OF THE HEALTH BENEFITS OF FOOD INGREDIENTS TO SUPPORT RESISTANCE - - PowerPoint PPT Presentation

TAKING UP THE CHALLENGE FOR SUBSTANTIATION OF THE HEALTH BENEFITS OF FOOD INGREDIENTS TO SUPPORT RESISTANCE AGAINST INFECTION

11-12-2019

Anita Hartog, Senior Scientist Nutrition & Health

Anita.Hartog@nizo.com

Potentially relevant company or other financial relationships:

• NIZO is a Contract Research Organisation for food and health
• We collaborate with …

CONFLICT OF INTEREST

• Independent, privately owned Contract Research

Organisation for food and health

• HQ in Ede, The Netherlands (Food Valley)
• Founded in 1948; 100 professionals

Application & Processing Centre Research Center

NIZO - FOR BETTER FOOD & HEALTH

TRACK RECORD

100 professionals

at NIZO

9 of the global top 10

Dairy Companies

The global top 5

Infant & Clinical

companies

6 of the global top 10

Ingredient companies

6 of the global top 10

Consumer goods companies

6 of the global top 10

Personal care companies Number of publications

• n average

per year 60 Number of consortia

• n average

5-10 per year

17 General labs

16 BSL-I labs* 4 BSL-II labs* 5 Food grade labs

*also for GMOs

Nutrition & Health

INFECTIOUS DISEASES: AMONG THE TOP 10 GLOBAL CAUSES OF DEATH

THE YOUNG AND THE OLD: IMMUNE COMPROMISED

Immune immaturity Immunosenescence

Simon AK et al. Proc. R. Soc. B 2015;282: 20143085.

• Potential targets for nutritional support of resistance against infection:
• General health status:
• Adequate nutritional status
• Immune system:
• General immune response
• Immune response induced by infection
• Direct anti-pathogenic:
• Reduced adhesion/invasion of pathogens
• Anti-microbial activity
• Microbiota community:
• Adequate diversity
• Adequate composition

NUTRITION CAN SUPPORT RESISTANCE AGAINST INFECTION

Plant ingredients Vitamins Milk components Dietary fibers

Health claims on foods are aimed at maintenance and improvement of health. EFSA claims on the immune system, the gastrointestinal tract, and defence against pathogens (EFSA NDA panel*):

FOOD INGREDIENTS WITH APPROVED HEALTH CLAIM

* EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2016;14(1):4369. Immune function: Vitamins: A, B6, B9, B12, C, D Minerals: Zn, Cu, Fe, Se Bowel function/ defecation: Chicory inulin, dried plums, rye fibre, lactitol, wheat and

• at and barley bran fibre

Absorption of micronutrients: Vitamins: C (Fe absorption)

• Literature:
• Ingredients with known mechanisms of action
• Use smart in silico tools; text mining to identify new candidates
• In vitro models: medium-high throughput screening
• Human cell-lines:

✓Gut/skin/lung epithelial cells: barrier function, pathogen adhesion, modulation of inflammation ✓Immune cells: support of immune function, modulation of systemic inflammation

• Micro-models of microbial communities

✓Support of healthy gut microbiota composition and function

IDENTIFICATION OF NEW FOOD INGREDIENTS WITH A POTENTIAL HEALTH BENEFIT RELATED TO INFECTION RESISTANCE

PROBLEM How to translate in vitro effects to a health benefit in healthy subjects?

• Gap between in vitro/animal models and field studies creates high attrition rate

High Attrition Rate

Data Driven Decision

• Human Challenge Models (HCM) as Proof of Concept (PoC) to enhance the efficacy of

health research

in vitro assays (HT, HC, mechanism) Human Challenge Model (Proof of Concept in Human)

Field trial (claim support in target population)

Animal models? Human Challenge Model (Proof of Concept in Human)

Appropriate outcome measures

• Number of episodes and severity or duration of infection. Establish infectious

nature of the disease: 1. By clinical diagnosis 2. By use of validated questionnaires for self-reported data 3. By microbiological data depending on the type of the infection

• Reduction of the presence of specific pathogens, their toxins or other

virulence factors. Justify relevance: 1. By the magnitude of reduction or 2. By evidence of a reduction in clinical outcomes related to infection accompanying the reduction in pathogens/toxins

FUNCTION CLAIMS FOR DEFENSE AGAINST PATHOGENS

* EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2016;14(1):4369.

