developing a gut health solution requires a new holistic approach
TRANSCRIPT
August 24, 2015
Developing a gut health solutionrequires a new holistic approachArie K. Kies
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Why are we interested?• DSM: technical solid company; lots of nutrition
knowledge• We want to strengthen support to customers further
Providing solutions according to their needs Through bright science
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• Reducing use of antibiotics (improving gut health)• …
Problems of customers?
Focus within poultry-feed industry:
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State of affairs• Efficacy AGP• Risks• Effect of termination • Research (opportunities)
– Genomics– Immune modulation
• Alternatives– Pre- and probiotics– Acids– Enzymes– Botanicals– Bacteriophages
2005
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State of affairs2015
• Research – Genomics– Immune modulation– Microbiomics
• Alternatives– Pre- and probiotics– Acids– Enzymes– Botanicals– Bacteriophages?
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State of affairs
• Little progress – Reducing AGP’s– Improving gut health
• Do we look to the right things?
A different angle is required
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Approach so far“AGP alternatives are being sought to improve health, immune status and performance in animal agriculture.”
“Most AGP alternatives try to prevent proliferation of pathogenic bacteria and modulate indigenous bacteria so that the health, immune status and performance are improved.”
“While the industry is focused on developing solutions that work similarly, AGPs' exact mode of action is not yet fully understood.”
Mallo, Feed International, 2015
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Approach so far“AGP alternatives are being sought to improve health, immune status and performance in animal agriculture.”
“Most AGP alternatives try to prevent proliferation of pathogenic bacteria and modulate indigenous bacteria so that the health, immune status and performance are improved.”
“While the industry is focused on developing solutions that work similarly, AGPs' exact mode of action is not yet fully understood.”
Mallo, Feed International, 2015
Why?
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Approach so far“AGP alternatives are being sought to improve health, immune status and performance in animal agriculture.”
“Most AGP alternatives try to prevent proliferation of pathogenic bacteria and modulate indigenous bacteria so that the health, immune status and performance are improved.”
“While the industry is focused on developing solutions that work similarly, AGPs' exact mode of action is not yet fully understood.”
Mallo, Feed International, 2015
Why?Possible?
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Approach so far“AGP alternatives are being sought to improve health, immune status and performance in animal agriculture.”
“Most AGP alternatives try to prevent proliferation of pathogenic bacteria and modulate indigenous bacteria so that the health, immune status and performance are improved.”
“While the industry is focused on developing solutions that work similarly, AGPs' exact mode of action is not yet fully understood.”
Mallo, Feed International, 2015
Possible?
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Mode of action of AGP’s?• How to explain consistent positive effect of AGP’s?
• Still consistent in modern diets?• Do we know what we are looking for??
Change in – microbial population?– microbial activity?– development intestine?
• AGP’s are not strain-specific• AGP’s are usually dosed below MIC
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Mode of action of AGP’s?AGP’s are not strain-specificExample Avilamycin (MIC90-values)Clostridium spp. (+) 8 (µg/ml)Bifidobacterium spp. (+) 32Lactobacillus spp. (+) > 128E. Coli (-) > 128Bacteroides fragilis (-) 32 (normally commensal)Enterococcus spp. (+) 4 (lactobacilli-order)
FDA, 2015
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Mode of action of AGP’s?AGP’s usually dosed below MICAgain Avilamycin as example
- Max. dose allowed in feed was 10 ppm- Assume 5-10* dilution in small intestine concentration (max.) 1-2 µg/ml
[MIC90 Clostridiae: 8 µg/ml]Specificity and MIC90-values alternatives? Place (in g.i.t.) of activity?
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Mode of action of AGP’s?
Koopman, 1999
A balanced, stable microflora protects against pathogensNumber Salmonellae/g fresh
feces
Problem not pathogens but dysbiosis
- Germfree mice- Measured with culturing
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Gastrointestinal Microbes of chickens
Schokker, unpublished
Microflora is dynamic. Effect of age:
Enterobacteriaceae (Escherichia, …)Enterococceae (Lactobacilli)
ClostridiaceaeLactobacilaceaeStreptococcaceae
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Gastrointestinal Microbes of chickens
Schokker, unpublished
Microflora is dynamic. Effect of age:
Enterobacteriaceae (Escherichia, …)Enterococceae (Lactobacilli)
ClostridiaceaeLactobacilaceaeStreptococcaceae
Need to develop balanced gut ecosystem May vary in time!
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Gut health solutionImproving gut health more consistently: - Last 10 years products developed that aid
overcoming the “AGP-gap”- Lack of consistent improvement in many products- Wet litter is still a recurrent issue- Despite a lot of (scientific) work
- Too little progress made- (Too) little interdisciplinary research
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Gut health solutionImproving gut health more consistently:
How to go on?
