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The Biology of Stress Lance Baumgard, Sara Stoakes and Rob Rhoads
Iowa State University Department of Animal Science
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Hypothesis Leaky gut explains the negative consequences of heat stress and off-feed events (all farm animals), and ketosis (dairy cows) problems
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Heat Stress: Economics and Food Security
Cost: (lost productivity, mortality, product quality, health care etc.) American Agriculture: > $4 billion/year Global Agriculture: > $150 billion/year It will get worse in the future if: Climate change continues as predicted Genetic selection continues to emphasize milk synthesis, lean tissue accretion, piglets/sow etc.. Heat producing processes St. Pierre et al., 2003; Baumgard and Rhoads, 2013
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Temperature Humidity Index (THI)
Easy way to measure and evaluate heat stress Based on cows only under shade….solar radiation is incredibly potent 72 thought to be when cows become susceptible Based on 60 year old data when cows were producing lb/d Modern cows are stressed at THI of 68
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Heat Stress
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Heat Stress Questions?? Does the decrease in feed intake explain the reduced milk yield during heat stress? Indirect vs. direct effects of heat If we have a better understanding of the biological reasons WHY heat stress reduces production, we’ll have a better idea of how to alleviate it.
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Effects of Heat Stress on Feed Intake
Lactation: Effects of Heat Stress on Feed Intake Heat -stressed Pair-fed Heat stress feed intake by ~30 % Rhoads et al., 2009
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Effects of Heat Stress on Milk Yield
Heat stress yield ~45% Pair-feeding yield by ~19% Thus, feed intake only accounts for ~50% of the reductions in milk yield Rhoads et al., 2009 Wheelock et al., 2010 Baumgard et al., 2011
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Body Weight Loss Pair-fed Heat Stress Rhoads et al., 2009
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Heat Stress Reduces Back-fat Mobilization
Rhoads et al., 2009 Wheelock et al., 2010 Baumgard and Rhoads, 2013
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Something other than the mammary gland is utilizing ~400 g more/day?
Milk Sugar Output Heat Stress Cows Secrete ~400 g less lactose/day than Pair-Fed Thermal Neutral Controls Something other than the mammary gland is utilizing ~400 g more/day? Rhoads et al., 2009 Wheelock et al., 2010
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Gastro-Intestinal Tract (GIT) Review Guts
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Reminder: Intestinal Functions
GIT is a tube running from the mouth to the anus Everything inside of the tube is technically “outside” of the body Digest and absorb nutrients GIT lumen is a inhospitable environment Prevent parasites, pathogens, enzymes, acids, toxins etc.. From infiltrating “self” Barrier function
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Human GIT Surface Area:
Lungs GIT ~50X ~150 X Skin ~2 m2 That’s an enormous amount of area to “defend”! No wonder 70% of the immune system resides in GIT
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Biology of Heat Stress Symptoms
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Heat Stress and Gut Health
Diversion of blood flow to skin and extremities Coordinated vasoconstriction in intestinal tissues Reduced nutrient and oxygen delivery to enterocytes Hypoxia increases reactive oxygen species (ROS) Reduced nutrient uptake increases rumen and intestinal osmolarity in the intestinal lumen Multiple reasons for increased osmotic stress Baumgard and Rhoads, 2013
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Intestinal Morphology
Thermal Neutral Heat Stress Pair-fed Pearce et al., 2011
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Heat Stress and Gut Health
Lipopolysaccharide (LPS) stimulates the immune system LPS promotes inflammation production….catabolic condition TNF, IL-1 etc.. Reduced appetite Stimulates fever Causes muscle breakdown Induces lethargy ....reduces productivity LPS can cause liver damage
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Compromised TJs Healthy TJs
Lumen Hypoxia Actin HIF-1α Myosin MLCK P MLCK TJs PGE2 TNFα IL-1β IL-16 INFᵞ APP IkB TLR4 NFkB P60 P65 Blood stream Submucosa
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The effects are rapid! Plasma LPS & LBP Pearce et al., 2015
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Heat Stress Summary Direct and indirect effects Hyperinsulinemia
↓DMI only accounts for 50% of reduced milk yield Hyperinsulinemia Blunted adipose mobilization Liver remains sensitive to catabolic signals Leaky gut Inflammation and acute phase protein response Unknown whereabouts of 400 g of glucose
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Leaky Gut and Ketosis?
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Transition Period Disorders: Mediated Largely by NEFA
? Transition Period Metabolic shift NEBAL Negative effects on future production Dystocia Milk fever Retained placenta Metritis Ketosis Displaced abomasum Fatty liver Lameness Death Only 50% of cows in North America complete the transition period without experiencing one of these problems Drackley, 1999
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Dogma Excess adipose tissue mobilization causes fatty liver and ketosis This is worse in high producing cows Industry Goal: Reduce blood NEFA
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Correlation Studies Many studies associate NEFA and BHBA with:
Increased risk of ketosis, decreased milk yield, LDA, metritis, retained placenta, laminitis, or poor reproduction Chapinal et al., 2011; Huzzey et al., 2011; Ospina et al., 2010a, 2010c; Duffield et al., 2009; LeBlanc et al., 2005 Plasma NEFA are markedly increased (>700 mEq/L) following calving in almost all cows ~15-20% get clinical ketosis What makes these cows more susceptible to ketosis? Predisposition to developing fatty liver?
