CLINICAL USE AND EFFICIACY IN IBS FODMAPS CLINICAL USE AND EFFICIACY IN IBS ALICIA LUSARDI NICOLE TEKKORA FEBRUARY 28, 2016

What is IBS? 1 Chronic GI disorder1,2 Description: Stomach distension, abdominal discomfort, and irregular bowel movements without disturbance to the lining of the GI tract1,2 Irregular bowel movements can include diarrhea, constipation, or a combination of the two1 Categorized as: IBS-D, IBS-C, IBS-M, or IBS-U1,6 IBS-D= most common (40-60% cases)6 Gold-standard diagnosis: Rome III (symptom-based specifications) along with elimination of any organic disorder1 Most prevalent GI condition encountered by medical professionals1 Up to half of patients seen by gastroenterologists have IBS1 IBS-D= diarrhea subtype, IBS-C= constipation subtype, IBS-M= mixed subtype, IBS-U= unspecified subtype (normal stool)

What is IBS? 2 Worldwide: 10-20% occurrence1 Mainly women between 30-50 yrs1 Affects 20% of young children3 High medical expense1 Associated with low quality of life1 Close to 2/3 IBS patients find symptoms to correspond with their diet1 Foods that worsen symptoms: Carbs not 100% absorbed, foods with high lipid content, caffeine, alcohol, spicy foods1

Gold Standard: Rome III Criteria1 3

What causes IBS?1 Cause is ? 4 Cause is ? Current research speculates: Increased responsiveness to pain or excessive responsiveness to pain in intestines Excessive bacterial proliferation in small intestine Minor visceral inflammation Stress and/or depression6 Not well understood, multiple facets likely contribute to disorder

Pathophysiology6 Inflammation: 5 Inflammation: Higher probability of developing IBS after GI infection Higher numbers of mucosal inflammatory signals Greater amounts of certain inflammatory mediators (i.e. IL-6 and IL-8) in the blood High levels of mucosal mast cells in the colon, which are essential for fighting against pathogens and could directly affect enteric sensory nerves Amplified communication between GI tract and CNS Caused by changes in GI tract within the lumen, bloating, and chemical changes Changes in CNS Irregular afferent processing and stimulation of brain areas controlling emotions and arousal Anxiety and depression Lack of control regarding communication between gut bacteria and the CNS

How do we treat IBS?1 Principal aim: decrease symptoms 6 Principal aim: decrease symptoms Hard to treat because of the wide array of symptoms, difficult to accurately assess effectiveness of treatments, and high placebo effect seen in studies4 Pharmacological approach: Bulking agents Anticholinergics Antispasmodics Antidiarrheals Antidepressants Not effective without combining with lifestyle changes Lifestyle modifications: DIET Physical activity CBT Hypnosis Anticholinergic= inhibits acetylcholine action, especially as a neurotransmitter -normally, acetylcholine is secreted by extrinsic nerves which allows the muscles w/in digestive organs to contract more forcefully and help them to move food through GI tract. Additionally, it stimulates digestive juice production by the stomach and pancreas (http://biology.about.com/od/organsystems/a/aa032907a.htm) Antispasmodic= relieves spasm of involuntary muscles

Diet Treatments1 FODMAP diet Gluten free diet 7 FODMAP diet Gluten free diet Probiotics supplementation Fiber supplementation Elimination diets

WHAT ARE FODMAPS? 1 8 FODMAP stands for “Fermentable Oligosaccharide, Disaccharide, Monosaccharide, Polyols” 1

What is the FODMAP Diet? 9 Represents a class of carbs that are not completely absorbed in the small intestine  H2 and CH4 fermented by bacteria in the small/large intestine, causing bloat and discomfort1,2 Discharge fluid into the small intestine, causing bloat and higher amount of water entering the large intestine1 Includes lactose, fructose, fructans, galacto-oligosaccharides, and polyols or sugar alcohols1 More commonly encountered in past 30 yrs due to increase in concentrated fruit juices and wide implementation of high fructose corn syrup in food/drink products5 Research proposes that FODMAPs heighten endothelial barrier permeability  immune response and inflammation4

What is the FODMAP Diet? 10 Studies have shown that FODMAPs increase digestion time and sensory afferent signals from the enteric system 6 On average, IBS patients consume 15-30 g/d; diet recommends lowering intake to 5-18g/d6 75% IBS patients see improvement by following low FODMAP diet4 Key: Adherence!4 Long-term effects of diet implementation have yet to be studied4 Possible issue: FODMAPs increase healthy gut microbiota so lack of consumption may lead to negative alterations in the composition of species4

LIST OF HIGH FODMAPS 11

Literature Review1 12 Nanayakkara et al., 2016: Review article (13 studies) 6 RCTs, 7 - mix of retrospective, prospective uncontrolled studies Small study sizes (< 100 participants) Females ages 35 to 50 Primary outcome measure = changes in GI symptoms (global and individual) Variety of scoring scales Food frequency questionnaires, food diaries Dietary advice given by specialized RD in most studies 2 studies dietary advice given by nurse.

