Presentation 1 Gut Microbiome and Human Health Karen Madsen, PhD University of Alberta Director of Center of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR) Disclosures

• Dr. Madsen’s research is funded through the following agencies: – Canadian Institutes for Health Research – Alberta Innovates – Weston Foundation – Digestive Health Strategic Clinical Network – Canadian Association of Gastrointestinal Surgery

• Dr. Madsen is a member of the Alberta Digestive Health Strategic Clinical Network; The Canadian Association of Gastroenterology Women’s Advocacy and Action Advisory Board; and the Department of Medicine Research Training Committee The Changing Face of Gut Microbes From enemies….. The Changing Face of Gut Microbes To fellow travellers….. Publications Related to Microbiome Humans have co-evolved with microbes

Specific microbial profiles associated with: • Mouth • Respiratory system • Skin • Stomach • Gut • Breast milk The microbiome can be considered a new “organ” The exists as an eco-system within us bacteria, viruses, fungi, archaea…..

Tree of life

• Over 50 known bacterial phyla

• Generally a balance of 6 main phyla found in gut

Proteobacteria Bacteroidetes Fusobacteria Firmicutes Disease Health Actinobacteria Verrucomicrobia Species and abundance change over the length of the gut A fine balance of gut microbes

Commensals Pathogens

• Inhibit pathogen growth • Sepsis, infection • Convert pro-drugs to active • Inflammation metabolites • Liver damage • Degrade polysaccharides of plant origin • Production of carcinogens • Produce folate and K • Diarrhea, constipation • Produce short-chain fatty acids • Stimulate and modulate immune function • Regulate body fat storage • Maintain barrier function and stimulate epithelial repair • Stimulate gut motility Individuals differ in the types and quantities of bacteria that colonize the gut …

Composition (Relative percentages) Absolute Numbers

D Vandeputte et al. Nature 1–5 (2017) doi:10.1038/nature24460 Bacteria are very different genetically from one another and have very different metabolic capacity How do microbes interact with the host? Host-microbial interactions maintain gut homeostasis and can drive pro- and anti- inflammatory immune responses

Grigg and Sonnenberg. J of Immunology 198:564. 2017 Altered host-microbial interactions can drive mucosal and systemic disease

Grigg and Sonnenberg. J of Immunology 198:564. 2017 AND MICROBIAL METABOLISM Diet, lifestyle, genetics and environmental factors all modulate microbiota

DIET

Dietary Patterns

Specific Foods • Whole grain • Fruits and nuts • Vegetables and

Food Constituents • Fiber/ • Fat • Protein • Phytochemicals

Food-associated commensal microbes What influences the microbiome over life?

Gastroenterology, Volume 146, Issue 6, 2014, 1489 - 1499 A large variability is seen in healthy adults in their microbial profiles - Diet is a main determinant of gut microbial composition

Voreades et al. Front. Microbiol. Sept 22, 2014 Gut microbial composition can remain relatively stable in healthy adults over time

David et al Genome Biology2014 15:R89 But….Perturbations can shift an individual’s microbiome to a new state

Subject A

Subject B

David et al Genome Biology2014 15:R89 Resistance and resilience of the gut microbiota influences health and disease

Resistance: Ability to resist perturbations (pathogens, drugs)

Resilience: Ability to return to a healthy state following perturbation

Sommer et al. Nature Rev Microbiology 2017 Dietary compounds serve as substrates for use by gut microbiota for production of numerous small molecules that influence health and disease

Holmes et al. Cell Metabolism 2012;16:559 Plasma metabolites differ significantly between and vegans

Wu et al. Gut 2014;65:63 Trends in Microbiology GUT DYSBIOSIS AND HUMAN DISEASE Low diversity and imbalances in gut microbiota are associated with human disease states

Health • High biodiversity and richness • Stable • Primarily Bacteroides and Firmicutes

Disease • Low biodiversity • Unstable • Loss of certain groups (SCFA producers) • Increased abundances of Proteobacteria and Fusobacteria Microbiome in Health and Disease

• Diseases associated with “imbalances” in gut microbiota – – Diabetes – Asthma – Allergies – Multiple sclerosis – Inflammatory bowel disease – Rheumatoid arthritis – NEC – – Colon and liver cancer – Cardiovascular disease

What causes this dysbiosis? Is dysbiosis a cause or a consequence of human disease? Evidence for both! Gevers et al Cell Host Microbe 15:382. 2014 A loss of certain microbial species can remove immune modulating metabolites

Huttenhower et al Immunity 2014 40(6):843 Integrated microbial metabolism necessary for health Production of butyrate requires microbial cooperation A loss of SCFA removes many beneficial effects GUT MICROBES AND THEIR METABOLITES CAN ALTER BRAIN FUNCTION AND MOOD

Consumption of Fermented Milk Product With Modulates Brain Activity

Kirsten Tillisch, Jennifer Labus, Lisa Kilpatrick, Zhiguo Jiang, Jean Stains, Bahar Ebrat, Denis Guyonnet, Sophie Legrain–Raspaud, Beatrice Trotin, Bruce Naliboff, Emeran A. Mayer

Healthy women • fermented milk product () • Non-fermented milk product • Nothing

2x daily for 4 weeks

After 4 weeks, women consuming the fermented milk product had altered activity of brain regions that control processing of emotion and sensation

Gastroentrology 144:2013 • Randomized, double-blind placebo controlled study of 44 adults with IBS

• Took daily B. longum for 6 weeks

• Clinical, questionnaires, fMRI, fecal microbiota, urine metabolomics, systemic inflammation

• BL reduced depression, but no effect on anxiety or IBS symptoms

• Correlated with reduced responses to negative emotional stimuli in multiple brain areas

Gastroenterology 2017 GUT MICROBES have a role in colorectal cancer Protection Initiators Modulate response to treatment If gut microbial dysbiosis is a contributing cause to the pathogenesis of disease, then

Using therapies aimed at the gut microbiota should help in the prevention or treatment of disease

How (and when) to manipulate the gut microbiome? Fiber Fruits, vegetables Prebiotics

Probiotics/Antibiotics Defined consortium

Fecal microbial transplants HOST DIET AND LUMINAL ENVIRONMENT CAN ALTER RESPONSES TO THERAPY AIMED AT MICROBIAL MODULATION LIMITATIONS AND CAVEATS Microbiome Science Challenges

• Association does not equal causation

• Are changes in microbial composition biologically relevant?