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↑ Inflammatory response ↑ Acute Phase Proteins: Serum Amyloid A
Gut Lumen LPS/LBP Complex TLR4 LPS Immune Cell Liver ↑ Inflammatory response ↑ Acute Phase Proteins: Serum Amyloid A Haptoglobin LBP follow LPS as it is translocated across the intestinal epithelium into the portal circulation where it must be bound to LBP in order to engage the TLR4 receptor of immune cells where it elicits an immune response (which includes production and increased circulation of acute phase proteins). Therefore an animal will increase circulating levels of LBP when there are high amounts of LPS in order to process and clear the bacteria. LBP Portal Circulation Sara Stoakes
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Objectives Measure biomarkers of leaky gut in cows that were retrospectively classified as ketotic (only diagnosed problem) and healthy herd mates n = 8 ketotic cows n = 8 “healthy” cows Initial experiment had non-ketotic objectives Nayeri et al., 2015
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Increased LBP in Ketotic Cows
Nayeri et al., 2013
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Objectives Confirm that the biomarkers of leaky gut increase during the transition period for clinically ketotic cows A compromised GIT barrier and subsequent endotoxin (LPS) infiltration may play a causative key role in ketosis development
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Trt: P = 0.02
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Similar to our previous data
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Transition Cow Problems are Associated with Biomarkers of Leaky Gut
Intestinal barrier becomes leaky Endotoxin induced immune activation Immune system has energetic cost Reprioritization of nutrients away from milk synthesis……………..$$$ problem
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Objectives: Determine Feed Restriction’s Impact on Leaky Gut “Out of Feed Events” are common in EVERY animal agriculture industry
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12 hours of feed restriction (40% of ad libitum intake) causes leaky gut in the pig
Lipopolysaccharide (LPS) LPS-BP b a b,c a,b a,c b a a Pearce et al., 2015
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The Effects of 7 day Feed Restriction on Inflammation in the cow
BUN-??? We saw linear tendencies for acute phase proteins LBP and SAA which both increased with the severity of feed restriction We saw a significant cubic effect in the acute phase protein haptoglobin, we saw the highest level of haptoglobin only in the treatment receiving 40% ad lib
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Effects of Feed Withdrawal (100%) on Milk Yield
22% b 39% c Milk yield really took a hit in both LPS and LPS-Eu cows. Interestingly, glucose did not recover milk yield like we thought it might. Milk yield decreased at both time points for both treatments by about 85%. Stoakes et al., 2015
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Could 12 h of FR causes leaky gut in cattle?
Don’t know….depends upon mechanism Decreased luminal nutrient delivery….then likely not Continues out-flow of ruminal nutrients Psychological stress Hunger-induced ACTH-Cortisol action…..then possible Cortisol causes leaky gut in multiple models Intestinal Mast cells are responsive to nerves Upon CRF stimulation they release proteases and TNF Both proteases and TNF cause tight junction breakdown
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Can “leaky gut” explain suboptimal production frequently observed in animal agriculture?
Heat Stress Inadequate feed intake “off-feed event” The negative effects on growth and milk yield are bioenergetically unexplainable by reduced feed intake Transition period Cause of ketosis? Weaning Shipping Overcrowding Unpalatable feed
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$$ Billion Dollar Question $$
Can the Feed or Animal Health Industry do anything about leaky gut???? Targets: Direct action at intestine Indirect via: Increased feed intake Rumen acidosis prevention Hind gut acidosis prevention Improved immune function
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Potential nutritional strategies to ameliorate intestinal permeability
Baumgard et al., 2014
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Lactating Dairy Cow Metabolic Adaptation to Heat Stress and Maladaptation to Lactation
Summary
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Successful Transition
Metabolic Flexibility: Decreased Insulin Sensitivity Baumgard and Rhoads, 2013
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Unsuccessful Transition
Fatty Liver, Excessive Ketone Synthesis LPS Metabolic Flexibility: Decreased Insulin Sensitivity Glucose redirected to immune system Baumgard and Rhoads, 2013
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Metabolic Inflexibility Remains Insulin Sensitive
LPS Metabolic Inflexibility Remains Insulin Sensitive Baumgard and Rhoads, 2013
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Ketosis: When to intervene?
Treat: High ketones Not coming into milk Not aggressively eating Looks sick Has a mild fever Don’t mess with High ketones….but she’s Eating like a champ Milking like a world-record holder Looks great No fever
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Summary Heat stress and ketotic cows have a similar metabolic and endocrine fingerprint Leaky gut is a common denominator in both The activated immune system utilizes an enormous amount of glucose. Dietary Strategies
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Conclusions Leaky gut may play an important role in suboptimal milk yield commonly observed during “stress” Strategies that can improve intestinal integrity need to be researched…in a “stressed model” If leaky gut is the fundamental cause of many typical on-farm problems….then it is a financial problem that dwarfs all others combined
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Acknowledgments Funding Support USDA NRI/AFRI # 2005-35203-16041
Dr. Victoria Sanz-Fernandez Dr. Sarah Pearce Dr. Jay Johnson Amir Nayeri Nathan Upah Sam Lei Erin Laughlin Erin Nolan David Valko Dr. Pat Gorden Mohannad Abumajieh Mohammad MalQaisi Johanna Mayorga Lozano Jake Siebert Mr. Howard Green Dr. Chel Moore Dr. Mark McGuire Dr. Arnaldo Burgos Dr. Howard Green Dr. Matt Waldron Dr. Lynn Davis Dr. Jeff DeFrain Dr. Mark Wilson Dr. Mike Socha Funding Support USDA NRI/AFRI # # # # # Zinpro Inc. Elanco Animal Health Kemin Inc.
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