FODMAPs: Emerging Science and Implications for Practice

FODMAPs: Emerging Science and Implications for Practice Megan Rossi, PhD RD @DrMegan_RD @Dr_Megan www.drmeganrossi.com

BDA guidelines for dietary management of IBS 1) Healthy eating and lifestyle Alcohol Caffeine Spicy food Fatty food Fluid intake Eating habits 2) Milk and dairy restriction 3) Dietary fibre Adapted from McKenzie. J Hum Nutr Diet. 2016; 29: 576-59 2

What is the low FODMAP diet? F ermentable Short chain CHO O ligo-saccharides many sugar units Fructans, Galactooligosaccharides D M i-saccharides two sugar units ono-saccharides one sugar unit Lactose Fructose MECHANISMS OF ACTION SUMMARY OF LITERATURE CONSIDERATIONS FOR PRACTICE A nd P olyols Sugar alcohols e.g sorbitol, mannitol 3

How FODMAPs induce symptoms: key components Osmotic load Bacterial fermentation Colonic hypersensitivity Symptom induction 4

1. Osmotic load n=16 healthy people Fructose (40g) Fructans (40g) Fructose + glucose (40g each) Glucose (placebo, 40g) MRI repeated hourly- 5 hrs Small bowel water content Murray et al, Am J Gastro. 2014; 109: 110-119 5

2. Bacterial fermentation n=16 healthy people Fructose (40g) Fructans (40g) Fructose + glucose (40g each) Glucose (placebo, 40g) MRI repeated hourly- 5 hrs Colonic gas volume Murray et al, Am J Gastro. 2014; 109: 110-119 6

1. Osmosis + 2. fermentation Staudacher, Nature Gastro 2014; 11: 256 OSMOTIC LOAD FERMENTATION Adapted from Prof Whelan

3. Colonic hypersensitivity n=29 healthy n=29 IBS >1 week washout Fructose (40g) Fructans (40g) Glucose (placebo, 40g) >1 week washout Fructose (40g) Fructans (40g) Glucose (placebo, 40g) Fructose (40g) Fructans (40g) Glucose (placebo, 40g) MRI repeated hourly- 5 hrs Small Colonic Symptom bowel gas water volume Intensity content 8 Major et al, Gut. 2014; In Press

How FODMAPs induce symptoms: key components Osmotic load Bacterial fermentation Colonic hypersensitivity Symptom induction 9

Dose-response relationship n=25 IBS Shepherd et al, ClinGastro Hep 2008; 6: 765 771 2 weeks >10 day washout 2 weeks Fructose (low, med, high) Fructans (low, med, high ) Fructose+Fructans (low, med, high ) Glucose (low, med, high) Fructose Fructans Fructose + fructans Glucose (low, med, high) (low, med, high ) (low, med, high ) (low, med, high) Symptom severity *Dose dependent difference p<0.002 for all groups (except glucose) 10

Body of evidence for the low FODMAP diet 10 studies RCT Sham diet Other best practice advice > 30 studies Increased quality of clinical ev vidence Cohort studies Case Control studies Case series, case reports Standardised diet Usual diet Types of controls (comparators) Hierarchy of study design 11

10 Randomised comparative trials References Responders Comparators Comparator FODMAP Eur J Nutrition, 2016 Staudacher 2012, J Nutr 23% 68% Abdominal pain Usual diet OR 1.81 Pedersen 2014, World J Gastro (-34/500) (-133/500) Population excl. IBS-C, n=41 All,n=82 Typical diet Halmos 2014, Gastro - (44.9/100) 70% (22.8/100) All, n=30 High FODMAP McIntosh 2016, Gut Ong 2010, J Gastro Hepatol GI symptoms 21% OR 1.81 (6/9) 72% (2/9) All (2 IBS-C), n=40 All, n=15 Hustoft 2016, Neurogastro Motil 30% 80% IBS- D&M, n=20 Placebo diet Staudacher 2016, DDW 42% 73% excl. IBS-C, n=104 IBS-SSS score Bohn 2015, Gastro OR 0.44 46% 50% All, n=75 Active intervention Peters 2016, Alim Pharm Ther Eswaran 2016, Am J Gastroentrol 72% 41% 71% 52% All, n=74 IBS-D, n=92

