Presentation 1

Gut Microbiome and Human HealthKaren Madsen, PhDUniversity 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 MicrobesFrom enemies…..

The Changing Face of Gut MicrobesTo 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 gut microbiota exists as an eco-system within us bacteria, viruses, fungi, archaea…..

• Over 50 known bacterial phyla

• Generally a balance of 6 main phyla found in gut

Tree of life

Health Disease

BacteroidetesFirmicutes

ActinobacteriaVerrucomicrobia

ProteobacteriaFusobacteria

Species and abundance change over the length of the gut

A fine balance of gut microbes

• Inhibit pathogen growth• Convert pro-drugs to active

metabolites• Degrade polysaccharides of

plant origin• Produce folate and Vitamin K• Produce short-chain fatty acids• Stimulate and modulate immune

function• Regulate body fat storage• Maintain barrier function and

stimulate epithelial repair• Stimulate gut motility

• Sepsis, infection• Inflammation• Liver damage• Production of

carcinogens• Diarrhea, constipation

Commensals Pathogens

Individuals differ in the types and quantities of bacteria that colonize the gut …

D Vandeputte et al. Nature 1–5 (2017) doi:10.1038/nature24460

Composition(Relative percentages) Absolute Numbers

Bacteria are very different genetically from one another and have very

different metabolic capacity

How do microbes interact

with the host?

Grigg and Sonnenberg. J of Immunology 198:564. 2017

Host-microbial interactions maintain gut homeostasis and can drive pro- and anti-

inflammatory immune responses

Altered host-microbial interactions can drive mucosal and systemic disease

Grigg and Sonnenberg. J of Immunology 198:564. 2017

DIET AND MICROBIAL METABOLISM

Dietary Patterns

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

Food Constituents• Fiber/carbohydrates• Fat• Protein• Phytochemicals

Food-associated commensal microbes

DIET

Diet, lifestyle, genetics and environmental factors all modulate microbiota

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

David et al Genome Biology2014 15:R89

Subject A

Subject B

Resistance and resilience of the gut microbiota influences health and disease

Sommer et al. Nature Rev Microbiology 2017

Resistance: Ability to resist perturbations

(pathogens, drugs)

Resilience:Ability to return to a healthy state following perturbation

Holmes et al. Cell Metabolism 2012;16:559

Dietary compounds serve as substrates for use by gut microbiota for production of numerous

small molecules that influence health and disease

Plasma metabolites differ significantly between omnivore 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– Obesity– Diabetes– Asthma– Allergies– Multiple sclerosis– Inflammatory bowel disease– Rheumatoid arthritis– NEC– Irritable bowel syndrome– 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

Huttenhower et al Immunity 2014 40(6):843

A loss of certain microbial species can remove immune modulating metabolites

Integrated microbial metabolism necessary for health

Production of butyrate requires microbial cooperation

A loss of SCFA removes many beneficial effects

GUT MICROBES AND THEIR METABOLITESCAN ALTER BRAIN FUNCTION AND MOOD

Consumption of Fermented Milk Product With Probiotic 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

Gastroentrology 144:2013

Healthy women • fermented milk product

(probiotics)• 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

• 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 incolorectal 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?

FiberFruits, vegetables

Prebiotics

Fecal microbial transplants

Probiotics/AntibioticsDefined consortium

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– Cross-sectional vs longitudinal sampling

Hanage WP (2014) Nature 512:247-8; Kim et al. Microbiome 5:52. 2017

CONCLUSIONS

Medical Practice in the Futureyour 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

Madsen Lab

• Dr. Troy Perry• Dr. Mike Laffin• Dr. Heekuk Park• Naomi Hotte• Robert Fedorak• Dr. Ammar Keshteli• Aiden Zalasky• Braden Millan• Matt Emberg

Collaborators• University of Alberta

– Dr. Karen Kroeker– Dr. Richard Fedorak– Dr. Leo Dieleman– Dr. Bryan Dicken– Dr. Andy Mason

• University of Calgary– Dr. Gil Kaplan

• George Mason University– Dr. Patrick Gillivet– Dr. Masoumeh Sikaroodi

Presentation 2

Diet for Gut Health: The FODMAP Diet and Beyond

Associate Professor Jane Muir

2

Disclosures• Board Member/Advisory Panel-

- Monash FODMAP Advisory Panel, Nestle Healthcare Nutrition, 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

3

Diet for Gut Health What is a healthy gut?

Update in IBS and FODMAP diet therapy.

Understanding Gluten and Wheat Avoidance.