• Could anything else explain the results? – Confounding factors (drugs, diet, age, sex) – Role of diet and specific foods/nutrients emerging area of research

• How to overcome technical limitations and challenges – Contamination/batch effects – Low microbial biomass – Bias related to sequencing methodology Hanage WP (2014) Nature 512:247-8; – Cross-sectional vs longitudinal sampling Kim et al. Microbiome 5:52. 2017 CONCLUSIONS Medical Practice in the Future your microbiome will be in your chart

• Therapy will be aimed at both the host and the microbiome of the host

• Manipulation of an individual’s microbiota with diet, probiotics, prebiotics, or defined bacterial cocktails will be done

• Infants will be monitored from birth to ensure colonization with a wide diversity of defined beneficial organisms occurs Acknowledgements

Collaborators Madsen Lab • University of Alberta • Dr. Troy Perry – Dr. Karen Kroeker • Dr. Mike Laffin – Dr. Richard Fedorak • Dr. Heekuk Park – Dr. Leo Dieleman • Naomi Hotte – Dr. Bryan Dicken • Robert Fedorak – Dr. Andy Mason • Dr. Ammar Keshteli • Aiden Zalasky • University of Calgary • Braden Millan – Dr. Gil Kaplan • Matt Emberg • George Mason University – Dr. Patrick Gillivet – Dr. Masoumeh Sikaroodi

Presentation 2 Diet for Gut Health: The FODMAP Diet and Beyond

Associate Professor Jane Muir Disclosures • Board Member/Advisory Panel- - Monash FODMAP Advisory Panel, Nestle Healthcare , Meat & Livestock Australia. • Consultant- - George Weston Foods, Meat & Livestock Australia, MGP Ingredients, Nestle Healthcare Nutrition, Sanitarium Health Food Co. • Employee - Monash University, Melbourne, Australia • Research Support- - NHMRC Research Fellowship, NHMRC, ARC linkage, Eva and Les Erdi Foundation, Menzies Foundation, Meat & Livestock Australia. • Other Funding Support- -The department financially benefits from the sales of a digital application and booklets on the low FODMAP diet. Funds raised contribute to research of the Department of Gastroenterology and to the University. A/Prof Muir receives no personal remuneration

2 Diet for Gut Health . What is a healthy gut?

. Update in IBS and FODMAP diet therapy.

. Understanding and Avoidance.

. Diet therapy in the management of Inflammatory Bowel disease.

. Strategies to change the composition of gut microbiota in IBS.

3 What is a healthy gut? What is optimal gut health for humans?

Absorption of Absence of infection, adequate nutrients gut disorders & disease • Irritable bowel syndrome (IBS). Good balance of • Inflammatory bowel gut microbiota disease (IBD)

Good laxation and prevention of constipation. What is optimal gut health for humans?

Colonic Contents What happens to the gut contents?

Gases Short Chain Fatty Acids Water movement CO2, H2, CH4, H2S acetate, butyrate, propionate

Selective growth of 75% of certain bacteria faecal PROTEIN matter is bacteria

Toxic by-products of protein Fermentation Bulking & ammonia & phenols laxation effect Important dietary components: What are they and what do they do?

DIETARY FIBRE . Laxation . Bulking RESISTANT STARCH . Transit time . Produce SCFA (eg. butyrate) . SCFA . Encourages growth of butyrate-producing bacteria FIBRE . Selective growth Butyrate Effects & activity of beneficial bacteria . Important fuel for colonic • SCFA. cells, . anti-inflammatory . Adapted from Cummings 1997 may protect from cancer. Different Effects of Fibres. (Adapted from Eswaran S,et al. Am J Gastroenterol. 2013 May;108(5):718-27. Sol. highly Sol. highly Insol. Insoluble Insoluble, Favourable ferment. ferment. Intermed. slowly non- Effects SCC ‘fiber’ ferment, ferment. ferment. ‘fiber’ ‘fiber’ ‘fiber’ Laxation + + +++ +++ ++ Faster - - ++ +++ ++ Transit time Balance of +++ + + + - bacteria (bifido) SCFA- +++ +++ ++ + - Anti- RS butyrate inflammatory- butyrate Ammonia/ +++ ++ phenols ‘Fibre’ FOS, GOS RS oats. Wheat cellulose, Types bran, sterculia, 9 psyllium 9 vegetables, 9 Practical guide to gut health: Bowel habit check-list. Getting to know your bowel habit- laxation.

Raging Diarrhea River Good flow- good time, Constipation River – (too fast, too wet). correct water content. too slow and dry. Clean. Good habitat. Concentrated. Poor habitat Poor habitat. Getting to know your stool.

Stool form is a marker of colonic transit time. May indicate constipation

Rating 3 to 4 is ideal

Trending towards diarrhoea

Nous ne pouvons pas afficher l’image. (Ref: Bristol Stool Chart) Food ‘fibre’ Guide (gm faeces / gm of fibre consumed).

• Different types of fibres have different effects on faecal bulk

We need a combination of fibres.

Adapted from Elia & NousCummings ne pouvons pas afficher l’image. Eur. J. Clin. Nutr 2007 Update in Irritable bowel syndrome (IBS) and low FODMAP diet therapy Clinical Problem - Irritable bowel syndrome (IBS).

. Symptoms: Abdominal Pain, distension, change in bowel habit. . Most common gastrointestinal complaint 10-15% of community

. Causes: Disturbance in gut motility, visceral hypersensitivity, alterations in gut microbiota. . Significantly reduced quality of life  Patients would sacrifice 10-15 years of their life for immediate cure * . Therapy palliative  no drug quick-fix *Drossman et al. International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol 2009;43:541-50.15 Food ingestion induces symptoms in IBS.

. 60 -80% of patients with IBS claim that certain foods trigger their symptoms . Wide variety of foods have been implicated

 Candidate dietary triggers • Small molecules  potentially osmotically active Short-chain carbohydrates • Slowly or not absorbed  will be osmotically active • Rapidly fermentable  will release gas 16 Dietary Triggers Short-chain carbohydrates  symptoms of IBS of Gut Symptoms Specific culprits ‘Windy’ foods

1965 1978 1966 1987 1969

Lactose GOS

maldigestion malabsorption Sweetener Fermentation  symptoms  symptoms  symptoms  symptoms

Fructose Avoid - Fructose & ±-free windy free diet fructans ‘FM’ diet diet foods F O D M A P s F O D M A P – what does it stand for?

Oligos: • Fructans • GOS (, )

Disaccharides: • lactose

Monosaccharides: • fructose

Polyols: • sorbitol • (see18 Tuck et al. Expert Rev Gastroenterol. Hepatol. 2014;8:819-34) Where are FODMAPs found in our diet?

XS Fructose Lactose Fructans GOS Polyols Fermentable Fructans Lactose And Polyols Polyols Fructose Polyols

Fructans GOS Fructans Polyols Fructans

Fructans Muir JG et al. J Agric Food Chem. 2007:55; 6619-6627. Muir JG et al J Agric Food Chem. 2009; 57(2):554-565. Fructose Biesiekierski J et al. Journal of and Dietetics . 2011;24:154-176. How FODMAPs trigger symptoms: Consider all indigestible and slowly-absorbed short- chain carbohydrates collectively Fructose Lactose Fructans Galacto-oligos Polyols Hypolactasia All distend intestine via osmotic effect + gas production

35 Diet A Low 30 FODMAP

25 Diet B High FODMAP Symptoms 20

Additive contribution to 15 symptoms in the presence 10 Hydrogen Production / ppm / Production Hydrogen 5 of visceral hypersensitivity 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Time / hours Murray et al, AJG 2014 Ong et al, JGH 2010 What is low and what is high FODMAP? We have established cut-off values

An upper limit of 0.5g of total Varney J et al FODMAPs: food composition, defining cutoff values and FODMAPs (excluding lactose) per international application.Journal of Gastroenterology and Hepatology. 2017;32 (Suppl 1) 53-61. sitting. Identify Low and High FODMAP Foods.

Rye bread Spelt bread The key principle of the Low FODMAP diet is Gluten free bread breads to replace high FODMAP foods with similar foods low in FODMAPs. Flakes of corn Oats Whole wheat grain biscuit XS Fructose cereals Wheat bran, pellets Mixed grain flakes with dried… Polyols Total GOS Total vegetables Zucchini Bok choy

Apple fruit Orange Muir JG et al. J Agric Food Chem. 2007:55; 6619-6627. Muir JG et al J Agric Food Chem. 2009; 57(2):554-565. 0,0 0,5 1,0 1,5 2,0 2,5 Biesiekierski J et al. Journal of Human Nutrition and Dietetics . 2011;24:154-176. FODMAP content (g/serve) 22 Identify Low and High FODMAP Dairy Foods.

milk-regular milk lactose free yoghurt- regular lactose yoghurt- lactose free Hard Cheese Soft cheese

0 5 10 15 20

FODMAP lactose g/serve 23 Where does dairy and milk- fit in with Low FODMAP diet?

