Efficacy of Low-FODMAPs Dietary Therapy for Irritable Bowel Syndrome in China

Efficacy of Low-FODMAPs Dietary Therapy Versus Traditional Dietary Advice for Diarrhea-predominant Irritable Bowel Syndrome in China - A Prospective Randomized Controlled Trial

The primary aim of our study is to carry out a randomized trial to evaluate the efficacy of low-FODMAPs dietary therapy compared to conventional therapy for IBS patients recruited from tertiary hospitals in China. Secondary aims of this research include an analysis of clinical, physiological and microbiological factors that may predict IBS patient response to this dietary intervention.

Visit 1：Enrollment & Screening & Run-in period Patients who meet the inclusion criteria will be asked to complete IBS Baseline Assessment Questionnaires according to Rome III.Subjects that meet the criteria will receive verbal and written information about the study and provide written informed consent. After meeting with the dietitian and physician who will provide instructions, they will be asked to complete Combined Nutrient and Lactulose Breath Test.[16] Additionally, a baseline food and symptom diary will be completed in a (minimum) 14 day run-in period after breath test (the first 48hr after the breath test will not be included in this analysis). This diary record prior to the intervention will document baseline symptom severity and capture the habitual diet of IBS patients. Visit 2: Randomization & Intervention. After the run-in period, patients will come back to the clinic to receive dietary instruction ahead of starting the intervention. At the same visit subjects will provide fresh stool for fermentation analysis (including short chain fatty acids and pressure detection) and blood for cytokines analysis. Subjects will then be randomly assigned to either low FODMAP diet (LFD) group or traditional dietary advice for IBS (TDA) group by computer-generated random number table. Participants will receive food instructions by a dietitian, according to their assignment. Throughout the study, only the dietitian will be aware of the assignment of the intervention given. Both diet therapy will last for 3 weeks, and all the subjects are instructed to complete daily food and symptom diary through a provided booklet. IBS Symptoms Severity Scores (IBS-SSS) is evaluated every week and the dietitian who is not aware of the allocation will make a telephone follow-up to assess patient adherence. Visit 3: End of treatment & Follow-up. After 3 weeks of intervention, the participants will attend a follow-up appointment and complete the IBS Post-Intervention Assessment Questionnaires. Fresh stools and blood are recollected at this visit to evaluate for possible change in gut microbiota and cytokines after diet intervention.

The low-FODMAPs diet(LFD) aims to keep oligosaccharides, fructose in excess of glucose, and polyol content at less than 0.5 g each per serving based on previously published data. low-FODMAPs diet therapy for 3 weeks

Traditional dietary advice (TDA) will focus more on how and when to eat rather than on what foods to ingest . Patients will be instructed to regularly eat, never too much or too little, never to be hungry or too full; to eat in peace and to chew thoroughly; reduce intake of fatty, spicy food, fiber, coffee and alcohol during the intervention period Traditional dietary advice for 3 weeks

The low-FODMAPs diet(LFD) aims to keep oligosaccharides, fructose in excess of glucose, and polyol content at less than 0.5 g each per serving based on previously published data. low-FODMAPs diet therapy for 3 weeks

Traditional dietary advice(TDA) will focus more on how and when to eat rather than on what foods to ingest . Patients will be instructed to regularly eat, never too much or too little, never to be hungry or too full; to eat in peace and to chew thoroughly; reduce intake of fatty, spicy food, fiber, coffee and alcohol during the intervention period traditional dietary advice for 3 weeks

Primary endpoint will be response to 3-week of diet intervention defined by shows >50 point reduction in IBS-SSS between baseline and post-intervention scores. The proportion of responders who met primary endpoint in each group will be compared.

Compare improvement about abdominal pain during 3-week intervention period between different groups according to Food and Drug Administration (FDA) individual composite end point (≥30% reduction in mean daily abdominal pain score).

Compare improvement about stool consistency during 3-week intervention period between different groups according to Food and Drug Administration (FDA) individual composite end point (a decrease in mean daily Bristol Stool Score (BSS) value of ≥1 compared with baseline for any 2 weeks of the intervention period).

Compare group changes from baseline in abdominal pain score，averaged over each treatment week for total three weeks.

Compare group changes from baseline in abdominal frequency, averaged over each treatment week for total three weeks.

Compare group changes from baseline in bloating score, averaged over each treatment week for total three weeks.

