IBS and the Low FODMAP Diet Najwa El-Nachef, MD NCSGNA Conference September 20, 2014

Irritable Bowel Syndrome Affects up to 20% of adults in US Common symptoms include abdominal pain, bloating, constipation and/or diarrhea More frequent among females Associated with significant decrease in quality of life Major economic burden on patients, healthcare systems and community Remains poorly understood Common gastrointestinal disorder In severe cases, the illness can cause in significnat disability and impairment in the quality of life Although IBS is common, it remains poorly understood Horwitz et al. N Engl J Med 2001;344:1846-50

Mechanism of IBS Motility Visceral Hypersensitivity Central Processing Genetic Factors Psychological factors Inflammation Gut Microflora Dietary Factors Poorly understood. Almost certainly a multifactorial process Lea et al. Gastroenterol Clin North Am 2005;34:247-55

Treatment for IBS Focus on reduction of symptoms Pharmaceuticals Psychological therapy Fiber Probiotics/Antibiotics Dietary and Lifestyle Interventions

Diet and IBS Relationship between diet and abdominal symptoms is well recognized From the patient’s perspective, the most frequently perceived cause for symptoms is food intolerance Up to 50% of patient’s with IBS symptoms worsen after a meal 60% of patients with IBS believe they have a food allergy True food allergies in adults are rare Many IBS patients report meal related exacerbations in symptoms which may be due to true food intolerances but can also be due to visceral hypersensitivity or changes in gut microbiota. Gut microbiota can be significantly altered by changing the intake of fiber and fermentable oligosaccharides, disaccharides, monosaccharides and polyols Lea et al. Gastroenterol Clin North Am 2005;34:247-55

Diet and IBS Dairy Free Low fat High Fiber No coffee/alcohol Food diary, self-eliminate Gluten free diet Irritable bowel syndrome (IBS) is a chronic debilitating disorder that is notoriously difficult to treat. Medication (antispasmodics, bulking agents, laxatives or antidepressants), diet and lifestyle adjustment have been the principal therapeutic options for treatment. Most patients are interested in the role of diet in IBS (Locke et al., 2000; Monsbakken et al., 2006; Halpert et al., 2007) and perceive that some of their symptoms are related to food (Monsbakken et al., 2006) and, consequently, many restrict their intake of certain foods to control symptoms (Halpert et al., 2007).

Fermentable Carbohydrates Dietary carbohydrates can be classified into sugars, oligosaccharides and polysaccharides based on their degree of polymerisation. “Fermentable” owing to their availability for fermentation in the colon, which is either due to the absence or reduced concentration of suitable hydrolase enzymes for digestion or in the case of monosaccharides because of incomplete absorption in the small intestine.

Mechanisms by which short-chain fermentable carbohydrates might induce symptoms in IBS Some short-chain fermentable carbohydrates are absorbed. For example, fructose can be absorbed via GLUT2 or GLUT5 transporters and lactose can be absorbed if hydrolysed by lactase. Unabsorbed fructose, polyols and lactose lead to osmotic shifts in the ileum. Unabsorbed fermentable carbohydrates are fermented in the colon leading to luminal gas production. In the setting of visceral hypersensitivity and altered colonic functioning the resulting luminal distension leads to symptom exacerbation. Abbreviations: CH4, methane, CO2, carbon dioxide; FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; GOS, galacto-oligosaccharides; H2, hydrogen; H2O, water The physiological basis for the genesis of many functional gut symptoms is luminal distension. Evidence for this comes from barostat and gas infusion studies.2,3 Luminal distension not only induces the symptoms of pain, the sensation of bloating and visible abdominal distension, but may also lead to secondary motility changes. Thus, minimizing the consumption of dietary factors that can distend the intestine would theoretically lead to improvement in global symptoms that characterize FGID. In the case of two of the most common types of FGID involving the intestine, irritable bowel syndrome (IBS) and functional bloating, the distal small and proximal large intestine would be the target regions of the gut. Dietary components that will putatively lead to luminal distension in the regions of interest will therefore be poorly absorbed in the proximal small intestine, will be small molecules (i.e. osmotically active), will be rapidly fermented by bacteria (with the potential to be fermented by small intestinal as well as cecal bacteria and to expand the bacterial population), and will be associated with hydrogen rather than methane production. Dietary FODMAP are the best fit for these principles.