. Current evidence suggest that IBS patients have a lower intake of dairy.. . Calcium intake in IBS patients – found that it was reduced (600mg/d low FODMAP vs 730 mg/d control)*.

. Low FODMAP diet is Not a dairy free diet – There are good lactose free options – Many people can tolerate some lactose.

(*Staudacher et al 2012) 24 Low FODMAP diet should be nutritionally adequate

. It is not all about fructose . It is not a gluten free diet . It is not a wheat free diet . It is not a dairy free diet . It is not a FODMAP free diet . It is still possible to follow healthy eating guidelines – Entire food groups are not restricted! 25 FODMAP diet therapy: How it is done.

Step 1 - Low FODMAP (2-6 weeks only) Replace all high FODMAP foods with foods low in FODMAPs in each food group

Step 2 – FODMAP re-introduction FODMAP Food challenges (6-8 week process)

Step 3. Personalized FODMAP diet Interpret food challenge results. Re-introduce food based on symptom response – only restrict foods and FODMAPs that trigger symptoms.

Tuck, C. Barrett, J. (2017) Re-challenging FODMAPs: the low FODMAP diet phase two. Journal of Gastroenterology and Hepatology, 32: 11–15. 26 Why do the FODMAP Re-introduce/Personalise the Diet?

. Aim: to identify sensitivities to individual FODMAP sub-groups and find a balance between good symptom control and expansion of the diet.

Why Re-Introduce? . Some FODMAPs are prebiotics (fructans & GOS) . Improve nutritional adequacy & social inclusion . Improve food variety . Patients learn specific triggers.

Tuck, C. Barrett, J. (2017) Re-challenging FODMAPs: the low FODMAP diet phase two. Journal of Gastroenterology and Hepatology, 32: 11–15. 27 Strong Evidence supports the use of the low FODMAP diet (n=30 IBS)

Low FODMAP diet Symptom severity Baseline diet Worse50 Typical Australian Diet 40 30 20 10 0 -7 -6 -5

No Day -4 -3 -2 1 -1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

28 Many research studies show the low FODMAP diet works in IBS

Effective in 7 out of 10 patients with IBS Efficacy of low FODMAP diet in IBS patients REF ; COUNTRY DESIGN STUDY INTERVENTION OUTCOMES

Staudacher et al. 2011; Non-randomised comparative study IBS patients who received standard (n = 39) • 76% of patients in the low FODMAP group reported UK or low FODMAP dietary advice (n = 43) satisfaction compared to the standard group (p=0.038) Staudacher et al. 2012; RCT open label Patients with IBS randomised to low • More patients in the intervention group reported adequate UK FODMAP diet (n=19) or habitual diet (n=22) control of symptoms (13/19, 68%) compared with controls (5/22, 23%; p=0.005) De Roest et al., 2013; Prospective symptom questionnaire Patients with IBS patients taught the low FODMAP diet (n=90) • 72% satisfied with symptom response New Zealand Halmos et al., 2014; RCT, single-blind, feeding trial Patients with IBS (n=30) • Significantly lower overall symptoms on the low FODMAP Australia Healthy subjects (n=8) – all low FODMAP diet-naïve diet compared to the Australian diet (p<0.001). Pedersen et al. 2014; RCT open-label Patients with IBS randomised to low FODMAP diet (n=42), • Significant reduction in symptom score with low FODMAP Denmark probiotics (n=41) and normal diet (n=40) diet and probiotic groups compared to the normal diet (p<0.01) Bohn et al., 2015; Multi-centre RCT, parallel, single-blind IBS patients received low FODMAP diet (n=33) vs traditional • IBS symptom severity reduced in both groups during the Sweden advice (n=34) for 4-weeks intervention (p<.0001)

Chumpitazi et al., Double-blind, crossover trial 2-day interventions in children with IBS (n=33) • Less abdominal pain occurred with the low FODMAP diet 2015; USA (p<0.05) Eswaran et al., 2016; RCT Patients with IBS-D randomised to either low FODMAP diet • Adequate relief reported in 52% on low FODMAP diet vs 41% USA (n=45) or modified NICE diet (n=39) for 4-weeks on the modified NICE diet (p=0.31). • Higher proportion had improved abdominal pain with low FODMAP diet (p=0.008)

Peters et al., 2016; RCT Patients with IBS randomised to either low FODMAP diet (n=24), • Improvements in overall symptoms at week 6 for Australia hypnotherapy (n=25) or combination therapy (n=25) for 6-weeks hypnotherapy (72%), diet (71%), and combination therapy (72%) Maagaard et al., 2016; Retrospective, cross-sectional study Questionnaire sent to IBS (n=131) and IBD (n=49) patients • 86% reported either partial (54%) or full (32%) efficacy Denmark previously educated on a low FODMAP diet • Greatest improvement of bloating (82%) & abdominal pain (71%)

McIntosh et al., 2016; Prospective, randomised,Nous ne pouvonssingle pas afficher l’image. blind IBS FODMAP diet-naïve patients (n=40) who received dietary • 72% had reduced symptoms on low vs 21% on the high Canada parallel study advice on either low or high FODMAP diet FODMAP diet (p=0.01) Staudacher et al. 2018; RCT placebo-controlled, single blind IBS patients receiving low FODMAP (n = 51) or sham dietary • Lower IBS-SSS score on low FODMAP vs sham diet (p=0.001) UK d i ( 53) Understanding Gluten and Wheat Avoidance Understanding Gluten and Wheat Avoidance.

(http://www.sciencemag.org/news/2018/05/what-s-really-behind-gluten-sensitivity) Clinical Problem No. 1: Celiac Disease.

(http://www.sciencemag.org/news/2018/05/what-s-really-behind-gluten-sensitivity) Celiac disease – the best understood gluten intolerance

. Is an autoimmune disease and affects around 1 % of the population . In genetically susceptible individuals -HLA DQ2/DQ8 . Gluten triggers a cascade of events . Patients with celiac disease have increased risk of certain cancers, osteoporosis & other autoimmune diseases. . Medical treatment is life-long strict avoidance of dietary gluten. 34 How much wheat trigger cause damage in Celiac disease?

1/100th of one slice of bread (50 mg) is all that is required to cause damage Very strict life long avoidance of gluten is the only treatment for celiac disease

35 Clinical Problem No. 2: Avoidance of wheat- and gluten- foods by non-celiacs.

(http://www.sciencemag.org/news/2018/05/what-s-really-behind-gluten-sensitivity) In Australian wheat-avoiders = 11% adults: Major reasons why. 1% have celiac disease CSIRO Food & Health Survey Dec 2010-Feb 2011 n = 1184 ≥ 18 years old

 Bloating, abdominal pain, fatigue  Mostly female who, like the alternative  40% strictly gluten-free

Golley et al, Pub Health Nutr 2014 Mostly Gastrointestinal Symptoms High quality RCT on existence of non-coeliac gluten sensitivity.