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Gut health solutionImproving gut health more consistently:
Holistic approach
Gut health: - A complex system- A complex problem- Many different angles; different competences
Input from different disciplines required!
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Gut health solutionA complex system -- interactions within the gut
Nutrition
Management, Environment, Genotype
Excretion
Nutrient utilization Immune competence
Performance
gutnutrition genotyp
e
microbiota
From: Smits, 2013
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Gut health solutionImproving gut health more consistently: Holistic approach (farm perspective)
• Farm management• Genetics• Quality day-old chicks• Feed
- Feeding schedule- Quantity- Form (particle size; mash vs. pellets)- Composition (feedstuffs, level)- Additives
• … Specific solution required per farm / company!
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Gut health solutionForm (particle size; mash vs. pellets)
But: caecal microbial diversity lower …
Day 0 - 34 Fine
Coarse
Feed Intake (g/b) 2991
3144
BW gain (g/b) 1730
1877
Water intake (g/b) 5445
5305
Gizzard weight (g/100 g BW)
1.36 1.60
Villus height (µm) 1517
1840
Crypt depth (µm) 292 230
Qaisrani et al., Poultry Sci. 2014; Qaisrani, 2014
RSM-based diet (‘badly’ digestible protein; different levels)
2 studies
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Gut health solutionAdditives
• “… Vitamin A in the womb determines … life-long immunity”• “… immune health in adulthood can be preset by nutritional
status during fetal life”
Bird, Nature Rev. Immunol., 2014
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Gut health solutionAdditives
Brown et al., Immunity, 2015
“- Retinoic acid (RA) stabilizes Th1 fate commitment - RA-RAR prevents development of pathogenic Th17 cells in vivo”
“Good”
“Bad”
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Gut health solutionImproving gut health more consistently: Holistic approach (scientific disciplines
perspective)• Animal nutrition• Human nutrition• Veterinary science• Human medical sciences
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Human medical sciences?- Clostridium perfringens Necrotic enteritis- Aetiology similar to C. difficile in humans
• Organism itself: non-invasive• Since 2000 dramatic increase severe cases (2/3 hospital
acquired)– “Most important risk factor for C. difficile infection remains
antibiotic use” [!!]– “Minimizing antibiotics use reduced infection rate by 77% (in a
450-bed hospital, Scotland)”– Treatment: antibiotics – Prevention probiotics? “… not recommended [at this moment]”,
but: “fecal microbiota transplantation seems very promising”
Leffler and Lamont, NEJM 2015
PageVan Nood et al., NEJM 2013
Human medical sciences?Fecal microbiota transplantation
Rates of cure:Patients without relapse for recurrent Clostridium difficile infectionAlso microbiota diversity increased dramatically by fecal transplantation
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Gut health solutionImproving gut health more consistently: Holistic approach (scientific perspective)
• Nutrition– Protein, energy, …
• Feed technology– Milling, pelleting, extrusion, …
• Physiology– Digestion, utilization, …
• Immunology– Immune competence, inflammation, …
• Microbiology– Strains, numbers, …
• “Omics”– Genomics, microbiomics, metabolomics, …
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Gut health solutionPractice: reducing protein often effectiveBut protein is required
Wijtten et al., Poultry Sci., 2004
♂
♀
CP: ~21 - ~27%
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Gut health solutionPractice: reducing protein often effective
Fermentation of undigested protein
Qaisrani, 2014
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Gut health solutionPractice: reducing protein often effective
Fermentation of undigested protein Metabolites
– Biogenic amines– Branched chain fatty acids– Phenols, thiols, ammonia, indoles, …– Nitrate
• Are they negative by definition? • Interaction with fermentable carbohydrates
M’Sadeq et al., An. Nutr., 2015
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Metabolomics: big data
>200.000 features for negative scan mode and >200.000 for positive, total ± 450.000
Filter 1: ± 80.000 left
Filter 2
Metabolites identified: 1000
Mass spectrometry Bioinformatics pipeline
MetabolitesAnim
als o
n di
ffere
nt d
iets
Correlations between diet, intestinal phenotype and metabolites/microbial species
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Program with different university-groups- Animal nutrition- Human medical research- Veterinary- Metabolomics- Microbiology- …
Understanding animal gut health; emphasis on undigested, fermented protein, in relation to energy
Impact microbial activity on dysbiosis Influence of nutritional interactions (feed composition, quality of
ingredients, technology, additives, …)
Gut health solution – our holistic approach
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The DSM gut health solution
Created for customers,
driving by science
