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Lotta Stenman, PhD

Senior Scientist

DuPont Nutrition & Health

Novel, gut microbiota –targeted solutions for healthy body weight and metabolism

VITAFOODS EUROPE, GENEVA

May 10, 2016

Outline

Probiotics

• Consumer relevance

• Role of probiotics, prebiotics and synbiotics in health

Evidence from preclinical studies to support role of gut microbiota for

Metabolic Syndrome

New research demonstrating role of probiotics & synbiotics

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Consumers seeking products with probiotics

• 45% of people indicate that they are actively buying products to improve their

general health and wellbeing; 92% say they are interested in purchasing such

products

• 40% indicate they are actively buying products to improve their immune system;

88% say they are interested in purchasing such products

• 39% indicate they are actively buying products to improve their digestive health; 87%

say they are interested in purchasing such products

Datamonitor; Health & Wellness Trends in Food & Drink, 2013

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103 110 125

141

185

0

50

100

150

200

2011 2012 2013 2014 2015

Probiotic New Product Launches

Consumer awareness is increasing, as are clinical studies,

resulting in product launch increases.

Consumer Acceptance of Probiotics Continues to Grow

0

500

1 000

1 500

2 000US National Library of Medicine Clinical

Studies Brands are driving this awareness through high growth in

clinical studies to validate probiotics usage.

• From 9 studies in 1995 to >1,500 in 2015

• Twice as many studies in 2015 compared to 2007

0%

20%

40%

60%

80%

100%

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Consum

er

Aw

are

ness

(Dots

)

Google

Tre

nd Index

(Lin

e)

Rapidly Growing Awareness and Searching

Consumers are increasingly aware and searching for

Probiotics

• Global Google Trends show 5X in the last decade.

• Double in the last 3 years

• More than half of NAFTA and Europe consumers are

aware of probiotics

Source: Google Trends, Natural Marketing Institute, US NIH, Mintel

Resulting in brands increasingly launching more

products annually.

• 16% annual increase since 2011 – 31% increase from

2014-15

Variety of ways to support the microbiota within us

Ad

ap

ted

fro

m N

atu

re (

20

06

) 4

44

(21

): 1

00

9

Probiotics Prebiotics

Synbiotics

Synergistic mixture of prebiotics & probiotics

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Richness of human gut microbiome correlates with

metabolic markers

Le Chatelier et al. Nature 500, 541–546 (2013) doi:10.1038/nature12506

- Impaired glucose metabolism

- Impaired lipid metabolism

- Increased body fat mass

- Chronic, low-grade inflammation

Distribution of low and high gene count individuals (n = 292).

• This study depicts human gut

microbial composition in a

population sample of 123 non-

obese and 169 obese Danish

individuals.

• The two groups of

individuals differ by the

number of gut microbial

genes and thus gut

bacterial richness.

• Obese individuals among the

lower bacterial richness

group also gain more weight

over time.

7

More ’mouths’ to feed, yet more energy available

Bäckhed et al 2004

Germ-free mice eat more but gain less weight

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Germ

fre

e m

ice

- B

od

y w

eig

ht

%

Donor Lean Obese

Turnbaugh et al. Nature (2006) 444: 1027

Gut microbiota and metabolic health – causal evidence

Vrieze et al. Gastroenterol (2012) 143:913

Gut microbiota as key regulator for Metabolic Disease: hypothesis

Modern

lifestyle, including high

fat diet & low

activity Increased

intestinal

permeability Microbial

componenets

LPS entering

the circulation Tissue

inflammation

Metabolic

Syndrome, Type

2 diabetes

Probiotics and prebiotics:

can this be reversed?

Systemic

complications

Insulin

resistance

2007

Cell culture study:

B420 improves epithelial barrier

function

2008-2013

Mouse studies:

B420 improves metabolic health and gut barrier function

2013-2016

Mouse studies:

Collaborations on B420 and/or Litesse

Ultra

2013-2016

Clinical study:

B420 with or without Litesse Ultra for

weight management

DuPont Research Pipeline for metabolic health: probiotics (B420),

prebiotics and synbiotics (B420 + Litesse Ultra)

Putaala et al. Res

Microbiol 2008

Amar et al. EMBO Mol

Med 2011

Stenman et al. Benef

Microbes 2014

Stenman et al. Diabetol

Metab Syndr 2015

Garidou et al. Cell Metab

2015

B420 supernatant

improves epithelial

integrity

in Caco-2 cells.

B420 ameliorates

weight gain in diet

–induced obese

mice, reducing fat

but not lean mass;

improves glucose

tolerance in HFD-

fed mice.

Microbiota of the

ileum regulates

cell homeostasis

in the small

intestine and can

determine the

outcome of

metabolic

disease.

https://clinicaltrials.gov/ct2/s

how/NCT01978691

Stenman et al. Benef Microbes 2014

B420 reduces fat mass, but

not lean mass

Echo MRI after 6 weeks of treatment

weig

ht

(g)

B420 ameliorates weight gain

Obesity model

Chronic treatment with B420 reduces body weight

gain and fat mass accumulation.

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B420 reduces metabolic endotoxemia and adipose tissue

inflammation in mice

0

1

2

3

4

5

6

7

Plasma LPS

(EU/ml)

NC Vehicle B420

a

b

a

High-fat diet

Plasma LPS (EU/ml)

Stenman et al. . Benef Microbes 2014 Amar et al. EMBO Mol Med 2011

The Gut Microbiota Regulates Intestinal

CD4 T Cells Expressing RORγt and

Controls Metabolic Disease

Garidou L, et al. Cell Metabolism. 22(1), 100–112, 2015.