Low FODMAP Diet Ingested FODMAPs are poorly absorbed in the small bowel Small, osmotically active molecules which draw water into the large intestine FODMAPs are also fermented by colonic microflora, producing hydrogen and/or methane gas The increase in fluid and gas leads to diarrhea, bloating, flatulence, abdominal pain, and distension Developed at Monash University in Melbourne by Australian dietitian Sue Shepherd

Low FODMAP Diet F: Fermentable O: Oligo- saccharides D: Di-saccharides M: Mono-saccharides A: and P: Polyols High FODMAP foods include those with excess fructose (honey, peaches, dried fruits), fructans, sorbitol and raffinose (lentils, cabbgage, legumes) These short-chain carbohydrates have common functional properties in that they are poorly absorbed, osmotically active (Barrett et al., 2010) and rapidly fermented by bacteria

Fructose Simple monosaccharide Found naturally in many fruits. Also a constituent of sucrose and fructans. Normally absorbed in small intestine by two mechanisms: GLUT-5 transporter- present throughout small intesine. GLUT-2 transporter- requires equal amounts of glucose for more effective absorption. Failure to completely absorb free fructose leads to its delivery in the colon. Colonic bacteria rapidly ferment free fructose to hydrogen, carbon dioxide and short-chain fatty acids. But one if three adults with symptoms of IBS malabsorb fructose Most people can absorb fructose, however one in three adults with symptoms of IBS malabsorb fructose . In fructose malabsorption the absorption of free fructose (in excess of glucose) is impaired

Fructans Major source of fermentable carbohydrates Minimal digestion due to absence of enzymes in the human GI tract to digest the fructosyl-fructose glycosidic bonds Wheat and onion are major sources Commercial fructans dervied from sucrose or chicory root are increasingly added to prepared foods due to their textural and sensory properties Oligosaccharides Minimal digestion of fructans occurs in small intestine due to the absence of enzymes in the human GI tract Storage carbohydrates in plants

Galacto-oligosaccharides Humans lack a-galactosidase enzymes, leading to the availability of GOD for colonic fermentation Milk, legumes and some grains, nuts and seeds

Polyols Sugar Alcohol Absorbed in small intestine by passive diffusion Present in fruits and vegetables Commonly used in artificial sweeteners (sorbitol, mannitol, xylitol) Large amounts can cause osmotic diarrhea

Foods to eliminate Fructans and galactans: wheat and rye in large amounts, onions, garlic, inulin, legumes, lentils, artichoke, soy milk and almond milk Lactose: milk, yogurt, ice cream, soft cheese Excess fructose: high fructose corn syrup, honey, agave, and various fruits (such as apple, pear and watermelon) Polyols: stones fruits (peach, plum, cherry), mushroom, cauliflower and sorbitol/mannitol

Permissible Foods Grains: rice, oats, gluten free pasta, some gluten free breads and cereals Fruits: berries (except blackberries), citrus, banana, grapes, honeydew or cantaloupe melon, kiwifruit Vegetables: Carrots, corn, eggplant, zucchini, peppers, green beans, lettuce, cucumber, potato, and tomato are a few. Meats: All meats; avoid processed meats that contain ingredients like high fructose corn syrup, milk solids, or onion/garlic powder Milk: Lactose free milk, rice milk, lactose free yogurt, hard or ripened cheeses like cheddar and feta

Wall Street Journal. November 8, 2011. http://online. wsj

What is the data?

Studies of the mechanisms underlying the effects of fermentable carbohydrates on gastrointestinal symptoms A high fodmap diet can result in increased gas and colonic distension from bacterial fermentation and increased water in the small bowel due to the high osmotoic load. In one study, a high FODMAP diet was associated with higher levels of breath hydrogen compared with a low FODMAP diet in both IBS patients and healthy controls but it induced GI symptoms and lethargy only in IBS patients.

