Diet Reintroduction Study in Irritable Bowel Syndrome

Research Plan Design: Blinded FODMAP reintroduction study Duration of study: 1 year

Patient population:

Eligible IBS patients

Visit 1 (-2 weeks): After providing written informed consent, baseline and descriptive data will be obtained including age, sex, race, pertinent medical history, prior IBS treatments, vital signs, weight, use of concurrent medications and supplements, duration of symptoms, and baseline symptoms. The investigators will also collect blood, stool and urine for a series of separately funded translational studies assessing immune activation, permeability, and microbiome.

After this visit, patients will enter a two-week screening period during which severity of symptoms will be assessed. Eligible patients will rate their average daily abdominal pain/discomfort as a 4 or higher on an 11 point numerical rating scale (NRS) (0-no pain, 10-intolerable pain) and IBS subtype of constipation-predominant, diarrhea- predominant, or mixed bowel habits (by Rome IV criteria19). Patients with an indeterminate subtype will be excluded. Patients will record symptoms (Table 1) daily using a web-based survey instrument. Experience from previous diet trials suggests that approximately 50% of participants will not fulfill these inclusion criteria after the screening period, and will be termed screen failures.

Visit 2 (weeks 0-2): IBS patients who fulfill the entry criteria will be invited to participate in the remainder of the trial. Instruction from an experienced research dietitian pertaining to the low FODMAP diet will be administered to all participants in an open-label fashion for 2 weeks. Patients are to continue to record symptoms daily. Our previous work has demonstrated that abdominal pain and bloating are the most responsive symptoms to the low FODMAP diet. As such, the primary measure for this study will be improvement in abdominal pain with improvement in bloating as a key secondary endpoint. If a subject experiences a ≥30% reduction in abdominal pain during the 2-week low FODMAP intervention compared to baseline, they will be invited to participate in the blinded, FODMAP reintroduction phase (below). If this ≥30% reduction is not obtained, this period of open-label low FODMAP diet will be extended an additional 2 weeks to ascertain if their symptoms improve to qualify for continuation.

Standard dietary compliance measures used in the counseling environment are to include prospectively recorded 3-day food diaries before and after the open label period. Body weight over the course of the study will also be followed. Food diaries will be analyzed for compliance via the Nutrition Data System for Research (NDSR) computer program, measuring fructose, lactose, sucrose, pectins, sorbitol, and added sugars. Blood, stool and urine samples will be collected for translational studies (separately funded).

Week 2: If a ≥30% reduction in abdominal pain is obtained from the low FODMAP diet, subjects will be eligible to continue in the study during which they will remain on a full FODMAP elimination diet. For 7 days (week 2-3) prior to the reintroduction of individual FODMAPs, subjects will ingest 1 daily servings of a low FODMAP nutrition drink (Pronourish, 170 calories each, Nestlé S.A., Vevey, Switzerland) to validate the low FODMAP content of this dietary supplement. Daily symptoms will be measured as above. If a participant does not experience a flare of symptoms with the supplement, they will continue onto the reintroduction phase. If the participant does experience a flare in symptoms, they will discontinue the product for 1 week before continuing in to the next phase (reintroduction phase) of the study. The supplement will be supplied with an unbranded label. Adverse events will be monitored during weeks 2-3 and significant adverse events (discontinuation of the supplement, worsening of GI symptoms back to baseline) will be recorded.

Visit 3 (weeks 3-13): FODMAP reintroduction (lactose, fructose, fructans, polyols, galactans) will be achieved by providing subjects with similar appearing and similar tasting snacks which will contain specific types of supplemental FODMAPs prepared by research dieticians at MCRU. The study team will ask the participants to continue on their low FODMAP diet during this reintroduction phase, with the addition of 1-2 supplemental low FODMAP drinks per day for convenience. The re-introduction of FODMAP containing foods will be conducted in a double-blind fashion where both subjects and investigators will be unaware of the type of FODMAP being reintroduced. The study dietitians will remain un-blinded to the subjects' FODMAP treatment since they will be responsible for preparing and providing the FODMAP containing supplement to the subjects. For the first 7 days of the re-introduction phase, subjects will receive a FODMAP containing food item; this treatment will be followed by a 7-day wash out period during which subjects will receive a similar food or supplement that does not contain the targeted FODMAP. The daily dose of fermentable carbohydrate contained in the study food or supplement will be administered in 2 doses (moderate for the first 3 days and higher amount for the later 4 days of the 7 day reintroduction period), with the content similar to that found in the typical American diet (internal data from healthy study subjects, published data18,20). To determine optimal dosing, the study team will conduct a careful systematic review and interviews with experienced dieticians and GIs to determine the optimal dose to each FODMAP with which to challenge. The order in which each specific FODMAP is tested will be randomized to minimize the chances of an order effect. Throughout the study period, symptom data will continue to be recorded on a daily basis (Table 1). If a subject is unable to tolerate any portion of the reintroduction phase, they will discontinue reintroduction of that specific FODMAP and revert again to a low FODMAP diet for washout.

Visit 4: Final study visit (13 weeks). Subjects will be unblinded as to which FODMAP components exacerbated symptoms, if any. This information will be disseminated to study participants by our dietitians immediately after their completion of the study period. The primary investigators remain blinded to this information through analysis of data. A three-day food diary will be obtained to ensure ongoing compliance with the low FODMAP diet. Serum samples for immune activation, stool for microbiome analysis, urine for metabolome analysis will be collected at Visit 2 and 3 and analyzed with funding from alternate sources. Body weight will again be assessed.