• Health has always been regarded as the

absence of disease.

• Health can also be defined as:

the body’s ability to adapt to changing circumstances and to show sufficient resilience under conditions of social, physical and emotional disturbance (challenge) to which we are exposed from time to time.

WHAT IS HEALTH?

Huber M. et al, BMJ. 2011;343:d4163

• Human Challenge Models (HCM): based on “health is the ability to adapt”
• Challenge = applying a stressor to healthy people and measure resilience to this stress
• Examples: pathogens, vaccination, high calorie meal, prescription drugs

HOW TO DEMONSTRATE A HEALTH BENEFIT IN HEALTHY SUBJECTS?

Subject 1 Subject 2

Stressor / Challenge

Subject 1 Subject 2

Both apparently healthy

Dietary intervention Hardly any change Dietary intervention Measurable change

• Healthy subjects - Health claims on foods are aimed at

maintenance and improvement of health

• Effect size - Stress resilience is a more sensitive marker of health

than steady state markers

• Controlled stress exposure
• Limited number of study subjects
• Limited study duration

WHY CHALLENGE MODELS?

NIZO CHALLENGE MODELS FOR INFECTION RESISTANCE

• Diarrheagenic E. coli challenge*
• Challenge: E. coli E1392/75-2A
• Outcomes: Gastro-intestinal symptoms, Bristol Stool Score,

stool frequency, % of fecal wet weight

• Vaccination**
• Challenge: Oral cholera vaccine, parenteral hepatitis B vaccine
• Outcomes: Vaccine-specific IgA, IgG, % responders
• Rhinovirus challenge***
• Challenge: HRV-16
• Outcomes: Common cold symptoms & viral load

*Bovee-Oudenhoven et al. Gastroenterology 2003;125(2):469-76., *Ten Bruggencate et al. J Nutr. 2016;146(2):249-55., **Van Splunter et al. Mucosal Immunol 2018;11(4):1254-64., ***Koch et al. PLoS One 2018;13(2):e0191937. & ***Turner et al. Benef Microbes. 2017;8(2):207-15

• E. coli: most common bacterial cause of diarrhea in adults and children in developing countries
• Major cause of traveller’s diarrhea
• 78 different O serotypes, 34 different H serotypes
• O6:H16 belongs to the most commen serotype
• Most prevalent colonization factors (90%): CFA/I, CFA/II, CFA/IV

DIARRHEAGENIC E. COLI CHALLENGE

Petri WA Jr et al. J Clin Invest. 2008;118(4):1277-90

Healthy men, 18-55yr, n=30-40 per arm 28 days: two weeks run-in, one inoculation; or 49 days: two weeks run-in, two inoculations Restrictions on calcium, alcohol, medicine

• E. coli inoculation (1E10 CFU) at day 14 (and day 35);

Stool consistency, stool frequency, quality of life, appetite, adverse events, compliance Diarrhoea, inflammation, pathogen persistence before and after challenge Inflammation & immunity before and after challenge: CRP, IP-10, serum IgA/IgG

STUDY DESIGN E. COLI CHALLENGE

Van Hoffen et al. Manuscript submitted for publication

• Increased total fecal output, relative fecal wet weight
• Increased stool frequency, increased Bristol Stool Scale
• Increased gastrointestinal complaints (Gastrointestinal Symptom Rating Scale)

OUTCOMES

• E. COLI INFECTION INDUCES DIARRHEA

11 14 17 20 60 70 80 90 100 100 200 300 400 500 32

Total fecal wet weight (g/day)

Total fecal wet weight % Fecal wet weight infection

Study day Percentage fecal wet weight

11 14 17 20 1 2 3 4 5 6 7 32 10 20 30

Bristol Stool Score GSRS infection

Study day Max Bristol Stool Score GSRS total daily score Van Hoffen et al. Manuscript Submitted for publication

