objectives, we will randomly allocate the patients to either the conventional management (CM) or reduced sulfur diet intervention group (INT) and obtain the Mayo score, concentrations of fecal hydrogen sulphide (H2S), methanethiol (MT), and dimethyl sulphide (DMS), and urinary dimethyl sulfone (DM202) and 3-indoxyl sulfate and fecal microbiome at baseline and after 8 weeks. The INT group will also receive diet counselling by a registered dietician (RD).
B)Hypothesis:
A reduced sulfur diet would result in improved disease severity compared to conventional management in UC patients.
C)Objectives:
Primary objective:
1\. To pilot-test the feasibility of a reduced sulfur diet added to conventional management with oral and/or topical 5-ASA ± corticosteroid therapy to improve disease severity, measured by a clinically meaningful improvement in Total Mayo Score \& partial Mayo Score from baseline to week 8 compared to conventional management alone.
Secondary objectives:
1. To pilot-test the feasibility of a reduced sulfur diet added to conventional management with oral and/or 5-ASA ± oral corticosteroids to lower exposure of the host to sulfur-containing compounds from baseline to week 8 measured by fecal hydrogen sulphide (H2S), methanethiol (MT), and dimethyl sulphide (DMS), and; urinary dimethyl sulfone (DM202), and 3-indoxyl sulfate concentration compared to conventional management alone.
2. To examine the effect of a reduced sulfur diet on the microbiome of patients with UC.
3. To identify patient experience with a reduced sulfur diet using health related quality of life (HRQoL), and patient experience with chronic disease care measures.
4. To examine the effect of a reduced sulfur diet on inflammatory cytokines in patients with UC.
D) Methods
Study Design :
This pilot randomized controlled trial will have an 8-week interventional design that will take place at the University of Calgary (UofC).
Patient Recruitment:
Dr. Raman, the principal investigator, will oversee recruitment of eligible patients. In addition, Dr. Panaccione, Director of the IBD unit at the University of Calgary, and co-investigator for this study who along with the eight physicians associated with the IBD group at the University of Calgary will identify eligible study patients through dedicated outpatient IBD clinics and refer to Dr. Raman and the study coordinator for recruitment. The Calgary IBD unit assesses approximately 600 patients per month with at least 20 of them meeting eligibility criteria for this research project. All patients with UC in the IBD clinic who meet inclusion criteria will be approached for participation by the study coordinator after approval from their gastroenterologist.
Randomization of the patients:
After the patient consents to participate s/he will be randomly allocated to either the conventional management (CM) or intervention group (INT). Randomization will be performed using a computerised random number generator and group assignment will be concealed from the study coordinator enrolling patients until the time of assignment using sealed envelopes.
Intervention:
The INT group will receive conventional management plus a reduced sulfur diet and diet counselling by an RD. Implementation of the diet will be delivered directly by the RD and will provide each patient with an individualized plan. A reduced sulfur diet includes reducing foods, food additives (e.g., carrageenan) and beverages high in sulfate/sulfur associated with increased severity of UC consuming drinking water low in sulfate (can be as high as 500 mg/L in Alberta so identifying drinking water source is necessary)21, limiting sulfur containing supplements (e.g., chondroitin sulfate), and consuming omega-3 fatty acid supplements to potentially help control overgrowth of sulfur-reducing bacteria in the colon14. Omega-3 fatty acid intake for cardiovascular disease prevention should be around 500 mg/d23. In a representative Canadian population, average intake was 291 mg/d and 85% of adults were not meeting daily requirements23. After dietary assessment if patients are not meeting their required daily intake of 500 mg/d of Omega-3, the RD will recommend increased fish consumption to 200 g per week or 1 g/d of an Omega-3 supplement. This will ensure the daily recommended intake of 500 mg/d is being met to reduce the chances of a deficiency; however, a therapeutic dose for UC will not be recommended (i.e., \> 4 g/d18). The CM group will receive one session with RD on reduced sulfur diet at the end of 8 weeks.
The reduced sulfur diet eating plan, resources on reduced sulfur eating, and RD counselling session will be designed and reviewed by experts in nutrition, dietary design, education resources and dietary behaviour change. Both the INT and CM groups will receive conventional management with visits to the clinic at 4 weeks to ensure completion of their 24-hour food recalls and food frequency questionnaires, and to discuss disease course with their physician.
