FODMAPs alter symptoms and the metabolome of patients with IBS : a randomised controlled trial Keith McIntosh, David E Reed, Theresa Schneider, Frances Dang, Ammar H Keshteli, Giada De Palma, Madsen, Premysl Bercik, Stephen Vanner R3 전민아 / Prof. 이창균 Gut, March 14, 2016 ; 0:1–11. doi:

Introduction  Irritable bowel syndrome  Definition  group of symptoms—including abdominal pain and changes in the pattern of bowel movements without any evidence of underlying damage  Classification  diarrhea is common(IBS-D)  constipation is common(IBS-C)  both are common (IBS-M)  neither occurs very often (IBS-U)  Cause  The causes of IBS are not clear : gut brain axis abnormality, infection, small intestinal bacterial overgrowth, genetic factors, food sensitivity, gut motility problems ?

Introduction  Irritable bowel syndrome  Diagnosis : Rome III criteria

Introduction  Irritable bowel syndrome  Treatment  Psychological therapies  Diet  Low FODMAP diet  High fiber diet  Medication  Laxatives in IBS-C  Antidiarrheal agent in IBS-D  Antispasmodics(anticholinergics)  Antidepressant (TCA, SSRI)

Introduction  Low FODMAP diet  Fermentable oligosaccharides, disaccharides and monosaccharides and polyols (FODMAPs) can induce IBS symptoms  low FODMAP diets showed marked improvement in IBS symptoms  benefiting up to 70% of patients  However, mechanisms underlying the low FODMAP diet are unclear  Do FODMAPs have a specific mechanism that explains their ability to alter IBS symptoms ?

Introduction  Low FODMAP diet

Introduction  Low FODMAP diet  The mechanism by which reducing FODMAP could decrease IBS symptoms could be multifactorial ① FODMAPs induce distension Activate nociceptors and enteric reflexes Increase symptom of IBS (worsen underlying visceral hypersensitivity) ② extend to patients with either diarrhoea or constipation, suggesting more than just a simple osmotic action ③ improve global symptoms such as depression ④ pivotal role in the microbiota in fermenting FODMAPs,the metabolic response of the patient’s microbiota to FODMAPs might also be important osmotic effect gas production resulting from fermentation in the colon

Introduction  Low FODMAP diet  Metabolomic measurements are increasingly recognised as a valuable tool to understand the impact of diet on the host  To examine the impact of FODMAPs on the metabolome we evaluated three measures,  5hr lactulose breath test (LBT)  Metabolic profiling in urine using direct infusion and gas chromatography mass spectrometry  partial 16s rRNA gene profiling(Illumina) to analyse stool microbiota composition, at baseline and following the diet intervention

Materials and methods  Subject  prospective, randomised, single blind parallel study  comparing the effect of a low-FODMAP versus high-FODMAP diet in patients with IBS  subjects were recruited from adult outpatient clinics at a single-centre academic teaching hospital in Kingston, Ontario, Canada between June 2013 and November 2014

Materials and methods  Subject  Inclusion criteria  18 years or older  met the Rome III criteria for IBS of any subtype including IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D), mixed type IBS (IBS-M) or unsubtyped IBS (IBS-U)  had symptoms for greater than 6 months  Exclusion criteria  history of gastric, small bowel or colonic surgery  active IBD, coeliac disease  pregnant  unable to come off the following medications: antibiotics (including use within past 4 weeks), stool bulking agents, narcotic analgesics or lactulose  Who are on one of the following special diets: Palaeolithic diet, gluten-free diet, low FODMAP diet or Atkins diet

Materials and methods  Study design screening randomisation End of diet Tx

Materials and methods  Study design  Visit 1: screening  Patients received verbal and written information about the study and gave informed consent  Patients were advised that the purpose of the study was to ‘assess whether changing the amount of certain foods in the diet affects symptoms of IBS by altering how bacteria interact with the gut’  Visit 2 (day 0): randomisation  Patients completed the IBS symptom severity questionnaire, underwent a baseline 5 h LBT and provided a urine and stool sample  randomised by the hospital statistician using a computer generated randomisation programme to either diet 1 (a high FODMAP content diet) or diet 2 (a low FODMAP content diet)