Delivery of Water/Fermentable Substrate Ileostomy volunteers Two diets tested for 4 days each. One high in FODMAPs and one low in FODMAPs All food prepared by investigators At baseline and on day 4, 24 hours effluent collected 10 patients, ileostomy because of IBD, no active disease Randomized, single blinded ?cross over study The aim of the present study was to directly test the principles upon which the hypothetical mode of action (Figure 1) is based – increased delivery of water and of fermentable substrate to the distal small bowel and proximal large bowel – and to quantify the magnitude of the effect. . Two test diets (4 days each) were used, one high in FODMAPs (HFD) and one low in FODMAPs (LFD). A washout period of at least 2 weeks separated the dietary periods to ensure that no carry-over effects occurred. Diets were matched for energy, macronutrients and fibre All food was prepared by the investigators Barrett et al. Aliment Pharmacol Ther 2010 Apr;31(8):874-82

Main effluent weight significantly less during LFD Subjects perceived significantly thicker consistency on LFD The major FODMAP contributors to effluent output weight were fructans and sorbitol, equating to 32% of both ingested fructans (7–78%) and sorbitol (0–70%) escaping digestion during the HFD None of the participants exhibited evidence of fructose malabsorption. As fructose is well absorbed in the presence of equimolar glucose, the potential for malabsorption is restricted to free fructose (or that in excess of glucose).25 The likelihood of fructose malabsorption depends upon the dose

Ingested FODMAPs of 32% (range 6–73%) was recovered in the high FODMAP diet effluent. Effluent collection weight increased by a mean of 22% (95% CI, 5–39), water content by 20% (2–38%) and dry weight by 24% (4–43%) with the high compared to low FODMAP diet arm. Output increased by 95 (28–161) mL. Volunteers perceived effluent consistency was thicker (95% CI, 0.6–1.9) with the low FODMAP diet than with the high FODMAP diet (3.5–6.1; P = 0.006). Barrett et al. Aliment Pharmacol Ther 2010 Apr;31(8):874-82

MRI Data with and without FODMAPs The objective of this study was to investigate whether ingestion of fructose and fructans (such as inulin) can exacerbate irritable bowel syndrome (IBS) symptoms. The aim was to better understand the origin of these symptoms by magnetic resonance imaging (MRI) of the gut. METHODS: A total of 16 healthy volunteers participated in a four-way, randomized, single-blind, crossover study in which they consumed 500ml of water containing 40g of either glucose, fructose, inulin, or a 1:1 mixture of 40g glucose and 40g fructose. MRI scans were performed hourly for 5h, assessing the volume of gastric contents, small bowel water content (SBWC), and colonic gas. Breath hydrogen (H2) was measured and symptoms recorded after each scan. RESULTS: Data are reported as mean (s.d.) (95% CI) when normally distributed and median (range) when not. Fructose increased area under the curve (AUC) from 0–5h of SBWC to 71 (23) l/min, significantly greater than for glucose at 36 (11–132) l/min (P<0.001), whereas AUC SBWC after inulin, 33 (17–106) l/min, was no different from that after glucose. Adding glucose to fructose decreased AUC SBWC to 55 (28) l/min (P=0.08) vs. fructose. Inulin substantially increased AUC colonic gas to 33 (20) l/min, significantly greater than glucose and glucose+fructose (both P<0.05). Breath H2 rose more with inulin than with fructose. Glucose when combined with fructose significantly reduced breath H2 by 7,700 (3,121–12,300) p.p.m./min relative to fructose alone (P<0.01, n=13). CONCLUSIONS: Fructose but not inulin distends the small bowel with water. Adding glucose to fructose reduces the effect of fructose on SBWC and breath hydrogen. Inulin distends the colon with gas more than fructose, but causes few symptoms in healthy volunteers. Murray et al. Am J Gastroenterol 2014;109:110-9

MRI Data Cont’d Dr. Murray and colleagues measured breath hydrogen as well as small bowel water content and colonic gas and distension usin gMRI scans of the abdomen in healthy volunteers. Intake of fructose, which has a high osmotic load, was associated with increased small bowel water content compared with glucose and inulin (osmotiically inactive fructan). However, inulin increased breath hydrogen and colonic gas to a greater extent than fructose and glucose.

