dr. jeffrey escobar - does immune activation alter growth potential and nutrient digestibility?
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Does Immune Activation Alter Growth Potential and Nutrient Digestibility? - Dr. Jeffrey Escobar, Novus, from the 2014 Allen D. Leman Swine Conference, September 15-16, 2014, St. Paul, Minnesota, USA. More presentations at http://www.swinecast.com/2014-leman-swine-conference-materialTRANSCRIPT
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Alterations in amino acid digestion and metabolism
during diseaseJeffery Escobar, Ph.D.
Executive ManagerNutritional Physiology Research
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Agenda
• Immune activation and metabolism alteration
• Plasma amino acids
– Changes during LPS challenge and their balance
• Amino acid digestibility
– Apparent, basal ENL, standardized
– Salmonella challenge
– Fate of undigested CP/AA
• Conclusions
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LPS induce inflammatory response
• Inflammatory cytokines
– TNF-α, IL-1b, IL-6
• Induce fever
• Reduce feed intake
• Stimulate – Skeletal muscle proteolysis
– Liver protein synthesis
• Produce acute phase proteins
Kawai and Akira, 2010
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Protein synthesis and accretion in immune challenged pigs
Orellana et al., 2002; Escobar et al., 2004
* P < 0.05
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Immune activation and metabolism
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mg/kg BWAA Nitrogen
Phe 0 0Trp 2 <1Val 10 5Ser 11 1Cys 12 1Tyr 16 1Pro 25 3Met 26 2Thr 28 4Gly 39 7Ile 41 4Asp+Asn 61 12Ala 66 10His 68 11Leu 72 8Arg 83 28Lys 104 20Glu+Gln 140 15
Excess release of AA and nitrogen from skeletal muscle protein over incorporation into mixed acute-phase proteins
– Increase in plasma urea nitrogen
Reeds et al., 1994
• Compare AA composition of skeletal muscle protein and a mixture of acute-phase proteins
• Assuming a typical increase in the synthesis of a mixture of acute-phase protein of 850 mg/kg BW
• The amount of skeletal muscle protein needed to be mobilized = 1,980 mg
• A difference of 1,150 mg/kg BW
• For a 100 kg pig:
– About 200 g of muscle protein mobilized
– About 13 g of excess nitrogen excreted
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LPS, cytokines, and plasma urea NP
lasm
a I
L-6
, p
g/m
L
Pla
sma u
rea n
itro
gen
, m
g/d
L
Hour after-injectionHour after-injection
Webel et al., 1997
12-h feed-deprived pigs
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Immune activation in fasted vs fed state
• Most acute immune activation studies with LPS have been conducted in the fasted state
– Normal food deprivation period: 8 - 24 h
• Although sick, pigs normally continue to eat, digest, and absorb nutrients
• Does acute immune activation in the fasted and fed state result in similar changes
– Digestion, absorption, metabolism, excretion
Arrival
24 h
LPS
-10 0
Surgery
Fasting Blood sampling
Feed
Recovery-2
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Blood urea nitrogen in fed pigs
Price, 2011
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Changes in plasma Phe with LPS
Price, 2011
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Changes in plasma Phe and urea nitrogen with LPS in fed pigs
Price, 2011
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Changes in plasma amino acids with LPS
Price, 2011
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Price, 2011
Area underthe curve
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Price, 2011
Area under the curve
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Estimating plasma amino acid balance
• Calculate the area under the curve for each AA
– Saline and LPS treated pigs
• Use correction factor of 0.075 L plasma/kg BW to convert AUC to µmolekg BW-1
h-1 as a unit of AA metabolism (Talbot and Swenson, 1970)
• Apply the following equation:
AA balance = (AUCLPS- AUCSAL) 0.075 L 1kg BW h2××
Price, 2011
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Negative AA balance: SAL > LPS
Price, 2011
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Positive AA balance: LPS > SAL
Price, 2011
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Summary of AA metabolism
Is lysine the most limiting AA during immune activation?
• Acute immune activation via LPS
– Induce similar changes in plasma urea nitrogen during the fasted and postprandial state.