Compare group changes from baseline in excessive wind score, averaged over each treatment week for total three weeks.

Compare group changes from baseline in stool consistency as measured by BSS, averaged over each treatment week for total three weeks..

Compare group changes from baseline in stool frequency, averaged over each treatment week for total three weeks.

Compare group changes from baseline in urgency score, averaged over each treatment week for total three weeks.

Compare group changes from baseline in incomplete defecation score, averaged over each treatment week for total three weeks.

Compare group changes between baseline and post-intervention(3 weeks later) about quality of life evaluated by IBS-QOL.

Compare group changes between baseline and post-intervention(3 weeks later) about mental health evaluated by GAD-7 and PHQ-9.

Compare group difference about stool fermentation production- short chain fatty acids, before and after 3-week intervention .

Compare group difference about fecal microbial α- diversity displayed by Shannon index before and after intervention.

Fresh feces will be collected from patients at baseline and the end of the intervention (three weeks intervention), and the fecal DNA will be extracted by MOBIO PowerSoil DNA Isolation Kit according to the instructions. The 16S rRNA sequencing will be performed from the extracted DNA. Within-community diversity (α- diversity displayed by Shannon index) will be further calculated according to the sequencing results.

Compare group difference about fecal microbial β- diversity displayed by Principal Component Analysis (PCA) before and after intervention.

Fresh feces will be collected from patients at baseline and the end of the intervention (three weeks intervention), and the fecal DNA will be extracted by MOBIO PowerSoil DNA Isolation Kit according to the instructions. The 16S rRNA sequencing will be performed from the extracted DNA. Between-community diversity (β- diversity displayed by Principal Component Analysis (PCA)) will be further calculated according to the sequencing results.

Fresh feces will be collected from patients at baseline and the end of the intervention (three weeks intervention), and the fecal DNA will be extracted by MOBIO PowerSoil DNA Isolation Kit according to the instructions. The 16S rRNA sequencing will be performed from the extracted DNA. LEfSe (linear discriminant analysis coupled with effect size measurements) will be further calculated according to the sequencing results.

Fresh feces collected from responders and nonresponders to interventions at baseline will be analyzed by 16S rRNA sequencing. Within-community diversity (α- diversity displayed by Shannon index) will be further calculated according to the sequencing results.

Compare stool microbial β- diversity displayed by Principal Component Analysis (PCA) between responders and non-responders

Fresh feces collected from responders and nonresponders to interventions at baseline will be analyzed by 16S rRNA sequencing. Between-community diversity (β- diversity displayed by Principal Component Analysis (PCA)) will be further calculated according to the sequencing results.

Fresh feces collected from responders and nonresponders to interventions at baseline will be analyzed by 16S rRNA sequencing. LEfSe (linear discriminant analysis coupled with effect size measurements) will be further calculated according to the sequencing results.

Compare stool fermentation production- short chain fatty acids, between responders and non-responders

Compare IBS symptom severity (measured by IBS symptom severity scale(IBS-SSS)) between responders and non-responders

Inclusion Criteria: 18-65 years old. Meet Rome Rome III criteria for IBS-D. All these patients should have no abnormality in blood, stool analysis or colonoscopy within the previous 2 years. No GI alarm symptoms. Exclusion Criteria: Presence of a severe cardiac, hepatic, nephritic, neurologic disease. Presence of mental disorders caused by schizophrenia, organic brain disorder or physical disease. Other comorbid medical conditions (eg.unstable diabetes, unstable thyroid disease). Previous abdominal surgery except appendectomy or hysterectomy. Pregnant or lactating women. Use of probiotics, prebiotics, lactulose, antidiarrheal agents or bowel preparation within the 4 weeks prior to the study. Participation in any other form of dietary therapy within the 4 weeks prior to the study. Difficulties in communication.

Zhang Y, Feng L, Wang X, Fox M, Luo L, Du L, Chen B, Chen X, He H, Zhu S, Hu Z, Chen S, Long Y, Zhu Y, Xu L, Deng Y, Misselwitz B, Lang BM, Yilmaz B, Kim JJ, Owyang C, Dai N. Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet compared with traditional dietary advice for diarrhea-predominant irritable bowel syndrome: a parallel-group, randomized controlled trial with analysis of clinical and microbiological factors associated with patient outcomes. Am J Clin Nutr. 2021 Jun 1;113(6):1531-1545. doi: 10.1093/ajcn/nqab005.