Studies investigating effectiveness on IBS symptoms 3 randomized controlled trials

Shepherd 2008 Double blinded, randomized placebo-controlled rechallenge trial 25 patients responded to dietary change Patients were randomly challenged by graded dose introduction of fructose, fructans or glucose taken as drinks 70-80% developed symptoms when rechallenged Double-blinded, randomized, quadruple arm, placebo-controlled rechallenge trial 25 patients provided food low in free fructose and fructans Patients randomly challenged by graded dose introduction of fructose, fructans, alone or in combination or glucose taken as drinks with meals for 2 weeks 10 day washout period in between Symptoms measured by daily diary entries and questionnaire Randomized placebo controlled cross over trial BACKGROUND & AIMS: Observational studies suggest dietary fructose restriction might lead to sustained symptomatic response in patients with irritable bowel syndrome (IBS) and fructose malabsorption. The aims of this study were first to determine whether the efficacy of this dietary change is due to dietary fructose restriction and second to define whether symptom relief was specific to free fructose or to poorly absorbed short-chain carbohydrates in general. METHODS: The double-blinded, randomized, quadruple arm, placebo-controlled rechallenge trial took place in the general community. The 25 patients who had responded to dietary change were provided all food, low in free fructose and fructans, for the duration of the study. Patients were randomly challenged by graded dose introduction of fructose, fructans, alone or in combination, or glucose taken as drinks with meals for maximum test period of 2 weeks, with at least 10-day washout period between. For the main outcome measures, symptoms were monitored by daily diary entries and responses to a global symptom question. RESULTS: Seventy percent of patients receiving fructose, 77% receiving fructans, and 79% receiving a mixture reported symptoms were not adequately controlled, compared with 14% receiving glucose (P < or = 0.002, McNemar test). Similarly, the severity of overall and individual symptoms was significantly and markedly less for glucose than other substances. Symptoms were induced in a dose-dependent manner and mimicked previous IBS symptoms. CONCLUSIONS: In patients with IBS and fructose malabsorption, dietary restriction of fructose and/or fructans is likely to be responsible for symptomatic improvement, suggesting efficacy is due to restriction of poorly absorbed short-chain carbohydrates in general Shepherd. Clin Gastroenterol Hepatol 2008; 6: 765–71.

Positive Global Symptoms 70% of patients receiving fructose, 77% receiving fructans, 79% receiving a mixture reported symptoms were not adequately controlled compared with 14% receiving glucose Symptoms were induced in a dose dependent manner and mimicked previous IBS symptoms Figure- proportion of pts who answered positively to the global symptom question at the maximal test dose they achieved. P<0.0039 Shepherd Clin Gastroenterol Hepatol 2008;6:765-771

Results for Overall Symptoms Pain Bloating Wind Nausea Tiredness Fructan v. Fructose Mix Gluocse 0.4589 0.0103 0.0005 0.1986 0.0974 0.0016 0.1907 0.0405 0.0640 0.0385 0.0003 0.8476 0.5727 0.2467 0.8838 0.4217 0.0148 Fructose v. Glucose 0.0020 0.0010 0.0078 0.0176 0.0028 0.0046 0.0611 0.2539 0.3065 0.7651 0.3312 Mix v. 0.0002 0.1265 0.3328 Results for Overall and Individual Symptoms During the Four Treatment Arms at Maximal Dose

Low FODMAP Diet v. Standard Dietary Advice Symptom Group Improved % P value Bloating Standard FODMAP 49 82 0.002 Abdominal pain 61 85 0.023 Flatulence 50 87 0.001 Nausea 29 67 0.04 Composite score 86 <0.001 Trend for diarrhea to improve and when degree of improvement was looked at there was some statistical significance Constipation not significant Consecutive patients with IBS who attended a follow-up dietetic outpt visit for dietary management of their symptoms were included. UK. Lactose, caffeine =m fat, smaller frequent meals Staudacher J Hum Nutr Diet 2011;5:487-95

Halmos 2014 Crossover trial, 30 patients with IBS and 8 healthy individuals Randomly assigned to groups that received 21 days either of diet low in FODMAPs or a typical Australian diet Washout period 21 day before crossing over to the alternate diet. Almost all food was provided during the interventional diet periods All stools were collected from days 17-21 and assessed for frequency, weight, water content A recent crossover trial conducted in Australia compared a low-fodmap diet to a typical australian diet which included high fodmap foods, for 21 days each. 30 pts with IBS. Pts with ibs had lower GI symptoms scored ona low fodmap diet compared with the australian diet. 75% of IBS pts had evidence of fructose malabsorption but this did not have an effect on their response to a low fodmap diet.