– Reduces the digestion and/or absorption of dietary nutrients or increases AA catabolism
– Alters plasma balance of amino acids
• Lysine was the most negative
• Alanine was the most positive
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Phe to Tyr conversion
Harper’s Biochemistry; Kilani et al., 1995; Hsu et al., 2006
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Changes in plasma Tyr with LPS
Price, 2011
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Changes in plasma Phe to Tyr
Price, 2011
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Amino acids:nutritional considerations
Rethink AA limitation order for metabolic purposes
• Dietary amino acids:
– Essential, conditional, nonessential
• “One which cannot be synthesized by the animal organism out of materials ordinarily available to the cells at a speed commensurate with the demands for normal growth” W.C. Rose, 1946
• Essentiality of amino acid for protein synthesis
– Which one is the most limiting AA?, second?
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van de Waterbeemd and Gifford, 2003
Digestibility vs. bioavailability
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EndogenousFactors
Species
Breed/strain
Gender
Physiological state
ExogenousFactors
Dietary AA balance
Anti-nutritional factors
Intake
Pathogens, disease?
Factors affecting AA digestibility
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Salmonella challenge in pigs
• Euthanized pigs (n=12) 24 and 72 h after oral inoculation to collect ileal digesta samples
• Salmonella Typhimurium DT104
– Nalidixic acid: 25 mg/mL
– Novobiocin: 20 mg/mL
• Intra-nasal inoculation 9.8×109 cfu
Lee, 2012
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Apparent ileal AA digestibility, %24 h after Salmonella inoculation
Lee, 2012
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Basal endogenous AA losses24 h after Salmonella inoculation
Lee, 2012
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Standardized ileal AA digestibility, %24 h after Salmonella inoculation
Lee, 2012
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Salmonella challenge in ileal cannulated pigs
• 8 growing pigs
• Ileal cannulation and recovery
• Intra-nasal inoculation 1.3×109 cfuSalmonella Typhimurium DT104 (NalRNovR)
• Collect ileal digesta every 8 h from0 to 72 h after inoculation
Lee, 2012
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Dynamic changes in AA digestibility in Salmonella challenged pigs
Lee, 2012
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Dynamic changes in AA digestibility in Salmonella challenged pigs
Lee, 2012
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Summary on digestibility and disease
• Can poor digestion leads to enteric disease?
• Enteric disease results in:
– Lower apparent AA digestibility
– Higher endogenous losses of AA
• Higher gut demand for nutrients and energy
– Production of mucins, digestibe enzymes, enterocytes, etc.
• Provide highly digestible dietary proteins
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Anti-nutritional effect of indigestible protein in the hindgut
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Hindgut AA fermentation
Meijers and Evenepoel 2011; Wikipedia
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Protein fermentation metabolites limiting pig growth
Yokoyama et al., 1982
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Dietary protease improvesintestinal environment
Dietary protease reduces protein fermentation and prevents increase in hindgut pH.
Wang et al., 2011
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Dietary protease improvesintestinal environment
Protease limits growth of undesirable bacteria and enhances growth of beneficial bacterial species.
Wang et al., 2011
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General conclusions
• Immune activation alters digestion, absorption, and metabolism of amino acids
• Fermentation of undigested proteins produce undesirable bacterial metabolites and alter gut environment and microbiota
• Feed pigs highly digestible ingredients or use available technologies to maximize AA digestibility and hence minimize protein fermentation
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Acknowledgements
• Students and technicians
– Dr. Kathryn Price
– Dr. Hanbae Lee
– Dr. Matthew Utt
– Elizabeth Ramirez
– Heather Totty
– Greg van Eyk
– Courtney Klotz
– Heather Reeves
– Pat Williams
• Collaborators
– Dr. Rodney Johnson
– Dr. David Baker
– Dr. William van Alstine
– Dr. Teresa Davis
– Dr. Monica Ponder
– Dr. Mark Hanigan
– Dr. Allen Harper
– Dr. Kevin Pelzer
• Virginia Tech Pratt Fellowship
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Thank You!
Obrigado Merci
Gracias
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谢谢
Asante sana
Благодаря ви
Mulţumesc
Cảm ơn lắm
감사합니다ありがとう
Tak! Danke Schoen!