Randomised, placebo-controlled, cross-over 1. Effect of  FODMAPs on overall symptoms rechallenge study of placebo vs low gluten (2gm) vs high gluten (16gm) .all food provided .dose effect to be determined .low FODMAP run-in period In 37 patients with ‘NCGS’ and normal or HLA DQ2/8 negative 2. Effect on overall symptoms

3 38 8 Understanding non-celiac gluten sensitivity: FODMAP content of grain products

rice-brown rice- white rice-noodles gluten-free bread quinoa-pasta pasta-gluten free GOS rice bubbles cornflakes Fructan wheat- pasta Fructose wheat -bread Gluten free bread muesli wheat-cous cous haricot 0 0,2 0,4 0,6 0,8 1 1,2 1,4 Biesiekierski, et al 2011 40 Diet therapy in the management of Inflammatory Bowel disease (IBD).

Ulcerative colitis Crohn’s disease Inflammatory bowel disease (IBD)- Ulcerative Colitis and Crohn’s disease

. 1 in 250 Australians affected with IBD (Crohn's Colitis Foundation of Australia)

. UC- Chronic inflammation of epithelial lining of large intestine. Crohn’s disease (CD) is an IBD which can occur in any part of the gut– common in the terminal ileum

. Symptoms: Abdominal pain, bloody diarrhoea, weight loss, tiredness, fever, nausea etc. (Wilson et al. Inflamm Bowel Dis 2010)

42 Low FODMAP Diet and UC Low FODMAP & IBD: Adoption in clinical practice

. Widely used in patients with inactive IBD with coexistent IBS symptoms ~35-45% quiescent IBD patients meet the criteria for IBS

Halpin SJ , Ford AC Am J Gastroenterol 2012;107:1474–82

44 Efficacy of Low FODMAP diet in IBD with IBS symptoms. Ref Study design Study patients Intervention Outcomes Cox et al. Gastro RCT single-blind N=52 quiescent IBD Low FODMAP vs sham • Higher % with adequate relief of GI symptoms 2018. Abstract dietary advice for 4 w following the low FODMAP diet (14/27, 52%) than sham diet (4/25, 16%) (P=0.007).

Cox et al. J RCT rechallenge N=29 quiescent IBD Low FODMAP diet followed • Fewer patients reported adequate symptom relief Crohn’s Colitis trial & IBS (12 CD, 17 UC) by pure sugar challenges with fructan challenge [18/29, 62.1%] 2018 with fructans, GOS and • But not GOS or sorbitol compared with glucose sorbitol [26/29, 89.7%] [p = 0.033] Pedersen WJG RCT open label N=89 IBD & IBS (28 Low FODMAP diet • 30 (81%) responders in the LFD group cf 19 (46%) in 2017 CD, 61 UC) education vs habitual diet the ND group, (p< 0.01) (83% quiescent, 17% for 6 w • LFD group had lower IBS-SSS score at & increased IBD mild/mod activity) QOL scores at 6-week Maagaard et al. Retrospective N=49 IBD & IBS (12 Low FODMAP dietetic • LFD produced full efficacy in 42% IBD patients WJG 2016** audit CD, 32 UC) education for 6-8 w + • Reduction in symptoms associated with improved reintroduction of FODMAPs QOL and normalised stool pattern

Prince et al. Prospective N=88 quiescent IBD Low FODMAP dietetic • Significant increase (%) reporting satisfactory Inflamm Bowel uncontrolled & IBS (39 CD, 38 UC, education for >6 w symptom relief low FODMAP diet (78% vs 16% Dis 2016 11 IBD-U) baseline ; P < 0.001).

Gearry et al. J Retrospective N=72 quiescent IBD Low FODMAP dietetic • 1 in 2 patients responded to diet Crohn’s Colitis audit & IBS (52 CD, 20 UC) education for 17 mo 2009 Nous ne pouvons pas afficher l’image. *rechallenge and long-term diets assessed only in n=1 study Low FODMAP & IBD: Gaps in research

. Limited data on long-term adapted diet in patients with IBD – Majority studies focused on Step 1 Low FODMAP diet – Danish Study (Maagaard et al. 2016): . 84% patients followed an ‘adapted low FODMAP diet’ and had reintroduced FODMAPs . Wheat , onion, garlic, dairy most commonly not reintroduced

. Maintenance of disease remission – adequate intake of a variety of fibre maybe important.

46 FODMAP diet in IBD- Important that go through the 3 Steps

Step 1 - Low FODMAP (2-6 weeks only) Replace all high FODMAP foods with foods low in FODMAPs in each food group

Step 2 – FODMAP re-introduction FODMAP Food challenges (6-8 week process)

Step 3. Personalized FODMAP diet Interpret food challenge results. Re-introduce food based on symptom response – only restrict foods and FODMAPs that trigger symptoms.

Tuck, C. Barrett, J. (2017) Re-challenging FODMAPs: the low FODMAP diet phase two. Journal of Gastroenterology and Hepatology, 32: 11–15. 47 Specific Carbohydrate diet (SCD) and IBD Ref Study design Study patients Intervention Outcomes Suskind et al. Prospective, N=12 mild to mod -taught SCD for 12 w • Significant reduction in disease activity index J Clin Gastro multi-centre, active IBD children (80% clinical remission) 2018 open-label • Decreased CRP levels, but • faecal calprotectin still elevated Suskind et al. Cross-sectional N=417 IBD (47% SCD (unknown whether • Patient reported clinical remission rates: Dig Dis Sci online survey Crohn’s, 43% UC, dietitian/doctor/self- • 33% at 2 months, 42% at 6 & 12 months 2016 10% indeterminate administered) • 47% reported associated improvement in colitis) ‘abnormal laboratory markers’ • Likelihood of remission higher in pts not requiring immunosuppressive meds, mesalamimse or biologics. Burgis et al. Retrospective N=11 active CD Strict SCD + liberalisation • At 12 mo, serum haematocrit, albumin and ESR 2016 audit children improved significantly with strict SCD Obih et al. Retrospective N=26 active IBD (20 SCD (n=26) vs standard • Significant improvement in paediatric crohn’s Nutrition audit CD, 6 UC) & N=10 medical therapy (n=10) disease activity index, C-reactive protein & 2016 IBD (7 CD, 3UC) calprotectin over time for both groups controls • Calprotectin levels not normalised on diet Cohen et al. Propestive N=10 active CD Dietitian-taught SCD for 12 w • 60% patients achieving clinical remission JPGN 2014 open-label • Sig improvements in clinical disease activity scores • 40% with mucosal healing on capsule endoscopy (but higher scores at 52 w) Suskind et al. Retrospective N=7Nous ne pouvonsCD pas afficher l’image. SCD • Symptomatic improvement after 3 mo 2014 • Improvement in laboratory markers Specific Carbohydrate Diet (SCD)Adapted from http://www.breakingtheviciouscycle.info/legal/listing/

Foods to Avoid Foods you can Eat

• All grains and some legumes • Some legumes, including dried navy beans, , peas, split peas • Bread, pasta, and other starchy foods • Most nuts

• All milk, high-lactose cheeses , commercial • Cheeses such as cheddar, Colby, Swiss, yogurt, heavy cream havarti, and dry curd cottage cheese, and Homemade yogurt fermented for >24 hours • Canned vegetables • Most fresh, frozen, raw or cooked vegetables, most fruits • Seaweed and seaweed byproducts, Canned • Unprocessed meats, poultry, fish, shellfish, and most processed meats eggs, • High-fructose corn syrup, or any processed • Honey for sweetening (if tolerated), Most oils, sugar, Ice cream, candy, chocolate tea, coffee, mustard, vinegar, and juices with no additives. High FODMAP 50 Specific Carbohydrate Diet: Gaps in knowledge

. Confusion about the details of the diet therapy (eg. which foods to avoid etc) . Understand the mechanism of action – Possible that reduction of fermentable load (ie. low FODMAP) = symptom improvement . Issues around the use of the diet – Adherence to the diet (ability to follow the diet) – Nutritional adequacy of the diet (important particularly with children) – Unclear about a structured re-introduction phase – What is the effect on dietary fibre intake (including prebiotic fibres) . The SCD a ‘whole diet’ approach - Need to undertake studies that compare improvements on SCD vs appropriate comparator diet.