Diet therapy in the management of Inflammatory Bowel disease.

Strategies to change the composition of gut microbiota in IBS.

What is a healthy gut?

What is optimal gut health for humans?

Absence of infection, gut disorders & disease• Irritable bowel

syndrome (IBS).• Inflammatory bowel

disease (IBD)

Absorption of adequate nutrients

Good balance of gut microbiota

Good laxation and prevention of constipation.

What is optimal gut health for humans?

Colonic Contents

Bulking & laxation effect

Short Chain Fatty Acids acetate, butyrate, propionate

GasesCO2, H2, CH4, H2S

Toxic by-products of protein Fermentation ammonia & phenols

Water movement

PROTEIN75% of faecal matter is bacteriaCARBOHYDRATE

Selective growth ofcertain bacteria

What happens to the gut contents?

Adapted from Cummings 1997

Important dietary components: What are they and what do they do?

DIETARY FIBRE Laxation Bulking Transit time SCFA

RESISTANT STARCH Produce SCFA (eg. butyrate) Encourages growth of

butyrate-producingbacteria

Butyrate Effects Important fuel for colonic

cells, anti-inflammatory may protect from cancer.

PREBIOTIC FIBRE Selective growth& activity of beneficial bacteria• SCFA.

99999

Favourable Effects

Sol. highly ferment. SCC

Sol. highly ferment. ‘fiber’

Insol. Intermed.ferment,‘fiber’

Insoluble slowly ferment. ‘fiber’

Insoluble, non-ferment.‘fiber’

Laxation + + +++ +++ ++Faster Transit time

- - ++ +++ ++

Balance of bacteria (bifido)

+++ + + + -

SCFA-Anti-inflammatory-butyrate

+++ +++RS butyrate

++ + -

Ammonia/ phenols

+++ ++

‘Fibre’Types

FOS, GOS RS oats. Wheat bran,

vegetables,

cellulose, sterculia, psyllium

(Adapted from Eswaran S,et al. Am J Gastroenterol. 2013 May;108(5):718-27.Different Effects of Fibres.

Practical guide to gut health:Bowel habit check-list.

Good flow- good time, correct water content.Clean. Good habitat.

Getting to know your bowel habit- laxation.

Constipation River –too slow and dry. Concentrated.Poor habitat.

Raging Diarrhea River (too fast, too wet).Poor habitat

Nous ne pouvons pas afficher l’image.

Getting to know your stool.

Rating 3 to 4 is ideal

Stool form is a marker of colonic transit time.

May indicate constipation

Trending towards diarrhoea

(Ref: Bristol Stool Chart)

Nous ne pouvons pas afficher l’image.

• Different types of fibres have different effects on faecal bulk

Adapted from Elia & Cummings Eur. J. Clin. Nutr 2007

Food ‘fibre’ Guide (gm faeces / gm of fibre consumed).

We need a combinationof fibres.

Update in Irritable bowel syndrome (IBS)and low FODMAP diet therapy

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Clinical Problem - Irritable bowel syndrome (IBS). Symptoms: Abdominal Pain, bloating

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.

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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

Short-chain carbohydrates

• Small molecules potentially osmotically active

• Slowly or not absorbed will be osmotically active

• Rapidly fermentable will release gas

Lactose Fructose Fructans GOS

Specific culprits

Short-chain carbohydrates symptoms of IBS

‘Windy’ foods

maldigestion symptoms

malabsorption symptoms

Fermentation symptoms

Lactose-free diet

Fructose ±sorbitol-free

diet

Fructose & fructans ‘FM’ diet

Polyols

Avoid windy foods

F O D M A P s

Sweetener symptoms

1965 1978 1966 1987 1969

DietaryTriggersof Gut Symptoms

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F O D M A P – what does it stand for?

Oligos:• Fructans • GOS (raffinose, stachyose)

Disaccharides:• lactose

Monosaccharides:• fructose

Polyols: • sorbitol• mannitol

(see Tuck et al. Expert Rev Gastroenterol. Hepatol. 2014;8:819-34)

Where are FODMAPs found in our diet?

XS Fructose Lactose Fructans GOS Polyols

Fructose

Fructose

Fructans

Fructans

Fructans

Fructans

Fructans

GOS

Polyols

Polyols

Polyols

Lactose

FermentableOligosaccharidesDisaccharidesMonosaccharidesAndPolyols

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. Biesiekierski J et al. Journal of Human Nutrition and Dietetics . 2011;24:154-176.