• Increased fecal calprotectin
• Increased serum CRP and IP-10
• Increased circulating neutrophils

OUTCOMES

• E. COLI INFECTION INDUCES TRANSIENT INFLAMMATION

13 15 21 34 10 1.5 10 2.0 10 2.5 10 3.0

Study day Fecal calprotectin (µg/g dry)

10 15 17 28 10 0 10 1 10 2 10 3 10 4

Study day Serum C-reactive protein (µg/L)

1 2 3 4 10 2.0 10 2.5 10 3.0 10 3.5

10 15 17 31

Study day Serum IP-10 (pg/mL)

10 15 31 0.0 2.0 4.0 6.0 8.0

Study day Blood neutrophils (*1E9 cells/liter)

• Increased fecal CFA/II specific sIgA
• Increased serum CFA/II specific IgG

OUTCOMES

• E. COLI INFECTION INDUCES ANTIBODIES SPECIFIC FOR E. COLI CFA/II

13 34 0.0 0.5 1.0 1.5 2.0

Study day Fecal sIgA-CFA/II (AU/mg dry)

10 28 10 0 10 1 10 2 10 3 10 4

Study day Serum IgG-CFA/II (AU/mL)

Intervention studies with food ingredients Milk calcium*:

• % of faecal wet weight decreased on day 2

after infection Milk fat**:

• Decreased symptoms on day 2 after infection:
• Stool frequency
• Gastro-intestinal symptoms (GSRS)

Probiotics***:

• Not effective in 2 studies
• Due to anti-inflammatory effect?
• E. COLI CHALLENGE MODEL: DIETARY INTERVENTIONS

*Bovee-Oudenhoven et al. Gastroenterology 2003;125(2):469-76. **Ten Bruggencate et al. J Nutr. 2016;146(2):249-55. ***Ouwehand et al. B J Nutr 2014;111(3):465-73, Ten Bruggencate et al. Eur J Clin Nutr. 2015;69(3):385-91.

ARE CHALLENGE MODELS: FEASIBLE IN THE YOUNG AND THE OLD?

Ethics Risks Biological readouts Logistics

• Infants: only if no impact on health, using non-invasive procedures (unless required for
• ther/medical reasons e.g. vaccination program)
• Elderly: only if no (major) impact on health, including healthy elderly, taking vulnerability into

account

• Think about mechanism of action of functional ingredients:
• Generic mechanism for young and old?
• Gaps regarding immune mechanism?
• Readouts relevant for young and old?

HOW TO TRANSLATE CHALLENGE OUTCOMES IN THE HEALTHY TO THE YOUNG AND THE OLD?

• Nutrition can play an important role in support of infection resistance
• Health claim approval is not easy:
• Requires dedicated and thorough dossier building
• Well-established mechanism of action
• Clinical evidence in relevant models and well-designed studies
• Human challenge models:
• Valuable tool to bridge the gap between preclinical evidence and field trials

CONCLUSIONS

NIZO

• Alwine Kardinaal
• Els van Hoffen
• Sandra ten Bruggencate
• Esther Floris
• Joyce Schloesser
• Maartje van den Belt
• Elly Lucas
• Petra Scholten
• Rianne Ruijschop
• Sabina Lukovac

ACKNOWLEDGEMENTS

Wageningen University & Research

• Michiel Kleerebezem (HMI)
• Jerry Wells (HMI)
• Marloes van Splunter (CBI)
• Joost van Neerven (CBI)
• Henriette Fick (HNE)

Amsterdam Medical Centre

• René Lutter
• Annemarie Teitsma-Jansen
• Saeeda Lone-Latif
• Yanaika Sabogal Pineros
• Barbara Smids
• Tamara Dekker

Do you want to know more? Please contact Ger Hartman: +31 (0)6 251 228 37 Ger.Hartman@nizo.com

CONTACT INFORMATION

THANK YOU FOR YOUR ATTENTION