51 Dysbiosis and IBS

Strategies to Change the Composition of Gut Microbiota: Use of Probiotics/Prebiotics. Probiotics – Direct Consumption of Bacteria

Can be difficult to show benefits in healthy = so often use gut disorders such as IBS

53 Probiotics – Direct Consumption of Bacteria

. Probiotics – microorganisms that convey a health benefit to humans . Countless types of potential probiotic bacteria exist – only a handful have been identified and well studied . Probiotic have now been studied in the context of many health conditions e.g. depression, allergy, IBS, IBD, etc. . Effects seem to be quite strain specific . Good evidence for the use of strain specific probiotics in IBS – single strain supplement now available. 54 COMMON PROBIOTICS

Probiotic Genus Active strain Generic products Dose (cfu) Lactobacillus L.casei Shirota Yakult 6.5 x 10 per bottle

L. rhamnosus GG Vaalia Innergy/yoghurt 1x1010 per 100ml

Metagenics Ultra Flora LGG 1x1010 per capsule

L. plantarum 299V Ethical Nutrients IBS Support 2 x 1010 per capsule

Metagenics Probex 2 x 1010 per capsule

Bifidobacteria B. animalis (lactis) DN173-010 Danone Activia 1.3 x1010 per 125g tub

B. Infantis 35624 Procter & Gamble METAALIGN 1 x 109 per capsule

B. animalis ProDigestis Ski Activ 1.7 x1010 per 170g tub

Saccharomyces S. Boulardii Ethical Nutrients Travel Bug 5 x 109 per capsule

Bioceuticals SB Floractiv Not stated

Escheria E. Nissle 1917 Mutaflor 2.5 x 108per capsule*

55 Smartphone Application: Probiotic Guide- Canada

56 Largest Probiotic Trial Showing Efficacy in Overall IBS Symptoms (n=362)

True response rate in 20% patients B. Infantis 35624

57 Whorwell et al. Am J Gastro 2006 Low FODMAP Diet in IBS: Probiotic VSL3# restores Bifidobacterium

. VSL3 # (multi-strain Bifidobacterium probiotic) restored the fecal-bifidobacterium. . However, gut symptom control was better on the low FODMAP diet.

Staudacher et al Gastroenterology 2017;153:936-947. 58 Prebiotics/IBS – Encouraging the growth of your own gut bacteria

59 Prebiotics in IBS

Ref Sample size Intervention Duration Results

Hunter et RCT; n=21 6g/d FOS 4 weeks No benefit al. 1999

Olesen et RCT; n=96 20g/d FOS 14 weeks Worse symptoms at 4 weeks al. 2000

Paineau et n=105 FBD 5g/d FOS 6 weeks • 43% reduced severity al. 2008 with mild • 75% symptoms less symptoms frequent • Discomfort increased

Silk et al. RCT; n=44 3.5g or 7g/d GOS 12 weeks Improvement in stool 2009 consistency, bloating, with 3.5g/d Dietary sources of ‘prebiotics’. Dietary Fibre Resistant starch Prebiotic Fibre Grapefruit (1 medium) Persimmon (1 fruit)

Fruit Banana ( 1 fruit ) (1 slice) . Peas (1/2 cup) Garlic ( 1 clove) Onion (1/2) bulb (1/2 cup) Vegetables Jerusalem ( 1) Red kidney beans (1/2 cup) Baked Beans (1/2 cup)

Legumes Split peas (1/2 cup) Weet-bix (2 biscuits) All Bran (1/2 cup) Gnocchi ( 1 cup) Pasta (1 cup) Grains Wholegrain wheat (2 slices) Breads, Cereals, Rye bread (2 slices)

0,0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 8,0 9,0 10,0 11,0

g/serve Diets High in Natural Prebiotic Fibre –For Health

Resistant starch • Wholegrains Fructans (FOS, rye & oligofructose, • Legumes ) • Banana, ripe • Wheat, rye, barley with green tips • , garlic & onion Galacto- • Watermelon, oligosaccharides persimmon, Fructose/sorbitol/ nectarines, white mannitol • Cashews & pistachios Challenges of increasing fibre in IBS

• Fibre intake and supplementation

• Difficult to reduce FODMAPs without compromising fibre intake

• Evidence-based fibre supplementation options limited5,6

5. Moayyedi Am. J. Gastroenterol 2015 63 6. Nagaran Eur J Gastroenterol Hepatol 2015 Summary . What is a healthy gut – colonic contents are important & indigestible carbohydrates (DF, RS, prebiotics) have major impact. . IBS and FODMAP diet therapy – High level of evidence for the use of Low FODMAP diet to treat IBS. It is a 3 phase diet – not strict diet for life . Understanding Gluten and Wheat Avoidance - the evidence suggests that it is the FODMAP (fructan) component of wheat and not gluten that triggers gut symptoms in non-celiac gluten sensitive people . Diet therapy in the management of IBD Clinical Problem - There is evidence for the use of the low FODMAP diet to control symptoms of IBS in IBD, however no evidence that treats the underlying inflammation. Need to use the 3 step approach. . Strategies to Change the Composition of Gut Microbiota in IBS Use of Probiotics/prebiotics. There is mixed evidence for the efficacy of probiotic (depends on strain) discuss with pt the best option for them. . Greatest potential for changing the composition of the gut contents is via the use of diet and in particular the , RS and prebiotic fibres. Presents challenge in IBS patients – RS may be better tolerated. 64 Acknowledge: Monash Research Team IT Prof Peter Gibson Postgraduate students Bala Natarajan Dr Jane Varney Paul Gill Dr Marina Iacovou Mary Ajamian Research chef Dr Rebecca Burgell Daniel So Dr CK Yao Trish Vietch Dr Jaci Barrett Research Technicians Dr Judy Moore Funding Sources: Alex Bogatyrev NHMRC, ARC linkage, Elizabeth Ly Eva and Les Erdi Foundation, USA-Commercial Menzies Foundation, Nia & Jim Rosella Monash Low FODMAP app Alan Greensmith George Weston Foods, Meat & Livestock Australia MGP Ingredients Research Administration Nestle Healthcare Nutrition Lyndal McNamara Ally Heywood Sanitarium . Erin Dwyer 6 Shirley Webber 5

Presentation 3 Yogurt, Gut Microbiota and Cardiometabolic Health

André Marette Laval University, Québec, Canada

Annual Symposium on Nutrition and Health Dairy Farmers of Canada Oct.31-Nov. 1, 2018

https://digestivehealthinstitute.org/fermentable-carbs-vs-fermented-foods/ Disclosure Consultation and honorarium • Danone Nutricia • Thetis Pharma • Valbiotis • Plexus

Funding (last 3 years) • CIHR, CDA, HSFC, FRQ, CFI, CRIBIQ, CFREF • NSERC-partnership with Agropur & Ultima Foods • Agriculture & Agri-Food Canada • Dairy Farmers of Canada • JA DeSève Fondation • Pfizer (Chair CIHR/industry) • Danone Nutricia • Thetis Pharma • Quebec federation of maple syrup producers • High-bush Blueberry Council Number of dairy publications indexed in PubMed over the last 25 years

4000 Total yogurt = 3296 3500 Probiotic yogurt = 742 Yogurt consumption = 977 3000 Yogurt and weight = 470 2500 Yogurt and health = 1015 Microbiota and yogurt = 111 2000

1500

1000

500

0 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 Dairy Milk Cheese Yogurt Mozaffarian D, et al N Engl J Med. 2011 364(25):2392-404.

