Host Institution

Fonterra Probiotics: From guts to glory… James Dekker April 16, 2015

Probiotic bacteria

“Live micro-organisms which, when

administered in adequate amounts,

confer a health benefit on the host”

FAO/WHO Report (2001)

3

Why work on Probiotic bacteria?

Part of the human diet for millennia

Hygiene hypothesis / “old friends” hypothesis

Health benefits delivered via a food

Strong synergy with dairy fermentations

Probiotics currently worth NZ$ 54 Billion* (supplements, yoghurts, juice)

Expected to grown to NZ$ 73 Billion* by 2020

Probiotic infant formula to claim 76% Share of NZ$ 33 Billion market in 2024

* Euromoniter data, 2016

Some published health effects of probiotic bacteria…

Anti-IBD

Anti-

Ulcerative colitis disease Traveller’s

diarrhoea

Antibiotic- associated diarrhoea

Rotaviral infection

Immune

Improved Natural Killer cell function

Improved phagocyte

function

Adjuvant effects

Reduced antibiotic use

Th1/Th2

Comfort

Constipation

Bloating

Gut transit time

Intestinal pain

Anti- Allergy

Immune programming

Eczema

Hay fever

Growth/Nutrition

Otitis media

Salmonellosis

E. coli

Improved barrier function

Pouchitis

Bacteriocin production

Metabolic Syndrome

Function

Improved microecology

Iron status

Improved sub- optimal growth

IBS

Probiotics

Diarrhoea

Crohn’s

Immune

Treg function

balance

Gut Comfort

Constipation

Bloating

Gut transit time

Eczema

Hay fever

Growth/Nutrition Anti-infection

Salmonellosis

E. coli O157 - H7

Low gut pH

Lactose intolerance

Pouchitis

Bacteriocin production

Gut

Bone health IBS

NEC

Respiratory infections

Anxiety Diabetes

Anti-inflammatory

Obesity

Gut/Brain Axis

Mood

Anxiety

Fonterra probiotics

Fonterra probiotics

Bifidobacterium animalis subsp. lactis HN019 (DR10™)

Lactobacillus rhamnosus HN001 (DR20™)

• Demonstrated efficacy: • Immune protection & gut health benefits • Anti-pathogen effects (in animal models) • Improved colonic transit time in adults

(HN019) • Protects against respiratory disease in infants

(HN019) • Protects against eczema in infants (HN001)

• Halal & Kosher certified

• Patent Protected

• Well researched strains: • 70+ peer-reviewed publications • Health benefits in healthy

populations • Established safety record

• Stability/Applications

• Superior long-term survival in dry powders

• Reduced cost-in-use • Demonstrated survival of gut transit

Probiotic bacteria

“Live micro-organisms which, when

administered in adequate amounts,

confer a health benefit on the host”

FAO/WHO Report (2001)

• An ideal probiotic must be shown to be:

– Safe – show no adverse effects on the host

– Stable – reach the consumer in a live state and survive in the human gastrointestinal tract

– Effective – provide a positive health benefit to the host

Efficacy Safety

Stability

Ideal Probiotic

Safety

Safety HN019 HN001

Food origin Strain identification Do not activate platelets Do not degrade mucin No abnormal antibiotic resistance Lack of toxicity in animal models Do not exacerbate autoimmune disease Published genome sequence Not associated with adverse events in humans US FDA-notified GRAS

Efficacy

Immune biomarker studies

Natural Killer (NK) Cells Phagocytic cells

• NK cell activity and phagocytosis play vital “surveillance” roles, recognising pathogens & alerting the rest of the immune system

• When fed to humans, both HN019 and HN001 improved NK cell and phagocyte activity

• So what…?

Bifidobacterium animalis subsp. lactis HN019

“India trial”, HN019+GOS childhood morbidity trial

• Community-based, randomised, double-blind and placebo controlled study conducted by Prof Sunil Sazawal (Johns Hopkins University)

• Conducted at Sangam Vihar, New Delhi, India.

• Participants were 634 healthy children aged 1-3 years old, randomised to:

• Control group = fortified reconstituted milk

• Synbiotic group = fortified reconstituted milk with:

» HN019 (1.9X107 CFU/day)

» galactooligosaccharide (GOS) (2.4 g/day)

• Intervention period = daily for 12 months, with 12 month follow-up

• Incidence of early childhood morbidities, and parameters of growth and development monitored by trained medical personnel

HN019/GOS reduced measures of childhood illness

No. of episodes OR (95% CI) p value HN019+GOS

(n=312) Control (n=312)

Gastrointestinal morbidity Diarrhoea episodes (1–4 y) 1641 1697 0.94 (0.88–1.01) 0.08

≤ 2 years mo 603 563 0.99 (0.89–1.11) 0.91

> 2 years 1038 1134 0.90 (0.83–0.98) 0.02

Dysentery episodes 125 154 0.79 (0.62–1.00) 0.05

Respiratory morbidity Pneumonia episodes 90 115 0.76 (0.58–1.00) 0.05

Severe ALRI episodes* 34 51 0.65 (0.42–1.00) 0.05

Febrile illness and others Days with severe illness 473 550 0.84 (0.74–0.95) 0.004