Literature Review1 Nanayakkara et al., 2016 13 Nanayakkara et al., 2016 Results - low FODMAP diets associated with: POSTIVES (+) NEGATIVES (-) GI symptom relief (both global and specific) Diet complex, requires training by specialized dietician Dose dependent effects Reduced bacterial abundance Adherence easy LT effects uncertain Studies not standardized on intervention nor outcome Reduced bacterial abundance, reduced bifidobacteria, potential adverse health effects

Literature Review cont.7 14 Marsh et al., 2015: Meta-analysis (22 studies) 6 RCT, 16 non-randomized (NR) Pooled Odds Ratio and 95% CI calculated for FODMAP effect on: Symptom Severity Score (SSS) –validated 1997 measure of abdominal pain, frequency of pain, bloating, bowel habit dissatisfaction, interference with quality of life 100 point Visual Analogue Scale (VAS) IBS Quality of Life (QOL) score – validated 1998 41 descriptive quality of life items – 5 point Likert response scale For non randomized – random effects model used. The IBS symptoms severity score (IBS SSS) validated in 1997 by Francis et al. [42 ] provides a measure of the overall severity of IBS. The IBS SSS questionnaire contains five questions that measure, on a 100-point visual analogue scale (VAS), the severity of abdominal pain, frequency of abdominal pain, abdominal bloating, bowel habit dissatisfaction and interference with quality of life. The IBS-QOL was validated in 1998 by Patrick et al. [43 ] as a conceptually valid self-administered questionnaire with highly reproducible results for assessing the perceived quality of life for individuals with IBS [43 ]. The IBS-QOL contains 41 descriptive IBS-specific quality of life items and uses a 5-point Likert response scale to determine how accurately the statement describes the responders feeling Meaningful clinical improvement is seen by a change in IBS-QOL score greater than 14 [44 ]. In the RCTs, the average difference in IBS-QOL means was 9.6, and in the nonrandomized interventions, there was an average improvement of 10.5 suggesting holistically a clinically significant improvement did not occur. However, compared to the control group in the RCTs where the mean increase in score was 0.4, it is evident that there is a significant improvement in IBS-QOL score. Additional time may be necessary for clinically significant improvements in quality of life for IBS patients to

Literature Review cont.7 15 Marsh et al., 2015 Results – Low FODMAP diets associated with: POSITIVES (+) Significant DECREASE in SSS RCT: OR 0.44, 95 % CI 0.25–0.76; I2 = 35.52, p = 0.00 NR: OR 0.03, 95 % CI 0.01–0.2; I2 = 69.1, p = 0.02 Significant IMPROVEMENT in QOL RCT: OR 1.84, 95 % CI 1.12–3.03; I2 = 0.00, p = 0.39 NR: OR 3.18, 95 % CI 1.60–6.31; I2 = 0.00, p = 0.89 Diet nutritional adequate, if provided with the right counseling Meta-analysis increases the power of statistical analyses by pooling the results of all available trials I2, a statistic that indicates the percentage of variance in a meta-analysis that is attributable to study heterogeniety When low nothing to explain, when high may want subgroup analysis. The high I2 values show that most of the variability across studies is due to heterogeneity rather than chance. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC192859/ Positive association between a low FODMAP diet and a significant decrease in IBS SSS 44% decrease in sym RCT 1.84 times more likely to report improvement in symptoms, NR 3.18 times more likely to report improvement in symptoms In contrast to other dietary restrictions, the low FODMAP diet allows the patients to consume foods from each of the core food groups, therefore, minimizing the effect on nutrition adequacy when appropriately implemented [51 ]. The overall evidence now supports that a low FODMAP diet can now be implemented as one of the key treatment strategies in managing IBS patients. Conflict of interest The authors declare that they have