Manipulating the gut microbiota to prevent or alleviate obesity-linked diseases

ω-3 and ω-6 Fermented dairy PUFAs products Natural sugars and sweeteners Probiotics Muscle Dietary proteins Liver Prebiotics Brain Adipose tissue Plant Bariatric polyphenols Pancreas surgery

Metabolic, gastro-hepatic and cardiovascular benefits

Compilation of scientific literature on About our book yogurt and its roles in nutrition and health Macronutrient profile of common yoghurts

Percent contribution of 100 g of commonly consumed yoghurts to the reference nutrient intakes for energy, fat, carbohydrates and protein in children.

Children aged 4-6 y

Melissa A. Fernandez, Mauro Fisberg, André Marette (2017). Chapter 28: ROLE OF YOGURT IN THE NUTRITION AND HEALTH OF CHILDREN AND ADOLESCENTS. Book: Yogurt in Health and Disease Prevention. Published, Academic Press

Based on the dietary reference values for children from the British Nutrition Foundation and Public Health England Composition of foods integrated dataset Children aged 7-11 y Yogurt contributes to intake of key nutrients at different age groups • Excellent source of % 50 45 iodine, vitamin B12, 40 phosphorus, calcium, 35 riboflavin and 30 thiamin for children 25 4-6 yo and adolescents 20 7-10 yo • Source of folate, 15 11-14 yo magnesium, 10 15-18 yo 5 potassium and 0 selenium • Concentrated source of nutrients for children Based on the dietary reference values for children from the British Nutrition Foundation and Public Health England • Excellent vehicle for Composition of foods integrated dataset of 100 g of low-fat fruit yogurt. (Fernandez et al. 2017) fortification Yogurt and Cardiometabolic Health Level of evidence of the effects of yogurt on cardiometabolic diseases.

Type 2 Cardiovascular Metabolic Obesity Hypertension diabetes disease syndrome

Cross-sectional √ √ √ √ √ studies

Prospective √ √ √ √ √ cohort studies

Meta-analyses (prospective None > 3 None ≥ 1 ≥ 1 cohorts)

Clinical studies Few None None Few None

Level of Poor Strong† Poor Moderate Poor evidence

+ + ? = ? Conclusions Systematic review of the association between dairy product consumption and risk of cardiovascular- related clinical outcomes (Drouin-Chartier et al. 2016) http://www.webmd.com/diabetes/news/20141125/yogurt-every-day-may-help-keep-diabetes-away#1 First take home messages • Yogurt contributes to intake of key nutrients and its consumption is associated with healthy lifestyles and dietary patterns • There is a favorable relationship between yogurt consumption and lower weight gain, and strong consistent evidence that yogurt intake is associated with reduced T2D risk • Favorable relationships between yogurt consumption and hypertension, CVD and metabolic syndrome are also emerging • RCTs and pre-clinical studies are needed to establish causal links and identify mechanisms of action of yogurt action Why yogurt consumption may reduce cardiometabolic diseases?

Nutrient rich food Lipids and lactose  energy source profile  contributes to High quality intakes of essential protein nutrients for health growth and Source of Ca, vitamin D and P maintenance  contribute to bone health of muscle mass

Source of bioactive lipids and proteins  di- and tri- Live cultures improve peptides, CLA, whey, lactose tolerance, medium-chain fatty acids increase concentrations that contribute to of some nutrients (eg. protection against CLA and bioactive cardiometabolic risk peptides) factors

Pairs well with other healthy foods  potential for increased intake of fruits, vegetables and grains

Adv Nutr. 2017 Jan 17;8(1):155S-164S.

Yogurt Fruits What about dairy fat? « This comprehensive assessment of evidence from RCTs suggests that there is no apparent risk of potential harmful effects of dairy consumption, irrespective of the content of dairy fat, on a large array of cardiometabolic variables ».

« This suggests that the purported detrimental effects of SFAs on cardiometabolic health may in fact be nullified when they are consumed as part of complex food matrices such as those in cheese and other dairy foods.

« Thus, the focus on low-fat dairy products in current guidelines apparently is not entirely supported by the existing literature and may need to be revisited on the basis of this evidence ». What about sugars in yogurt?

Plain unsweetened yogurt ranks highly in all nutrient profiling systems and is considered nutrient dense

http://albertonrecord.co.za/141015/healthy-friday-5-low-fat-foods-that-are-bad-for-you/ What about sweetened yogurt?

• Yogurt contains lactose as an endogenous source of sugar but may also contain added sugar. • Yogurt can be a source of added sugars in certain populations • Very young children (low diet diversity) • Spanish population (high yogurt consumption) But still remains a minor source compared to many other calorie-dense nutrient- poor foods • Epidemiological studies make no distinction between sweetened, artificially- sweetened and unsweetened yogurt, but Consistently show favorable associations, despite presence of added sugar and artificial or natural sweeteners • Consumers of plain yogurt may add more sugar than what is found in already sweetened yogurt, so We need to educate the consumers about the risk of adding sugars (Williams et al. 2017; Ruiz et al. 2017; Cooper et al. 2017; Ste-Eve et al. 2016) Is it fermentation products ? • Enhanced • Improved lactose tolerance • Low pH of yogurt – ideal for mineral absorbability

• Release bioactive molecules • Conjugated linoleic acid (CLA) • Lactate Marco et al. Current Opinion in • Bioactive peptides Biotechnology 2017, 44:94–102 • Exopolysaccharides

Fernandez ,…Marette. • Lactic acid bacteria Adv Nutr Nov 15;8(6):812-829, 2017 • Antagonist behavior with other bacteria • Favors healthy gut microbiota

• Increase concentrations of oligosaccharides • Prebiotic CONCLUSIONS

▸ Different types of dairy products have specific effects on glucose and lipid metabolism

▸ Fermented dairy products and especially yogurt-type product generally exerted greater cardiometabolic and anti-inflammatory effects.

▸ Fermented dairy products and particularly yogurt-type product markedly increase gene expression of the Reg3 AMPs in the small intestine, a well known anti-inflammatory mechanism to limit bacterial-epithelial cell interactions.

▸ These immunometabolic effects are associated with major changes in the gut microbiota composition of obese prediabetic and dyslipidemic mice. Take home message Lactic acid bacteria, peptides and other products released during fermentation may explain some of the health benefits of yogurt consumption on cardiometabolic diseases. Students/PDFs/RA Mélissa Fernandez Éliane Picard-Deland Collaborators Partners Noémie Daniel Université Laval Lais Rossi Perazza Denis Roy Jose Luis M. Gonzalez Yves Pouliot Sylvie Gauthier Michaël Bouchard Patrick Mathieu Thibault Varin Agriculture/Agri-Food Canada Mélanie Le Barz Martin Lessard Geneviève Pilon Mylène Blais Marie-Julie Dubois Université de Sherbrooke Philippe St-Pierre Claude Asselin Christine Dion Christine Dallaire TransBioTech Valérie Dumais Yvan Boutin Joanie Dupont-Morissette

Presentation 4 : Perceptions and Realities

Susan I. Barr, PhD, FDC Professor Emeritus University of British Columbia Disclosures

• Member, Nutrition Expert Scientific Advisory Committee, Dairy Farmers of Canada (DFC; research grant reviews) • Member of Medical Advisory Board, International Dairy Foods Association • Honorarium provided by DFC for this presentation • I am not lactose intolerant! Outline: Lactose Intolerance •Definitions •What are the symptoms and why do they occur? •How is it diagnosed? •Should milk be avoided? •What strategies can be used? Why Do We Care About Lactose Intolerance?