How FODMAPs trigger symptoms:Consider all indigestible and slowly-absorbed short-chain carbohydrates collectively

All distend intestine via osmotic effect + gas production

SymptomsAdditive contribution to

symptoms in the presence of visceral hypersensitivity 0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Time / hours

Hyd

roge

n P

rodu

ctio

n / p

pm

Diet A LowFODMAPDiet B HighFODMAP

Ong et al, JGH 2010Murray et al, AJG 2014

Fructose Lactose Fructans Galacto-oligos PolyolsHypolactasia

What is low and what is high FODMAP? We have established cut-off values

An upper limit of 0.5g of total FODMAPs (excluding lactose) per sitting.

Varney J et al FODMAPs: food composition, defining cutoff values and international application.Journal of Gastroenterology andHepatology. 2017;32 (Suppl 1) 53-61.

0,0 0,5 1,0 1,5 2,0 2,5

OrangeApple

Bok choyZucchini

GarlicOnion

Mixed grain flakes with dried…Wheat bran, pellets

Whole wheat grain biscuitOats

Flakes of corn

Gluten free breadSpelt bread

Rye bread

FODMAP content (g/serve)

XS Fructose

Polyols

Total GOS

Total Fructan

22

breads

cereals

vegetables

fruitMuir JG et al. J Agric Food Chem. 2007:55; 6619-6627. Muir JG et al J Agric Food Chem. 2009; 57(2):554-565. Biesiekierski J et al. Journal of Human Nutrition and Dietetics . 2011;24:154-176.

The key principle of the Low FODMAP diet isto replace high FODMAP foods with similarfoods low in FODMAPs.

Identify Low and High FODMAP Foods.

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Identify Low and High FODMAP Dairy Foods.

0 5 10 15 20

Soft cheese

Hard Cheese

yoghurt- lactose free

yoghurt- regular

milk lactose free

milk-regular

lactose

FODMAP lactose g/serve

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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)

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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!

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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-introductionFODMAP Food challenges (6-8 week process)

Step 3. Personalized FODMAP dietInterpret 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.

27

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.

Why do the FODMAP Re-introduce/Personalise the Diet?

Tuck, C. Barrett, J. (2017) Re-challenging FODMAPs: the low FODMAP diet phase two. Journal of Gastroenterology and

Hepatology, 32: 11–15.

2828

0

10

20

30

40

50

Day -7 -6 -5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20

Symptom severityWorse

Low FODMAP diet

Baseline diet

Typical Australian Diet

No

Strong Evidence supports the use of the low FODMAP diet (n=30 IBS)

Effective in 7 out of 10 patients with IBS

Many research studies show the low FODMAP diet works in IBS

Nous ne pouvons pas afficher l’image.

Efficacy of low FODMAP diet in IBS patientsREF ; COUNTRY DESIGN STUDY INTERVENTION OUTCOMES

Staudacher et al. 2011; UK

Non-randomised comparative study IBS patients who received standard (n = 39)or low FODMAP dietary advice (n = 43)

• 76% of patients in the low FODMAP group reported satisfaction compared to the standard group (p=0.038)

Staudacher et al. 2012; UK

RCT open label Patients with IBS randomised to lowFODMAP diet (n=19) or habitual diet (n=22)

• More patients in the intervention group reported adequate control of symptoms (13/19, 68%) compared with controls (5/22, 23%; p=0.005)

De Roest et al., 2013; New Zealand

Prospective symptom questionnaire Patients with IBS patients taught the low FODMAP diet (n=90) • 72% satisfied with symptom response

Halmos et al., 2014; Australia

RCT, single-blind, feeding trial Patients with IBS (n=30) Healthy subjects (n=8) – all low FODMAP diet-naïve

• Significantly lower overall symptoms on the low FODMAP diet compared to the Australian diet (p<0.001).

Pedersen et al. 2014; Denmark

RCT open-label Patients with IBS randomised to low FODMAP diet (n=42), probiotics (n=41) and normal diet (n=40)

• Significant reduction in symptom score with low FODMAP diet and probiotic groups compared to the normal diet (p<0.01)

Bohn et al., 2015; Sweden

Multi-centre RCT, parallel, single-blind IBS patients received low FODMAP diet (n=33) vs traditional advice (n=34) for 4-weeks

• IBS symptom severity reduced in both groups during the intervention (p<.0001)

Chumpitazi et al.,2015; USA

Double-blind, crossover trial 2-day interventions in children with IBS (n=33) • Less abdominal pain occurred with the low FODMAP diet (p<0.05)