Literature Review cont.7 16 Marsh et al., 2015 NEGATIVES (-) Pooling of data a challenge No validated biomarkers for individual symptoms Heterogeneity across NR high, I2 as high as 69.1 Short study periods in RCTs – 3 to 6 weeks Lack of adherence figures across studies, most self reported, subject to bias Some studies not peer-reviewed Potential adverse effects on gut microbiota Pooling comparable data on functional symptoms from the different studies was challenging as not all studies provided the data required for meta. Heterogenity for NR may be due to different study durations 5 weeks to 35 months. LT studies are needed to determine effects. If FODMAP works to change microbiota, suggested a min of 8 weeks Staudacher et al. Some studies peer reviewed, this is due to the fact that The low FODMAP diet is a relatively novel area of research with the majority of studies focusing on the effects of a low FODMAP diet on IBS symptoms published in the last five years. As such, we deemed it necessary to include both abstracts and peer-reviewed papers to gain adequate data to statistically analyze the effect of following a low FODMAP diet on IBS symptoms. The validity of non-peerreviewed data can be questionable which presented a weakness to the study; however, we aimed to control for this by contacting the authors of all abstracts for further information regarding data figures and study protocol diet significantly reduces luminal bifidobacteria after 4 weeks and suggests the use of a pre- or probiotic for those following the low FODMAP diet in the long term

Literature Review cont.8 17 Halmos et al., 2014: RCT, single blind cross over 30 IBS, 9 healthy 21 days on low FODMAP or typical Australian diet Food provided on low FODMAP diet Washout period of 21 days between arms Symptoms evaluated using 0-100mm Visual Analogue Scale Adherence measured through diet record and breath test Addressed confounding by providing all intervention diets that were matched for nutrients except for FODMAP content Gastrointestinal symptoms were measured daily during the baseline week and interventional diet periods using a 100-mm visual analogue scale (VAS), where 0 indicated no symptoms and 100 represented the worst symptoms ever experienced. The VAS score was used to measure overall gastrointestinal symptoms, abdominal pain, bloating, passage of wind, and dissatisfaction with stool consistency as previously applied.10 Differences of 10 mm or more arbitrarily were considered clinically significant. Of the 30 IBS participants, 10 had IBS-D, 13 had IBS-C, 5 had IBS-M, and 2 had IBS-U. Adherence to the diets was assessed through recorded food diaries. The median (range) number of days in which participants were adherent for the 42 days of the combined interventional diets was 41 (33–42) for the IBS and 42 (39–42) for the healthy cohort. If adherence for at least 17 days of the 21 days of controlled diet (>81% of the days) was arbitrarily considered compliant, then all participants were adherent to the typical Australian diet, and 80% of IBS participants (24 of 30) and 100% of healthy controls were adherent to the low FODMAP diet. Another method of assessing adherence was the hourly breath tests that were conducted on day 19 of the 2 controlled diets (Supplementary Figure 3). The area under the curve for breath hydrogen on the low FODMAP diet (22.8 IQR, 14.3–44.4 ppm$ 8 h) was less in all participants than that on the typical Australian diet (80.9 IQR, 46.8–159.8 ppm$ 8 h; P < .001).

Literature Review cont.8 18 Halmos et al., 2014 POSTITIVES (+) NEGATIVES (-) 70% IBS symptom relief (21/30 10mm better or more) Short-term GI symptoms less on FODMAP (28mm, CI 95% 16.7mm-28.8mm; p<.001) vs. Australian Diet (44.9mm, CI 36.6mm-53.1mm; p<.001) Small sample size Statistically significant between diets p<.001 FODMAP diet provided, not reflective of reality Study design Long term studies need, microbiota effect uncertain

Literature Review cont.9 19 Shepard et al., 2008: double blind, RCT Placebo controlled, re-challenge trial 26 patients with IBS or FM, previously responded to FODMAP diet (22 weeks) 2 week period, given 1 of 4 test substances, graded dose Fructans Fructose Fructans/ Fructose mix Glucose 4 arms, 14 day washout period between each Instructed to continue on low FODMAP diet

Literature Review cont.9 20 Shepard et al., 2008 Primary end point “were your symptoms adequately controlled at the end of this phase?” Secondary end points, mean VAS scores on individual symptoms at highest dose SIGNIFICANT NOT SIGNIFICANT Intensity of symptoms increased at highest dose for Fructans, Fructose, Fructans + Fructose (p<.01) Intensity of symptoms did not increase for glucose (p>.0.2)