Lactose Intolerance (real or perceived)

Avoidance of dairy products

Lower intakes of key nutrients (e.g., calcium, vit D)

Potential implications for health Perceived Lactose Intolerance in Adult Canadians: A National Survey

• Nationally-representative sample, n = 2251 • 16% reported lactose intolerance (21% in 2017 DFC survey) Self-reported Lactose intolerance P Yes No Milk products & alternatives (svg/d) 1.40 ± 0.08 2.33 ± 0.03 <0.001 Calcium supplement use (%) 52% 37% <0.001 Calcium (milk products, fortified 739 ± 30 893 ± 13 <0.001 beverages, supplements; mg/d)

Barr SI. Appl Physiol Nutr Metab 2013:38:830-835 Definitions Definitions • Lactose: sugar in milk (galactose-glucose) • Lactase: enyzme that digests lactose • : • Retention of lactase activity into adulthood • Dominant inheritance • Primary lactase deficiency (lactase nonpersistence): • Normal developmental decrease in lactase activity after weaning, resulting in lactose maldigestion • Seen in ~70% of world’s population Lactose Maldigestion = Lactose Intolerance Lactose Intolerance •Clinical signs and symptoms after consuming lactose in those who maldigest lactose •Prevalence not known… Lactose Intolerance = Lactose Maldigestion PLUS Symptoms Lactose Intolerance = Milk Allergy •Maldigestion of milk sugar versus immune response to milk protein •Different symptoms, diagnosis and management Symptoms and Physiology Lactose Intolerance Symptoms

•Bloating •Abdominal pain/cramping •Gas/flatulence •Diarrhea Credit: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Lactose Digestion Lactase Small Intestinal Cell

CH2OH CH2OH O O HO H OH H H O OH H OH H H H H

H OH H OH Lactose Lactose Digestion Lactase Small Intestinal Cell

CH2OH CH2OH O O HO OH H OH H H

OH H OH H H H OH H

H OH H OH Galactose Glucose Lactose Digestion Lactase Small Intestinal Cell

CH2OH O HO OH H

OH H H H

H OH CH2OH O H H

OH H OH H

H OH Lactose Maldigestion Lactase Small Intestinal Cell

CH2OH CH2OH O O HO H OH H H O OH H OH H H H H

H OH H OH

Lactose Lactose Maldigestion

O O O Small Intestinal Cell

O O O H2O

O O O

O O O H2O Lactose Maldigestion

Hydrogen (enters bloodstream; exhaled) Colon

Methane Short Chain Fatty Acids

H2O H2O enter bloodstream; used as fuel Lactose Maldigestion and Intolerance **Substantial** amounts of undigested lactose

Water enters intestine to BLOATING balance osmotic pressure

GAS Undigested lactose PAIN reaches colon and is fermented by bacteria DIARRHEA How is Lactose Intolerance Diagnosed? Diagnosis: Breath Hydrogen

• Overnight fast 30 • Baseline breath hydrogen 25 • Give lactose dose (often 25-50 g) 20 • Monitor breath hydrogen every 30 min for 3-6 hr 15 • Monitor symptoms 10

Hydrogen (ppm) Hydrogen Lactose digester 5

0 0 60 120 180 Time (min) Diagnosis: Breath Hydrogen

• Overnight fast 30 Lactose maldigester • Baseline breath hydrogen 25 • Give lactose dose (often 25-50 g) 20 • Monitor breath hydrogen every 30 min for 3-6 hr 15 • Monitor symptoms 10 Hydrogen (ppm) Hydrogen Lactose digester • Increase in breath H2 of >20 ppm 5 = maldigestion 0 • Maldigestion + symptoms 0 60 120 180 = intolerance Time (min) What Happens in the Real World?

• “Are you lactose intolerant?” • 159 Vancouver adults recruited • Completed questionnaire • Method of diagnosis assessed

Lovelace H, Barr SI. J Am Coll Nutr 2005;24(1):51. How was Lactose Intolerance Diagnosed?

All Participants (n=159)

Physician Other health Self-diagnosed diagnosed practitioner 54% (n=86) 42% (n=67) 4% (n=6)

Lovelace H, Barr SI. J Am Coll Nutr 2005;24(1):51. How was Lactose Intolerance Diagnosed?

All Participants (n=159)

Physician Other health Self-diagnosed diagnosed practitioner 54% (n=86) 42% (n=67) 4% (n=6)

Report of ‘Valid’ test symptoms n=7 (2.5%) n=60 Lovelace H, Barr SI. J Am Coll Nutr 2005;24(1):51. Should Lactose Intolerant Individuals Avoid Milk? Symptoms: Milk or Lactose-hydrolyzed Milk

• 30 people with *severe* self-reported lactose intolerance after <1 cup milk • 10 avoided all milk products • 20 exclusively used lactose-digestive aids • Lactose digestion assessed with breath hydrogen test (15 g lactose in water) • 9 digested lactose fully • 21 were maldigesters

Suarez FL et al. N Engl J Med 1995;333:1-4 Study Protocol (double blind) Week 1 Week 2

7 days of milk* 7 days lactose- with breakfast free milk with breakfast

All

7 days lactose- 7 days of milk* free milk with with breakfast breakfast

Monitored symptoms each day * Sweetener added so taste of milk and lactose-free milk were identical Suarez FL et al. N Engl J Med 1995;333:1-4 Symptoms in Lactose Maldigesters (n=21)

Severe 5

Strong 4

Moderate 3 Lactose No lactose Mild 2

Trivial 1

None 0 Bloating Pain Diarrhea Flatus

Suarez FL et al. N Engl J Med 1995;333:1-4 Symptoms in Lactose Digesters (n=9)

Severe 5

Strong 4

Moderate 3 Lactose No lactose Mild 2

Trivial 1

None 0 Bloating Pain Diarrhea Flatus

Suarez FL et al. N Engl J Med 1995;333:1-4 Authors’ Conclusions • “People who identify themselves as severely lactose-intolerant may mistakenly attribute a variety of abdominal symptoms to lactose intolerance.” • “When lactose intake is limited to the equivalent of 240 ml of milk or less a day, symptoms are likely to be negligible and the use of lactose-digestive aides unnecessary.”

Suarez FL et al. N Engl J Med 1995;333:1-4 What About >1 Cup?

• Suarez FL et al. Tolerance to the daily ingestion of two cups of milk by individuals claiming lactose intolerance. Am J Clin Nutr 1997; 65:1502.