Materials and methods  Study design  Visit 3(day 21): end of diet treatment  Patients completed a final IBS symptom severity questionnaire, provided a urine and stool sample and repeated the LBT  collected patients’ diet diaries and reviewed their compliance with the diets

Materials and methods  Intervention  During visit 2, each subject met individually for 30–60 min with the GI dietician to review the components of their assigned diet and to obtain advice on sample menus(5 sample meals)  Outcome assessments  Symptoms : IBS symptom severity system (IBS-SSS)  abdominal pain (severity and days of pain), distension, dissatisfaction with bowel habit and a quality of life measure (Max score 500)  Lactulose breath test  Urine mass spectrometry analysis of metabolome  Deep sequencing analysis of 16S rRNA with Illumina  Primary end point  Lactulose breath test (area under the curve, AUC)

Results  Patient characteristics  The study enrolled 40 patients with IBS, 2 withdrew from the low FODMAP group and 1 from the high FODMAP group  Most patients were IBS-D or IBS-M  Patients were well matched for age, gender, medications, BMI and IBS subtype

Results  Symptom scores  Baseline IBS-SSS were not different between the two groups (289.6±19.17 vs 279.8±18.36, p=0.48) Low FODMAP group had a mean decrease in global symptom scores of 28% compared with baseline (P<0.001) high FODMAP group reported a mean increase of 7% in symptoms (not significantly different from baseline) marked decrease in abdominal pain scores in the low FODMAP group (52% reduction; p<0.01) high FODMAP group reported significantly more days of pain Patients in the low FODMAP group also reported a trend towards a reduction in abdominal distention When asked whether they were satisfied with the intervention, only those in the low FODMAP group reported a significant increase in satisfaction

Results  Symptom scores  Individual scores showing almost all patients improved in the low FODMAP group whereas most patients in the high FODMAP group were unchanged or worse

Results  Symptom scores  We correlated the FODMAP diet diary scores (independent of their diet assignment) and global IBS symptom scores and found a positive correlation between IBS symptom severity and their level of FODMAP consumption (p=0.002, R2=0.25)

Results  Lactulose breath test  Small differences in H2 AUC were observed in the post LBTs in the high FODMAP group compared with the low FODMAP group

Results  Urinary metabolomic evaluation  Baseline metabolomic profiles of patients in the two diet groups were not different from each other(p=0.77, R2=0.13 and Q2=−0.62)

Results  Urinary metabolomic evaluation  Following dietary intervention there was a significant separation in metabolomic profiles of patients with IBS in the two diet groups  The observed separation was found to be statistically significant

Results  Urinary metabolomic evaluation  Three metabolites (histamine, p-hydroxybenzoic acid (pHBA) and azelaic acid) were primarily responsible for discrimination between the two groups

Results  Urinary metabolomic evaluation  Histamine, a measure of immune activation, was reduced eightfold in the low FODMAP group ( p<0.05)

Results  16s RNA profiling of colonic microbiome  There was no difference in α-diversity (within-community, species diversity and richness) or β-diversity (betweencommunity) between samples from before and after high or low FODMAP diets and the results were similar across all types of IBS  However, when analysing only the samples after 3 weeks of a high FODMAP or a low FODMAP diet, faecal samples from the low FODMAP group showed higher Actinobacteria richness and diversity (corrected p=0.046 and 0.02, respectively) compared with the high FODMAP group

Results  16s RNA profiling of colonic microbiome  bacteria from the genus Adlercreutzia(Coriobacteriaceae), Dorea (Lachnospiraceae) and the family of Actinomycetaceae were lower after a high FODMAP diet(uncorrected p=0.02, 0.05 and 0.044, respectively)  high FODMAP diet decreased the relative abundance of bacteria involved in gas consumption, likely contributing to symptoms

Results  Correlating microbial changes with diet, symptoms and metabolome  We observed several significant correlations between bacterial relative abundance and symptoms, H2 production and urine metabolome

Conclusion  FODMAPs modulate histamine levels and the microbiota, both of which could alter symptoms  Patients with IBS who consumed a low FODMAP diet had a significant improvement in symptoms and changes in their metabolome  We also found evidence however that low FODMAP diets could potentially have long-term negative consequences, as reported by others  The current recommendation at most centres is that a strict restriction of FODMAPs is not the long-term goal of the diet  Low FODMAP diet might induce potential ‘unhealthy’ changes at the microbial level but requires long-term studies