Literature Review cont.9 21 Shepard et al., 2008 Potential issues: liquid vs. solid form, blinding on liquids may have been compromised due to taste Greatest for fructose and fructans suggesting 2 FODMAPs may be additive Small number completed all arms at highest dose reducing statistical power First, blinding of the test substance might be compromised because of differences in taste and sweetness. Taste was similar across the 4 drinks (orange flavoring), and variations of sweetness were not detectable in preliminary taste testing in healthy volunteers. Second, physiologic responses to fructose or fructans delivered in liquid form might be different from their delivery within food. Because ingestion of liquids with solids slows the gastric emptying of those liquids,33 patients were carefully instructed to consume drinks only during meals with food to most closely mimic normal eating situations. Although this might still have resulted in faster gastric emptying, faster small intestinal transit, and potentially greater malabsorption of fructose, the same cannot be said of fructans, which have virtually no absorption in the small intestine under any conditions.10,27 The high-dose intake for fructans was estimated by

Literature Review cont.6 22 Staudacher et al., 2012: RCT 41 patients with bloating and diarrhea IBS Rome III criteria (constipation excluded) Intervention group – No FODMAPs Control group – Regular Diet 7 day baseline evaluation consisting of food diary, stool consistency and validated symptom scale Each group contacted weekly by RD Final week patients completed 7 day symptom, stool and food diary Study sought to illuminate the effect of FODMAPs on luminal microbiota, SCFA, and GI symptoms

Literature Review cont.6 23 Staudacher et al., 2012: RCT FINDINGS MICROBIOTA Lower concentrations and proportions of bifidobacteria (P<0.001) in intervention group vs. control Inversely correlated with baseline concentrations (pearson r2 -0.54; P = 0.033) SCFA No difference between groups Lower intake of SCFA in the intervention group compared with controls (P = 0.001).

Literature Review cont.6 24 Staudacher et al., 2012: RCT GI SYMPTOMS Intervention group reported more “adequate symptom control” (13/19, 68%) vs. control (5/22, 23%) p=0.005 Intervention group experienced reduction in scores for bloating (P = 0.007), urgency (P = 0.047), and overall symptoms (P = 0.006) compared with the control group At baseline, the incidence of symptoms did not differ between groups, except for nausea, which was less frequent in the intervention group. However, at follow-up, there was a lower incidence of bloating, abdominal pain, and overall symptoms in the intervention group compared with the control group (Table 3). Likewise, the severity of symptoms was similar between groups at baseline, except for nausea, which was less severe in the intervention group. However, at follow-up, there were lower mean daily severity scores for bloating, flatulence, tiredness, and overall symptoms in the intervention group compared with the control group. Diarrhea severity scores were similar in groups at follow-up (Table 3). Stool frequency and consistency was similar at baseline, but at follow-up, after adjusting for baseline, the intervention group reported lower stool frequency than the control group and a greater proportion of stools with normal consistency (type 3 or 4) in the intervention group (Table 4).

Literature Review cont.6 25 Staudacher et al., 2012: RCT Paradox- FODMAPS reduces bifidobacteria BUT…. Bifidobacteria associated with: Reduced abdominal pain in healthy and IBS Therapeutic effects in IBS Long term studies needed Supplementation with probiotics? Restriction of fermentable short-chain carbohydrates is an effective management strategy for IBS, resulting in reductions inoverall symptoms and bloating Do changes in microbiota persist? we demonstrated that the reverse is true when prebiotic carbohydrates are restricted in that IBS patients with higher fecal bifidobacteria at baseline had a greater reduction. It is likely that the effect of microbial changes on colonic health will be individually variable and long-term studies are required to confirm the implications of these findings on disease risk. Also luminal different from mucosa. Only luminal measured

Literature Review cont.10 26 Böhn et al., 2015: RCT, single-blind, parallel 75 patients 38 assigned to FODMAP 37 to diet normally prescribed for IBS (regular meal pattern; avoid large meals; and reduced intake of fat, insoluble fibers, caffeine, and gas producing foods – beans, cabbage, and onions) Symptoms assessed with Symptom Severity Scale (SSS) 4 weeks 4 day food diary before and after intervention Adherence assessed through food diaries