Eswaran et al., 2016;USA

RCT Patients with IBS-D randomised to either low FODMAP diet (n=45) or modified NICE diet (n=39) for 4-weeks

• Adequate relief reported in 52% on low FODMAP diet vs 41% 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; Australia

RCT Patients with IBS randomised to either low FODMAP diet (n=24), hypnotherapy (n=25) or combination therapy (n=25) for 6-weeks

• Improvements in overall symptoms at week 6 for hypnotherapy (72%), diet (71%), and combination therapy (72%)

Maagaard et al., 2016; Denmark

Retrospective, cross-sectional study Questionnaire sent to IBS (n=131) and IBD (n=49) patients previously educated on a low FODMAP diet

• 86% reported either partial (54%) or full (32%) efficacy • Greatest improvement of bloating (82%) & abdominal pain

(71%)

McIntosh et al., 2016; Canada

Prospective, randomised, single blind parallel study

IBS FODMAP diet-naïve patients (n=40) who received dietary advice on either low or high FODMAP diet

• 72% had reduced symptoms on low vs 21% on the high FODMAP diet (p=0.01)

Staudacher et al. 2018;UK

RCT placebo-controlled, single blind IBS patients receiving low FODMAP (n = 51) or sham dietary d i ( 53)

• Lower IBS-SSS score on low FODMAP vs sham diet (p=0.001)

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)

34

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.

Celiac disease – the best understood gluten intolerance

35

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

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.

Bloating, abdominal pain, fatigue

Mostly female who, like the alternative

40% strictly gluten-free

Golley et al, Pub Health Nutr 2014

CSIRO Food & Health SurveyDec 2010-Feb 2011

n = 1184 ≥ 18 years old

Mostly Gastrointestinal Symptoms

1% have celiac disease

38 38

Randomised, placebo-controlled, cross-over rechallenge study of placebo vs low gluten (2gm) vs high gluten (16gm) all food provideddose effect to be determinedlow FODMAP run-in period

In 37 patients with ‘NCGS’ and normal small intestine or HLA DQ2/8 negative

1. Effect of FODMAPs on overall symptoms

2. Effect on overall symptoms

High quality RCT on existence of non-coeliac gluten sensitivity.

0 0,2 0,4 0,6 0,8 1 1,2 1,4

haricot beanswheat-cous cous

mueslirye bread

wheat -breadwheat- pasta

cornflakesrice bubbles

pasta-gluten freequinoa-pasta

gluten-free breadrice-noodles

rice- whiterice-brown

GOS

Fructan

Fructose

Biesiekierski, et al 2011

Gluten free

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

40

Diet therapy in the management of Inflammatory Bowel disease (IBD).

Ulcerative colitisCrohn’s disease

42

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 oflarge 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)

Low FODMAP Diet and UC

44

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

Low FODMAP & IBD: Adoption in clinical practice

Nous ne pouvons pas afficher l’image.

Ref Study design Study patients Intervention Outcomes Cox et al. Gastro 2018. Abstract

RCT single-blind N=52 quiescent IBD Low FODMAP vs sham dietary advice for 4 w

• Higher % with adequate relief of GI symptoms following the low FODMAP diet (14/27, 52%) than sham diet (4/25, 16%) (P=0.007).

Cox et al. JCrohn’s Colitis 2018

RCT rechallenge trial

N=29 quiescent IBD & IBS (12 CD, 17 UC)

Low FODMAP diet followed by pure sugar challenges with fructans, GOS and sorbitol

• Fewer patients reported adequate symptom relief with fructan challenge [18/29, 62.1%]

• But not GOS or sorbitol compared with glucose [26/29, 89.7%] [p = 0.033]

Pedersen WJG 2017

RCT open label N=89 IBD & IBS (28 CD, 61 UC) (83% quiescent, 17% mild/mod activity)

Low FODMAP diet education vs habitual diet for 6 w

• 30 (81%) responders in the LFD group cf 19 (46%) in the ND group, (p< 0.01)

• LFD group had lower IBS-SSS score at & increased IBD QOL scores at 6-week

Maagaard et al. WJG 2016**

Retrospective audit

N=49 IBD & IBS (12 CD, 32 UC)

Low FODMAP dietetic education for 6-8 w + reintroduction of FODMAPs

• LFD produced full efficacy in 42% IBD patients• Reduction in symptoms associated with improved

QOL and normalised stool pattern

Prince et al. Inflamm Bowel Dis 2016

Prospectiveuncontrolled

N=88 quiescent IBD & IBS (39 CD, 38 UC, 11 IBD-U)

Low FODMAP dietetic education for >6 w

• Significant increase (%) reporting satisfactory symptom relief low FODMAP diet (78% vs 16% baseline ; P < 0.001).