First RCT-Usual vs. Low FODMAP diet IBS (excl IBS-C) n=41 Control n=22 (Usual diet) Intervention n=19 (Low FODMAP) 4 weeks Gastrointestinal Symptom Rating Scale Global symptom question Do you have adequate relief of your IBS symptoms? Controls 23% FODMAP 68% P = 0.003 Staudacher et al, J Nutrition 2012; 142: 1510-19 Placebo effect? 13

Randomised comparative trials References Responders Comparators Comparator FODMAP Population Usual diet Staudacher 2012, J Nutr Pedersen 2014, World J Gastro 23% (-34/500) 68% (-133/500) excl. IBS-C, n=41 All,n=82 Typical diet Halmos 2014, Gastro - (44.9/100) 70% (22.8/100) All, n=30 McIntosh 2016, Gut 21% 72% All (2 IBS-C), n=40 High FODMAP Ong 2010, J Gastro Hepatol (6/9) (2/9) All, n=15 Hustoft 2016, Neurogastro Motil 30% 80% IBS- D&M, n=20 Placebo diet Staudacher 2016, DDW 42% 73% excl. IBS-C, n=104 Bohn 2015, Gastro 46% 50% All, n=75 Active intervention Peters 2016, Alim Pharm Ther 72% 71% All, n=74 Eswaran 2016, Am J Gastroentrol 41% (23%) 52% (51%*) IBS-D, n=92

Typical vs. Low FODMAP diet IBS n=30 3 week 3 week washout 3 week Typical Aus Diet Typical Aus Diet Low FODMAP Low FODMAP Composite GI symptom score Dissatisfaction with stool consistency Pain, bloating, wind, stool consistency Does it work in the real world? Objective stool measures Halmos et al, Gastroenterology 2014; 146: 67 75

Sham vs. Low FODMAP diet IBS (excl. IBS-C) n=104 Sham diet n=53 Low FODMAP n=51 4 weeks Gastrointestinal Symptom Rating Scale IBS symptom severity scoring Sham Low FODMAP Placebo Real world How does it compare to other therapies? 17

First-line vs. Second-line dietary management IBS n=75 1 st line n=37 Low FODMAP n=38 4 weeks IBS-SSS Lower response to LFD: 68-80% Suboptimal? 1 Low FODMAP dietary advice eg. consumption of spelt bread Dietary data Significant reduction in fat 50% 46% 1. Gibson. J Gastroenterology, 150: 1046-7, 2016. 19

Emerging science: evidence beyond symptom response References Responders Comparators Comparator FODMAP Population Usual diet Staudacher 2012, J Nutr Pedersen 2014, World J Gastro 23% (-34/500) 68% (-133/500) excl. IBS-C, n=41 All,n=82 Typical diet Halmos 2014, Gastro - (44.9/100) 70% (22.8/100) All, n=30 McIntosh 2016, Gut 21% 72% All (2 IBS-C), n=40 High FODMAP Ong 2010, J Gastro Hepatol (6/9) (2/9) All, n=15 Hustoft 2016, Neurogastro Motil 30% 80% IBS- D&M, n=20 Placebo diet Staudacher 2016, DDW 42% 73% excl. IBS-C, n=104 Bohn 2015, Gastro 46% 50% All, n=75 Active intervention Peters 2016, Alim Pharm Ther 72% 71% All, n=74 Eswaran 2016, Am J Gastroentrol 41% 52% IBS-D, n=92 21

Emerging science: evidence beyond symptom response IBS n=40 High FODMAP n=20 Low FODMAP n=20 3 weeks IBS Severity Scoring System 21% vs. 72% (p<0.009) IBS-D & M n=20 Low FODMAP 3 weeks IBS Severity Scoring System 100% 8 fold (p<0.05) 22

MECHANISMS OF ACTION SUMMARY OF THE LITERATURE CONSIDERATIONS FOR PRACTICE Clinical Guidelines Level D evidence is limited

MECHANISMS OF ACTION SUMMARY OF LITERATURE CONSIDERATIONS FOR PRACTICE What happens in practice? 3- step process Restriction (3-6 weeks) Re-introduction challenge (3 day/ challenges) Personalisation (long term) KEY: total FODMAP load at one meal and per day Copyright King s College London

MECHANISMS OF ACTION SUMMARY OF EVIDENCE CONSIDERATIONS FOR PRACTICE Resources: Getting App y Restriction (3-6 weeks) Re-introduction challenge (3 day/ challenges) Personalisation (long term)