Literature Review cont.10 27 Böhn et al., 2015 POSTIVES (+) NEGATIVES (-) Symptom severity reduced in both groups (p<.0001) No difference found between groups (p=.62) Study design OBSERVATIONS Responders were more likely to have low FODMAP intakes Older women, more likely to respond. Not all FODMAPs created equal, future studies should evaluate Therefore, asking the patient about food items that produce GI symptoms or testing for the presence of carbohydrate malabsorption might be helpful when choosing a strategy for the dietary advice given to the patients, but this needs to be evaluated in prospective trials. However, bloating, abdominal pain, and flatulence are the symptoms in which the greatest symptom improvement on a low-FODMAP diet has been found,34,35 and these symptoms are prominent in all IBS subtypes.2 Both a low-FODMAP diet and a traditional IBS diet improved IBS symptoms, without any clear differences between the 2 strategies. Future studies should aim to further improve strategies for providing dietary advice to patients with IBS, potentially combining elements from different strategies and ideally customizing dietary advice for different patient populations. Monitoring calorie and nutrient intakes in patients who follow dietary advice seems to be important. Supplementary

Common Shortcomings Small sample sizes 28 Small sample sizes Methodological issues with blinding, contribute to bias, 40% Long term effects unknown- studies needed Altered microbiota? Nutrient deficiencies?

Conclusion1 Associated with high medical costs 29 IBS is estimated to effect 10 to 15% globally 2/3 of patients associate symptoms with changes in diet Accounts for 50% of GI visits Associated with high medical costs Clincial trials have not shown significant effects for elimination and high fiber. Probiotics have several methodolgical issues (strain differences, dosing) results inconclusive. Pharmalogical alone is not sufficient to treat symptoms

Conclusion1,7 Pharmacological agents not effective alone 30 Pharmacological agents not effective alone Other dietary interventions not shown to be effective: Elimination diets (wheat, diary, caffeine) have not shown clinically significant effects High Fiber diets Probiotics – issues around strain, dose, inconclusive Low FODMAP diets shown to be effective in reducing IBS symptoms

References 31 Nanayakkara WS, Skidmore PM, O’Brien L, Wilkinson TJ, Gearry RB. Efficacy of the low FODMAP diet for treating irritable bowel syndrome: The evidence to date. Clinical and Experimental Gastroenterology. 2016. p. 131–42. Pedersen N, Vegh Z, Burisch J, Jensen L, Ankersen DV, Felding M, Andersen NN, Munkholm P. Ehealth monitoring in irritable bowel syndrome patients treated with low fermentable oligo-, di-, mono-saccharides and polyols diet. World Journal of Gastroenterology 2014;20:6680-4. Chumpitazi BP, Cope JL, Hollister EB, Tsai CM, McMeans AR, Luna RA, Versalovic J, Shulman RJ. Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome. Aliment Pharmacol Ther 2015;42:418-27. Maagaard L, Ankersen DV, Vegh Z, Burisch J, Jensen L, Pedersen N, Munkholm P. Follow-up of patients with functional bowel symptoms treated with a low FODMAP diet. World Journal of Gastroenterology 2016;22:4009-19. Wong WM. Restriction of FODMAP in the management of bloating in irritable bowel syndrome. Singapore Med J 2016;57:476-84.

References 32 Staudacher HM, Whelan K. Altered gastrointestinal microbiota in irritable bowel syndrome and its modification by diet: probiotics, prebiotics and the low FODMAP diet. Proc Nutr Soc 2016;75:306-18. Marsh A, Eslick EM, Eslick GD. Does a diet low in FODMAPs reduce symptoms associated with functional gastrointestinal disorders? A comprehensive systematic review and meta-analysis. Eur J Nutr. 2016;55:897–906. Halmos EP, Power V a, Shepherd SJ, Gibson PR, Muir JG. A Diet Low in FODMAPs Reduces Symptoms of Irritable Bowel Syndrome. Ygast [Internet]. Elsevier, Inc; 2014;146:67–75.e5. Available from: http://dx.doi.org/10.1053/j.gastro.2013.09.046%5Cnpapers2://publication/doi/10.1053/j.gastro.2013.09.046 SHEPHERD S, PARKER F, MUIR J, GIBSON P. Dietary Triggers of Abdominal Symptoms in Patients With Irritable Bowel Syndrome: Randomized Placebo-Controlled Evidence. Clin Gastroenterol Hepatol [Internet]. 2008;6:765–71. Available from: http://www.sciencedirect.com/science/article/pii/S1542356508001511 Böhn L, Störsrud S, Liljebo T, Collin L, Lindfors P, Törnblom H, Simrén M. Diet Low in FODMAPs Reduces Symptoms of Irritable Bowel Syndrome as Well as Traditional Dietary Advice: A Randomized Controlled Trial. Gastroenterology. 2015;149:1399–1407.e2.