Germ-free mice:

B420 and Litesse positively

modulate the gut microbiota

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B420 and Litesse

restore small intestinal T lymphocyte populations in mice

Garidou et al. Cell Metabolism 2015

TH17 Treg TH1

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Germ-free mice:

B420 and Litesse positively modulate the gut microbiota

Garidou et al. Cell Metabolism 2015

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Germ-free mice:

B420 and Litesse positively modulate the gut microbiota

Garidou et al. Cell Metabolism 2015

TH17 Treg TH1 TH17

HFD-induced Type 2 diabetes decreases the number of

ileum IL17/RORγt CD4 T cells, the reduction of which seems

to confer some of the adverse effects of a high-fat diet

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B420 and Litesse

restore adipose tissue microbiota in mice on a high-fat diet

Garidou et al. Cell Metabolism 2015

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2007

Cell culture study:

B420 improves epithelial barrier

function

2008-2013

Mouse studies:

B420 improves metabolic health and gut barrier function

2013-2016

Mouse studies:

Collaborations on B420 and/or Litesse

Ultra

2013-2016

Clinical study:

B420 with or without Litesse Ultra for

weight management

DuPont Research Pipeline for metabolic health: probiotics

(B420) and synbiotics (B420 + Litesse Ultra)

Putaala et al. Res

Microbiol 2008

Amar et al. EMBO

Mol Med 2011

Stenman et al. Benef

Microbes 2014

Stenman et al. Diabetol

Metab Syndr 2015

Garidou et al. Cell

Metab 2015

On-going work

Manuscript in

development

Researc

h

Pu

blicati

on

s

Preclinical studies have shown that weight gain and insulin resistance may

be prevented by oral administration of the

probiotic Bifidobacterium animalis ssp. lactis 420.

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Randomized controlled trial: Probiotic with or without fiber

modulates body fat mass, in overweight and obese adults

Purpose: investigate the effects of these products,

individually and combined, on change in body fat mass in a

double-blind, randomized, placebo-controlled intervention

trial.

Conducted at four research clinics in southern Finland.

Supplement provided once per day for six months.

Good Clinical Practice – a benchmark for the food industry i.e. harmonized rules for conducting clinical studies worldwide

Consistent with the Declaration of Helsinki Regulatory pressure to move

towards ICH-GCP Food industry to become more ”pharma-like” and supporting:

Improved safety of participants

Proper documentation of studies

Reduces the risk of bias

Recording of Adverse Events

Complete reporting of data and practices for their analysis (Intention-to-

Treat and Per Protocol populations)

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Aim: Test the effect of separate or combined

supplementation of probiotic (Bifidobacterium lactis

420) and polydextrose on body fat mass

• Randomized, double-blind, multi-center, parallel design

• Study design and execution follows GCP guidelines

• N = 225 in total (56 per arm), drop-out rate 18 %

• BMI 28-34.9, otherwise healthy

1 month

Follow

-up

NCT01978691

Placebo: microcrystalline cellulose (MCC)

Probiotic: B420 + MCC

Prebiotic: Litesse® Ultra polydextrose

Synbiotic: Litesse® Ultra + B420

Baseline 6 months

Investigational products

(once per day)

• Placebo

12 g microcrystalline

cellulose

•B420

12 g microcrystalline

cellulose

1010 CFU/day B. lactis

420

• Litesse Ultra

12 g Litesse® Ultra

polydextrose

• Litesse Ultra + B420

12 g Litesse® Ultra

polydextrose

1010 CFU/day B.

lactis 420

130

kcal/

day

Stenman et al. Unpublished data

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Metabolic Syndrome clinical study team

Principal Investigator

Prof. Aila Rissanen, PhD

CRO: Smerud

Yvonne Peltonen, PM

Pia Brandt, sCRA

Nils Meland, Statistician

Alexandra Pölzl, Data manager

Hilde Kloster-Smerud, PhD

Study sites:

VL-Medi Oy

PI: Dan Apter, PhD

CRST

PI: Mika Scheinin, PhD

FinnMedi Oy

PI: Marja-Leena Lähdeaho, PhD

Kerava Health Centre

PI: Juri Linros

DuPont study management

team:

Lotta Stenman, PhD

Sampo Lahtinen, PhD

Markus Lehtinen, PhD

Anneli Tarpila, PhD

Investigational Product

manufacturing and QC:

Tad Stewart

Angela Paulsen

Sample analysis team at

DuPont:

Jaana Larsson-Leskelä

Sari Pohjola

Henri Ahokoski

Kirsi Stenström

Anna Lyra, PhD

Markku Saarinen

Rie Tofte

LPS analyses (Vaiomer S.A.S.):

Jeffrey Christensen, PhD

Michael Courtney, PhD

Rémy Burcelin, PhD

Metabolomics :

Henrik Max Jensen, PhD

Christian Clement Yde, PhD

Santosh Lamichhane

Food diary data extraction:

Auli Väänänen

Tiina Roine

Gut microbiota sequencing:

Buffy Stahl, PhD

Ashley Hibberd

Wesley Morovic

Bryan-James Zabel

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