• Suarez FL et al. Lactose maldigestion is not an impediment to the intake of 1500 mg calcium daily as dairy products. Am J Clin Nutr 1998;68:1118. 2010 NIH Consensus Conference

• Extensive review of the literature • Reviewed 28 randomized blinded trials of lactose versus lactose-free beverages • Almost all lactose maldigesters tolerated ~12-15 g of lactose without noticeable symptoms; symptoms occur at dosages ranging between 20-50 g lactose

https://www.ahrq.gov/downloads/pub/evidence/pdf/lactoseint/lactint.pdf 2010 NIH Consensus Conference

• Lactose intolerance (LI) is real; true prevalence unknown • Most lactose maldigesters are not LI; many who believe they are LI fully digest and absorb lactose • Real or perceived LI can lead to milk avoidance and thus inadequate calcium and vitamin D intakes – implications for bone health • Dairy products do NOT need to be eliminated

https://consensus.nih.gov/2010/docs/LI_CDC_2010_Final%20Statement.pdf What Do We Do With This Information??? “Perception is Reality” What Strategies Can be Used? Lactose Maldigestion = Lactose Intolerance

Lactose Intolerance Lactose Tolerance Lactose in Milk Products No Symptoms

Yogurt, plain 2%, 175 ml

Cottage Cheese, 125 ml

Cream, 30 ml

Ice Cream, 125 ml

Cheddar Cheese, 50 g

Milk, 2%, 250 ml

0 2 4 6 8 10 12 14 Lactose (g) Practical Suggestions

Dairy Products Non-Dairy Alternatives • Use smaller portions • Use products fortified with • Consume with a calcium and vitamin D • Use milk products with less lactose (e.g., hard cheese, yogurt) or lactose-free options

Use “food first”, but consider supplement use if recommended intakes cannot be achieved. Colonic Adaptation?

• Preliminary data: • Gradual increase in lactose intake over time  • Adaptation of colonic bacteria  • Reduced symptoms • Early studies poorly controlled Colonic Adaption?

• Galacto-oligosaccharides (GOS): 2-4 galactose residues; not digested by humans GAL GLU • Like undigested lactose, GOS enter colon Lactose and are fermented by bacteria • Would providing increasing amounts of GOS to lactose intolerant individuals: • Shift colonic bacterial metabolism? GAL GAL • Reduce symptoms after an oral lactose load?

Galacto- (GOS) Savaiano DA et al. Nutrition Journal 2013; 12:160 Subjects and Protocol

Subjects • Lactose intolerant Day 0 Day 1-35 Day 36 • 25 gm lactose load at baseline GOS showed maldigestion (breath Lactose-free hydrogen) and symptoms diet Baseline Endline • Assigned to GOS or placebo (corn 25 g Lactose 25 g Lactose syrup) for 35 d (dose increased from Challenge Challenge 1.5 – 15.0 g/d) Corn syrup Lactose-free • Day 36: 25 g lactose tolerance test diet repeated (breath hydrogen and symptoms)

Savaiano DA et al. Nutrition Journal 2013; 12:160 Median Breath H2 after 25 g Lactose P = 0.19 100 100

80 80

60 60

40 Day 0 40 Day 0 Day 36 Day 36 20 20 Breath Hydrogen (ppm) Hydrogen Breath Breath Hydrogen (ppm) Hydrogen Breath 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Time (hrs) Time (hrs)

Galacto-oligosaccharides Placebo (corn syrup) Savaiano DA et al. Nutrition Journal 2013; 12:160 Impact on the Gut Microbiome

• Stool samples analyzed; no effect of GOS on Shannon Diversity or Species Richness indices • However, GOS increased relative abundance of bifidobacterial populations

Azcarate-Peril et al., PNAS 2017, 114(3):E367-E375. https://doi.org/10.1073/pnas.1606722113 Symptom Reduction (Day 36 vs Day 0)

GOS Placebo • Symptoms after 25 g lactose challenge decreased in BOTH GROUPS • Total symptom reduction scores did not differ (p = 0.73) • Trend (NS) for a greater reduction in abdominal pain with GOS versus corn syrup

Total symptoms: p = 0.73 Savaiano DA et al. Nutrition Journal 2013; 12:160 Study Conclusions?

• Some effect of GOS on the microbiome (although little impact on breath H2) • Large placebo effect (both groups improved, no difference in total symptoms) • Role of ‘colonic adaptation’ remains unclear • Even if some benefit occurred with GOS, what does it mean? Using a lower lactose dose (e.g. ~12 g vs. 25 g) would avoid all symptoms. Overall Conclusions Conclusions • It is normal to digest lactose incompletely • Very few people who believe they are lactose intolerant have been clinically diagnosed; many who believe they are lactose intolerant digest lactose fully • Lactose maldigestion does not need to lead to lactose intolerance; almost all individuals with lactose maldigestion can consume “useful” quantities of milk and dairy products without symptoms • Role of microbiome requires more clarification • Sensitivity is needed when working with people who believe they are lactose intolerant Thank you! References: Review Articles

• Corgneau M, Scher J, Ritie-Pertusa L et al. Recent advances in lactose intolerance: tolerance thresholds and currently available answers. Critical Reviews in Food Science and Nutrition 2017;57:15, 3344-3356. https://doi.org/10.1080/10408398.2015.1123671 • Suchy FJ, Brannon PM, Carpetner TO et al. NIH Consensus Development Conference Statement: Lactose Intolerance and Health. NIH Consens State Sci Statements 2010;27(2):1-27. https://consensus.nih.gov/2010/docs/LI_CDC_2010_Final%20Statement.pdf • Wilt TJ, Shaukat A, Shamliyan T, et al. Lactose Intolerance and Health. No. 192 (Prepared by the Minnesota Evidence- based Practice Center under Contract No. HHSA 290-2007-10064-I.) AHRQ Publication No. 10-E004. Rockville, MD. Agency for Healthcare Research and Quality. February 2010. https://www.ahrq.gov/downloads/pub/evidence/pdf/lactoseint/lactint.pdf • Zaitlin P, Dwyer J, Gleason GR. Mistaken beliefs and the facts about milk and dairy foods. Nutrition Today 2013;48(3): 135- 143. https://pdfs.semanticscholar.org/809b/cd7d470a87a36e4ea30b4178355e04256f7f.pdf References: Cited Studies

• Azcarate-Peril MA, Ritter AJ, Savaiano D et al. Impact of short-chain on the gut microbiome of lactose-intolerant individuals. PNAS 2017, published online January 3, 2017, E367-E375. http://www.pnas.org/content/114/3/E367.short • Barr SI. Perceived lactose intolerance in adult Canadians: a national survey. Applied Physiology Nutrition and Metabolism 2013;38:830-835. https://doi.org/10.1139/apnm-2012-0368 • Lovelace HY, Barr SI. Diagnosis, symptoms, and calcium intakes of individuals with self-reported lactose intolerance. Journal of the American College of Nutrition 2005;24:51-57. https://doi.org/10.1080/07315724.2005.10719443 • Savaiano DA, Ritter AJ, Klaenhammer TR et al. Improving lactose digestion and symptoms of lactose intolerance with a novel galacto-oligosaccharide (RP-G28): a randomized, double-blind clinical trial. Nutrition Journal 2013;12:160 http://www.nutritionj.com/content/12/1/160 • Suarez FL, Savaiano DA, Levitt MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. New England Journal of Medicine 1995;333:1-4. https://www.nejm.org/doi/full/10.1056/NEJM199507063330101 • Suarez FL, Savaiano D, Arbisi P, Levitt MD. Tolerance to the daily ingestion of two cups of milk by individuals claiming lactose intolerance. American Journal of Clinical Nutrition 1997;65:1502-1506. https://doi.org/10.1093/ajcn/65.5.1502 • Suarez FL, Adshead J, Furne JK, Levitt MD. Lactose maldigestion is not an impediment to the intake of 1500 mg calcium daily as dairy products. American Journal of Clinical Nutrition 1998;68:1118-1122. https://doi.org/10.1093/ajcn/68.5.1118