Gearry et al. JCrohn’s Colitis 2009

Retrospective audit

N=72 quiescent IBD& IBS (52 CD, 20 UC)

Low FODMAP dieteticeducation for 17 mo

• 1 in 2 patients responded to diet

Efficacy of Low FODMAP diet in IBD with IBS symptoms.

*rechallenge and long-term diets assessed only in n=1 study

46

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.

47

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-introductionFODMAP Food challenges (6-8 week process)

Step 3. Personalized FODMAP dietInterpret 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.

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

Specific Carbohydrate diet (SCD) and IBD

Nous ne pouvons pas afficher l’image.

Ref Study design Study patients Intervention Outcomes

Suskind et al. J Clin Gastro 2018

Prospective, multi-centre, open-label

N=12 mild to mod active IBD children

Dietitian-taught SCD for 12 w • Significant reduction in disease activity index (80% clinical remission)

• Decreased CRP levels, but• faecal calprotectin still elevated

Suskind et al. Dig Dis Sci 2016

Cross-sectional online survey

N=417 IBD (47% Crohn’s, 43% UC, 10% indeterminate colitis)

SCD (unknown whether dietitian/doctor/self-administered)

• Patient reported clinical remission rates:• 33% at 2 months, 42% at 6 & 12 months• 47% reported associated improvement in

‘abnormal laboratory markers’• Likelihood of remission higher in pts not

requiring immunosuppressive meds, mesalamimse or biologics.

Burgis et al. 2016

Retrospective audit

N=11 active CD children

Strict SCD + liberalisation • At 12 mo, serum haematocrit, albumin and ESR improved significantly with strict SCD

Obih et al. Nutrition 2016

Retrospective audit

N=26 active IBD (20 CD, 6 UC) & N=10 IBD (7 CD, 3UC) controls

SCD (n=26) vs standard medical therapy (n=10)

• Significant improvement in paediatric crohn’s disease activity index, C-reactive protein & calprotectin over time for both groups

• Calprotectin levels not normalised on diet

Cohen et al. JPGN 2014

Propestive open-label

N=10 active CD Dietitian-taught SCD for 12 w • 60% patients achieving clinical remission• Sig improvements in clinical disease activity

scores• 40% with mucosal healing on capsule

endoscopy (but higher scores at 52 w)

Suskind et al. 2014

Retrospective N=7 CD SCD • Symptomatic improvement after 3 mo• Improvement in laboratory markers

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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, lentils, peas, split peas

• Bread, pasta, and other starchy foods • Most nuts

• All milk, high-lactose cheeses , commercial yogurt, heavy cream

• Cheeses such as cheddar, Colby, Swiss, 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 and most processed meats

• Unprocessed meats, poultry, fish, shellfish, eggs,

• High-fructose corn syrup, or any processed sugar, Ice cream, candy, chocolate

• Honey for sweetening (if tolerated), Most oils, tea, coffee, mustard, vinegar, and juices with no additives.

Specific Carbohydrate Diet (SCD)

High FODMAP

51

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.

Strategies to Change the Composition of Gut Microbiota: Use of Probiotics/Prebiotics.

Dysbiosis and IBS

53

Probiotics – Direct Consumption of Bacteria

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

54

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.

Probiotics – Direct Consumption of Bacteria

55

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

Metagenics Ultra Flora LGG

1x1010 per 100ml

1x1010 per capsule

L. plantarum 299V Ethical Nutrients IBS Support

Metagenics Probex

2 x 1010 per capsule

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

Bioceuticals SB Floractiv

5 x 109 per capsule

Not stated

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

COMMON PROBIOTICS

56

Smartphone Application: Probiotic Guide- Canada

57

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

True response rate in 20% patients

Whorwell et al. Am J Gastro 2006

B. Infantis 35624

58

VSL3# (multi-strain probiotic) restored the fecal-bifidobacterium.

However, gut symptom control was better on the low FODMAP diet.

Staudacher et al Gastroenterology 2017;153:936-947.