MECHANISMS OF ACTION SUMMARY OF THE LITERATURE CONSIDERATIONS FOR PRACTICE Cautions and limitations Nutrition adequacy Gut microbiota Staudacher et al 2012 J Nutr 142:1510-1518 Staudacher et al 2012 J Nutr 142:1510-1518 Delivery cost Halmos et al 2014 Gastro 146:67-75 139.20 per patient vs. 67.19 per patient Hustoftet al 2016 Bohn et al 2016 (UEG)

Summary Mechanisms underpinning the diet Osmotic load + fermentation + colonic hypersensitivity Whom can we help the most Those with pain, bloating&/or diarrhoea Emerging science: Evidence beyond symptom control Immune regulation Implications for practice 3 step process, dietitian-led Caution nutrition deficiencies 27

@ _ @ _ @ Prof Kevin Whelan Dr Miranda Lomer Dr Peter Irving Heidi Staudacher Dr Jane Muir Prof Peter Gibson Prof Robin Spiller Dr Luca Dr Giles Major

MECHANISMS OF ACTION SUMMARY OF EVIDENCE CONSIDERATIONS FOR PRACTICE What happens in practice? 3- step process Restriction (3-6 weeks) Re-introduction challenge (3 day/ challenges) Personalisation (long term) KEY: total FODMAP load at one meal and per day Copyright King s College London

MECHANISMS OF ACTION SUMMARY OF EVIDENCE CONSIDERATIONS FOR PRACTICE Credibility of resources > 2.3 million results (24/10/16) Accuracy of data? Not comprehensive too restrictive Conflicting

MECHANISMS OF ACTION SUMMARY OF EVIDENCE CONSIDERATIONS FOR PRACTICE Resources: Getting App y Restriction (3-6 weeks) Re-introduction challenge (3 day/ challenges) Personalisation (long term)

Who is the diet for? Rome IV http://www.balancedgrub.com

Emerging science: evidence beyond symptom response? IBS n=40 High FODMAP n=20 Low FODMAP n=20 IBS-D & M n=20 Low FODMAP (LFD) 3 wks 3 weeks LFD + FOS LFD + placebo IBS Severity Scoring System 21% vs. 72% (p<0.009)***mechanisms OF ACTION LFD + *** FOS Dysfunctional signalling between SCFA & mast cells 8 fold (p<0.05) 3 wks LFD + placebo IBS Severity Scoring System 30% vs. 80% (p=0.013) Mechanically induced mast cell degranulation Dietary artefact/ confounders? 10 days 10 days 33

Predicting response 34

Randomised comparative trials Responders References Comparators Comparator FODMAP Usual diet Typical diet Staudacher, 2012 Pedersen, 2014 Halmos, 2014 23% (-34/500) - (22.8/100) 68% Specific symptoms Stool frequency & consistency, bloating, pain, flatulence Pain,distension, satisfaction with (-133/500) IBS, n=82 bowels Both IBS-D &C, BUT stool 70% (44.9/100) Bloating, pain, wind frequency + IBS, n=30 form only IBS-D Population IBS-C (12%), NS IBS-D&M, n=41 High FODMAP McIntosh, 2016 Ong, 2010 21% (6/9) 72% (2/9) Pain intensity, satisfaction with IBS, n=40 bowels, distension NS Only 5% IBS-C Pain, bloating, flatus, nausea, heartburn, lethargy IBS, n=15 Placebo diet Hustoft, 2016 30% 80% Pain, distention, bowel habit* IBS- D&M, n=20 Staudacher, 2016 42% 73% Pain, bloating, flatulence, urgency IBS(excl-C), n=104 Active intervention Bohn, 2015 Peters, 2016 Eswaran, 2016 46% 72% 41% 50% 71% 52% Stool frequency (within grp) No difference Pain (51% vs 23%*) IBS, n=75 IBS, n=74 IBS-D, n=92 35

Comparing total FODMAP intakes What quantity of FODMAPs (g) defines a low FODMAP diet? What is the threshold of FODMAPs (g) needed to see a reduction in symptoms? Total FODMAP intake (g) Study Control diet Low FODMAP diet Halmos et al, 2014 23.7 (typical Australian diet) Staudacheret al, 2012 29.6 (typical UK diet) Long Term Study, 2015 29.4 (normal diet) 3.05 17.7 20.9