Gastroenterology. 2014 Jan;146(1):67-75. e5. doi: 10. 1053/j. gastro Gastroenterology. 2014 Jan;146(1):67-75.e5. doi: 10.1053/j.gastro.2013.09.046. Epub 2013 Sep 25. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Halmos EP1, Power VA2, Shepherd SJ2, Gibson PR3, Muir JG3. Author information 1Department of Medicine, Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia; Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Victoria, Australia. Electronic address: Emma.Halmos@monash.edu. 2Department of Medicine, Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia. 3Department of Medicine, Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia; Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Victoria, Australia. Abstract BACKGROUND & AIMS: A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) often is used to manage functional gastrointestinal symptoms in patients with irritable bowel syndrome (IBS), yet there is limited evidence of its efficacy, compared with a normal Western diet. We investigated the effects of a diet low in FODMAPs compared with an Australian diet, in a randomized, controlled, single-blind, cross-over trial of patients with IBS. METHODS: In a study of 30 patients with IBS and 8 healthy individuals (controls, matched for demographics and diet), we collected dietary data from subjects for 1 habitual week. Participants then randomly were assigned to groups that received 21 days of either a diet low in FODMAPs or a typical Australian diet, followed by a washout period of at least 21 days, before crossing over to the alternate diet. Daily symptoms were rated using a 0- to 100-mm visual analogue scale. Almost all food was provided during the interventional diet periods, with a goal of less than 0.5 g intake of FODMAPs per meal for the low-FODMAP diet. All stools were collected from days 17-21 and assessed for frequency, weight, water content, and King's Stool Chart rating. RESULTS: Subjects with IBS had lower overall gastrointestinal symptom scores (22.8; 95% confidence interval, 16.7-28.8 mm) while on a diet low in FODMAPs, compared with the Australian diet (44.9; 95% confidence interval, 36.6-53.1 mm; P < .001) and the subjects' habitual diet. Bloating, pain, and passage of wind also were reduced while IBS patients were on the low-FODMAP diet. Symptoms were minimal and unaltered by either diet among controls. Patients of all IBS subtypes had greater satisfaction with stool consistency while on the low-FODMAP diet, but diarrhea-predominant IBS was the only subtype with altered fecal frequency and King's Stool Chart scores. CONCLUSIONS: In a controlled, cross-over study of patients with IBS, a diet low in FODMAPs effectively reduced functional gastrointestinal symptoms. This high-quality evidence supports its use as a first-line therapy. Halmos et al. Gastroenterology 2014;146:67–75

A benefical response to a low-FODMAP diet has been speculated to be primarily due to avoiding gluten, however; this has not been supported by studies. “I don’t know what the heck gluten is either but I’m avoiding it- just to be safe.”

Is Gluten the Key Player? Supplementary Figure 1 Recruitment pathway and reasons for screen failure. Recruitment survey was a 23-item questionnaire about symptoms, diet, and investigations for celiac disease described previously.<ce:cross-ref refid="bib20" id="crosref0245"> 20 </c...

Figure 2 Change in symptom severity from run-in for each dietary treatment over 7-day study period. Data shown represent mean ± SEM. Differences across the treatment arms were compared by Friedman test, in which overall symptoms ( P  = .001), bloating ( P ... No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates Figure 2 Change in symptom severity from run-in for each dietary treatment over 7-day study period. Data shown represent mean ± SEM. Differences across the treatment arms were compared by Friedman test, in which overall symptoms ( P  = .001), bloating ( P ... Biesiekiersk Gastroenterology, Volume 145, Issue 2, 2013, 320 - 328.e3 i

Is FODMAP Accepted by Patients?

FODMAP Popularity 668,000 results on Google 16,000“Likes” on Facebook Several Apps available Many complain too restrictive Gluten free has many pages and each with a couple hundred thousand followers 37 million for gluten free

Summary FODMAPs do not cause IBS Delivery of dietary FODMAP to the distal small and proximal large intestine is a normal phenomenon, one that will generate symptoms if the underlying bowel response is exaggerated or abnormal.

Summary Limited data, which are mainly composed of studies with relatively small sample sizes, support IBS symptom improvement with a low-FODMAP diet. Beneficial effect of a low FODMAP diet does not appear to be predominantly based on gluten avoidance No definite biomarkers as of now that are associated with symptom response

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