Low FODMAP Diet in IBS: Probiotic VSL3# restores Bifidobacterium

Bifidobacterium

59

Prebiotics/IBS– Encouraging the growth of your own gut bacteria

Ref Sample size Intervention Duration Results

Hunter et al. 1999

RCT; n=21 6g/d FOS 4 weeks No benefit

Olesen et al. 2000

RCT; n=96 20g/d FOS 14 weeks Worse symptoms at 4 weeks

Paineau et al. 2008

n=105 FBDwith mild symptoms

5g/d FOS 6 weeks • 43% reduced severity• 75% symptoms less

frequent• Discomfort increased

Silk et al. 2009

RCT; n=44 3.5g or 7g/d GOS 12 weeks Improvement in stool consistency, bloating, flatulence with 3.5g/d

Prebiotics in IBS

.

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

Rye bread (2 slices)Wholegrain wheat (2 slices)

Pasta (1 cup)Gnocchi ( 1 cup)

All Bran (1/2 cup)Weet-bix (2 biscuits)

Split peas (1/2 cup)Baked Beans (1/2 cup)

Red kidney beans (1/2 cup)Jerusalem artichoke ( 1)

Leek bulb (1/2 cup)Onion (1/2)

Garlic ( 1 clove)Peas (1/2 cup)

Watermelon (1 slice)Banana ( 1 fruit )

Persimmon (1 fruit)Grapefruit (1 medium)

Brea

ds, C

erea

ls,

Grai

nsLe

gum

esVe

geta

bles

Frui

t

g/serve

Dietary FibreResistant starchPrebiotic Fibre

Dietary sources of ‘prebiotics’.

Diets High in Natural Prebiotic Fibre –For Health

Resistant starch

Fructose/sorbitol/mannitol

• Wholegrains rye & barley

• Legumes• Banana, ripe

with green tips

Fructans (FOS, oligofructose,

inulin)

Galacto-oligosaccharides

• Wheat, rye, barley• Artichokes, garlic &

onion• Watermelon,

persimmon, nectarines, white peaches

• Cashews & pistachios

63

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 20156. Nagaran Eur J Gastroenterol Hepatol 2015

64

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 dietary fiber, RS and prebiotic fibres. Presents challenge in IBS patients – RS may be better tolerated.

Acknowledge:

65

Prof Peter GibsonDr Jane VarneyDr Marina IacovouDr Rebecca BurgellDr CK YaoDr Jaci BarrettDr Judy Moore

USA-Commercial Alan Greensmith

Postgraduate studentsPaul GillMary AjamianDaniel So

Research TechniciansAlex BogatyrevElizabeth LyNia & Jim Rosella

ITBala Natarajan

Research chefTrish Vietch

AdministrationAlly Heywood

Funding Sources:NHMRC, ARC linkage,Eva and Les Erdi Foundation, Menzies Foundation,Monash Low FODMAP appGeorge Weston Foods,Meat & Livestock AustraliaMGP IngredientsNestle Healthcare NutritionSanitarium .

Research DietitiansLyndal McNamaraErin DwyerShirley Webber

Monash Research Team

Presentation 3

Yogurt, Gut Microbiota andCardiometabolic Health

André MaretteLaval University, Québec, Canada

Annual Symposium on Nutrition and HealthDairy Farmers of Canada

Oct.31-Nov. 1, 2018

https://digestivehealthinstitute.org/fermentable-carbs-vs-fermented-foods/

DisclosureConsultation 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

Total yogurt = 3296Probiotic yogurt = 742Yogurt consumption = 977Yogurt and weight = 470Yogurt and health = 1015Microbiota and yogurt = 111

0

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Dairy Milk Cheese Yogurt

Mozaffarian D, et alN Engl J Med. 2011 364(25):2392-404.

MuscleLiverBrain

Adipose tissuePancreas

Dietaryproteins

Fermented dairyproducts

Natural sugarsand sweeteners

ω-3 and ω-6 PUFAs

Plant polyphenols

Metabolic, gastro-hepatic and cardiovascular benefits

Probiotics

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

Prebiotics

Bariatricsurgery

About our book

Compilation of scientific literature on yogurt and its roles in nutrition and health

Macronutrient profile of common yoghurts

Children aged 4-6 y

Children aged 7-11 y

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

Based on the dietary reference values for children from the British Nutrition Foundation and Public Health England Composition of foods integrated dataset

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

Yogurt contributes to intake of key nutrients at different age groups

05

101520253035404550

4-6 yo7-10 yo11-14 yo15-18 yo

• Excellent source of iodine, vitamin B12, phosphorus, calcium, riboflavin and thiamin for children and adolescents

• Source of folate, magnesium, potassium and selenium

• Concentrated source of nutrients for children

• Excellent vehicle for vitamin D fortification

Based on the dietary reference values for children from the British Nutrition Foundation and Public Health England Composition of foods integrated dataset of 100 g of low-fat fruit yogurt. (Fernandez et al. 2017)

%

Yogurt and Cardiometabolic Health

Obesity Type 2 diabetes Hypertension Cardiovascular

diseaseMetabolic syndrome

Cross-sectionalstudies √ √ √ √ √

Prospective cohort studies √ √ √ √ √

Meta-analyses(prospective

cohorts)None > 3 None ≥ 1 ≥ 1

Clinical studies Few None None Few None

Level of evidence Poor Strong† Poor Moderate Poor

Conclusions + + ? = ?