Days with ear discharge 1550 1613 0.93 (0.87–1.00) 0.06

Days with high fever 2798 2865 0.95 (0.90–1.00) 0.05

Measles 5 10 0.49 (0.17–1.42) 0.19 Doses of antibiotics

consumed 7402 7625 0.94 (0.91–0.97) 0.001

* ALRI = acute lower respiratory infection Sazawal et al (2010), PLOS One, 5:e12164

HN019+GOS improved iron status

HN019+GOS (n=230) Control (n=213)

Sazawal et al (2010), J Pediatr Gastroenterol Nutr. 51:341-6.

*OR = 0.55, 95% CI = 0.35 – 0.89)

0

10

20

30

40

50

60

Anaemic Iron deficient

Anaemic and iron deficient

p = 0.09

p = 0.08

p = 0.01

%

*

Children in treatment group showed statistically significant improvement in general health parameters:

• Protection against respiratory disease (35%)

• Protection against dysentery (22%)

• Protection severe illnesses (non diarrhoeal) (16%)

• Protection against sickness with high temperature (febrile illness) (32%)

• Protection against ear infection (7%)

• Decreased antibiotic use (6%)

• Improved growth (growth rates closer to WHO standards)

• Clinically-meaningful reduction in iron deficiency anaemia

HN019 & GOS trial: Key findings

Sazawal et al (2010), PLOS One, 5:e12164; Sazawal et al (2010), J Pediatr Gastroenterol Nutr. 51:341-6

HN019 for Gut Comfort

It hurts!

HN019 and colonic transit time (CTT) in healthy adults

• Average CTT for a healthy individual is 18 – 72 h • Variable or abnormal CTT is associated with

gastrointestinal ill-health, pain, or discomfort • Constipation is one of the most common digestive

complaints

• Placebo-controlled double-blind clinical trial on healthy adults with mild GI symptoms in USA

– Placebo control group (n=33) – High-dose HN019 (1010 CFU/day) (n=34) – Low=dose HN019 (109 CFU/day) (n=33)

• Subjects treated for 14 days • CTT assessed using radio-opaque beads • Also examined frequency of digestive

discomfort symptoms

Waller et al (2011) Scan. J. Gastro.

HN019 improved gut transit in a dose-dependent manner:

Treatment baseline CTT post-treatment CTT P value

High HN019 49 ± 30 h 21 ± 32 h <0.001

Low HN019 60 ± 33 h 41 ± 39 h 0.01

Placebo 43 ± 31 h 44 ± 33 h n.s.

Waller et al (2011) Scan. J. Gastro.

Change in Gastrointestinal Symptom Severity after 14 Days Supplementation with HN019 or Placebo:

Symptom

High Dose HN019 (n=33)

Low dose HN019 (n=26)

Placebo (n=29)

Vomiting - 17% * - 12% - 2%

Regurgitation - 24% * - 20% * - 5%

Gurgling - 16% * - 31% ‡ - 7%

Nausea - 23% † - 22% † - 7%

Abdominal pain - 27% † - 35% ‡ - 12%

Diarrhea - 6% 0% -17% * Flatulence - 15% * - 19% * - 8%

Constipation - 29% ‡ - 32% ‡ -15% * Irregular bowel movements - 20% † - 25% † - 11%

*p<0.05

†p<0.01

‡p<0.001

HN019 improved GI symptoms

Waller et al (2011) Scan. J. Gastro.

Lactobacillus rhamnosus HN001

“Wellington eczema trial”

• Double blind randomized placebo-controlled trial that examined the onset of eczema in infants at risk of allergic disease supplemented with HN001 (6x109 CFU/day), HN019 (9x109 CFU/day), or placebo

• Around 150 mothers/infants per group • Maternal supplementation = daily, from 35 weeks gestation

until 6 months if breastfeeding • Infant supplementation = daily, from birth until 2 years. • Primary outcome = onset of eczema

Effect of HN001 and HN019 on Eczema at 6 years

Placebo HN019 HN001

Treatment Period

0

20

40

60

0 2 4 6

% Eczema

Year

Cumulative eczema prevalence

Wickens et al, Clin Exp Allergy, 2013, 43:1048-1057

Stability

Stability

Water Activity

Storage temp.

(°C)

34 32 30 28 26 24

0.12 0.13 0.14 0.15 0.16 0.17 0.18 0.19 0.20 0.21 0.22

HN019

Probiotic “A”

(Indicative data only)

Conclusions 1 What is research for? • What can it do? What’s the health benefit?

• Is it safe? • Are you sure??? • Will it work in our products? At a cost-effective dose? • What do we have to show so that we can say what we are

allowed to say? • What is an acceptable level of proof? • How does it work? What’s the reason to believe? • New news = what can we say and when?

Conclusions 2

Same species, different properties...

• All probiotics are not equal!

• Specific probiotic strains have specific health benefits