Level of evidence of the effects of yogurt on cardiometabolic diseases.

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 linksand identify mechanisms of action of yogurt action

Why yogurt consumption may reduce cardiometabolic diseases?

High quality proteingrowth and maintenance of muscle mass

Source of Ca, vitamin D and P contribute to bone health

Nutrient rich food profile contributes to intakes of essential nutrients for health

Lipids and lactose energy source

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

Source of bioactive lipids and proteins di- and tri-peptides, CLA, whey, medium-chain fatty acids that contribute to protection against cardiometabolic risk factors

Live cultures improve lactose tolerance, increase concentrations of some nutrients (eg. CLA and bioactive peptides)

Yogurt Fruits

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

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 thebasis 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 digestion

• Improved lactose tolerance• Low pH of yogurt – ideal for mineral absorbability

• Release bioactive molecules• Conjugated linoleic acid (CLA)• Lactate• Bioactive peptides• Exopolysaccharides

• Lactic acid bacteria • Antagonist behavior with other bacteria • Favors healthy gut microbiota

• Increase concentrations of oligosaccharides• Prebiotic

Marco et al. Current Opinion in Biotechnology 2017, 44:94–102

Fernandez ,…Marette.Adv Nutr Nov 15;8(6):812-829, 2017

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 benefitsof yogurt consumption on cardiometabolic diseases.

CollaboratorsUniversité Laval

Denis RoyYves Pouliot

Sylvie GauthierPatrick Mathieu

Agriculture/Agri-Food CanadaMartin LessardMylène Blais

Université de SherbrookeClaude Asselin

TransBioTechYvan Boutin

Students/PDFs/RAMélissa Fernandez

Éliane Picard-DelandNoémie Daniel

Lais Rossi PerazzaJose Luis M. Gonzalez

Michaël BouchardThibault Varin

Mélanie Le BarzGeneviève Pilon

Marie-Julie DuboisPhilippe St-Pierre

Christine DionChristine Dallaire

Valérie DumaisJoanie Dupont-Morissette

Partners

Presentation 4

Lactose Intolerance: Perceptions and Realities

Susan I. Barr, PhD, FDCProfessor 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 PYes No

Milk products & alternatives (svg/d) 1.40 ± 0.08 2.33 ± 0.03 <0.001Calcium supplement use (%) 52% 37% <0.001Calcium (milk products, fortified beverages, supplements; mg/d) 739 ± 30 893 ± 13 <0.001

Barr SI. Appl Physiol Nutr Metab 2013:38:830-835

Definitions

Definitions• Lactose: sugar in milk (galactose-glucose)• Lactase: enyzme that digests lactose• Lactase persistence:

• 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

HO O

CH2OH

OH

H

OH

H

H

OH

H

O

CH2OH

H

OH

H

H

OH

H

H

O

H

Lactase Small Intestinal Cell

Lactose

Lactose Digestion

HO O

CH2OH

OH

H

OH

H

H

OH

H

O

CH2OH

OH

H

OH

H

H

OH

H

H

H

Lactase Small Intestinal Cell

OH

Galactose Glucose

Lactose Digestion

HO O

CH2OH

OH

H

OH

H

H

OH

H

H

Lactase Small Intestinal Cell

O

CH2OH

H

OH

H

H

OH

HH

OH

Lactose Maldigestion

O

CH2OH

OH

H

OH

H

H

OH

H

O

CH2OH

H

OH

H

H

OH

HHO

H

O

H

Small Intestinal Cell

Lactose

Lactase

Lactose Maldigestion

OOO

Small Intestinal CellOO

O

OOO

OOO H2O

H2O

Lactose Maldigestion

ColonHydrogen (enters bloodstream; exhaled)

MethaneShort Chain Fatty Acids

enter bloodstream; used as fuelH2O H2O

**Substantial** amounts of undigested lactose

Water enters intestine to balance osmotic pressure

Undigested lactose reaches colon and is fermented by bacteria

Lactose Maldigestion and Intolerance

BLOATING

GAS PAIN

DIARRHEA

How is Lactose Intolerance Diagnosed?

Diagnosis: Breath Hydrogen• Overnight fast• Baseline breath hydrogen• Give lactose dose (often 25-50 g)• Monitor breath hydrogen every

30 min for 3-6 hr• Monitor symptoms

0

5

10

15

20

25

30

0 60 120 180

Hyd

roge

n (p

pm)

Time (min)

Lactose digester

Diagnosis: Breath Hydrogen• Overnight fast• Baseline breath hydrogen• Give lactose dose (often 25-50 g)• Monitor breath hydrogen every

30 min for 3-6 hr• Monitor symptoms• Increase in breath H2 of >20 ppm

= maldigestion• Maldigestion + symptoms

= intolerance

0

5

10

15

20

25

30

0 60 120 180

Time (min)Hy

drog

en (p

pm)

Lactose maldigester

Lactose digester

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)

Self-diagnosed54% (n=86)

Physician diagnosed42% (n=67)

Other health practitioner

4% (n=6)

Lovelace H, Barr SI. J Am Coll Nutr 2005;24(1):51.

How was Lactose Intolerance Diagnosed?

All Participants(n=159)

Self-diagnosed54% (n=86)

Physician diagnosed42% (n=67)

Other health practitioner

4% (n=6)

‘Valid’ testn=7 (2.5%)

Report of symptoms

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)

Suarez FL et al. N Engl J Med 1995;333:1-4

7 days of milk* with breakfast

7 days lactose-free milk with

breakfast

7 days lactose-free milk with

breakfast

7 days of milk* with breakfast

All

Week 1 Week 2

Monitored symptoms each day* Sweetener added so taste of milk and lactose-free milk were identical

Symptoms in Lactose Maldigesters (n=21)

0

1

2

3

4

5

Bloating Pain Diarrhea Flatus

LactoseNo lactose

Suarez FL et al. N Engl J Med 1995;333:1-4

Severe

Strong

Moderate

Mild

Trivial

None

Symptoms in Lactose Digesters (n=9)

0

1

2

3

4

5

Bloating Pain Diarrhea Flatus

LactoseNo lactose

Suarez FL et al. N Engl J Med 1995;333:1-4

Severe

Strong

Moderate

Mild

Trivial

None

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 Nutr1997; 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

0 2 4 6 8 10 12 14

Milk, 2%, 250 ml

Cheddar Cheese, 50 g

Ice Cream, 125 ml

Cream, 30 ml

Cottage Cheese, 125 ml

Yogurt, plain 2%, 175 ml

Lactose (g)

No Symptoms

Practical Suggestions

Dairy Products • Use smaller portions• Consume with a meal• Use milk products with less

lactose (e.g., hard cheese, yogurt) or lactose-free options

Non-Dairy Alternatives• Use products fortified with

calcium and vitamin D

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• Like undigested lactose, GOS enter colon

and are fermented by bacteria• Would providing increasing amounts of GOS

to lactose intolerant individuals:• Shift colonic bacterial metabolism?• Reduce symptoms after an oral lactose load?

GAL GLU

Lactose

GAL GAL

Galacto-oligosaccharide(GOS)

Savaiano DA et al. Nutrition Journal 2013; 12:160

Subjects and ProtocolSubjects• Lactose intolerant • 25 gm lactose load at baseline

showed maldigestion (breath hydrogen) and symptoms

• Assigned to GOS or placebo (corn syrup) for 35 d (dose increased from 1.5 – 15.0 g/d)

• Day 36: 25 g lactose tolerance test repeated (breath hydrogen and symptoms)

Baseline 25 g Lactose

Challenge

GOSLactose-free

diet

Corn syrupLactose-free

diet

Endline25 g Lactose

Challenge

Day 0

Savaiano DA et al. Nutrition Journal 2013; 12:160

Day 1-35 Day 36

Median Breath H2 after 25 g Lactose

0

20

40

60

80

100

0 1 2 3 4 5 6

Brea

th H

ydro

gen

(ppm

)

Time (hrs)

Day 0Day 36

0

20

40

60

80

100

0 1 2 3 4 5 6

Brea

th H

ydro

gen

(ppm

)

Time (hrs)

Day 0Day 36

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

P = 0.19

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)

• 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 = 0.73Savaiano DA et al. Nutrition Journal 2013; 12:160

GOS Placebo

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

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