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The real cost of Inflammation in PRODUCTION–a view across species. Ms Megan Abeyta - Iowa State University
- 1. Department of Animal Science Impacts of Leaky Gut and Inflammation on Production Across Species Megan Abeyta PhD Candidate Iowa State University maabeyta@iastate.edu
- 2. 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 an inhospitable environment Prevent parasites, pathogens, antigens, enzymes, acids, toxins etc.. From infiltrating “self” Barrier function
- 3. Lungs GIT ~50X ~150 X Skin ~2 m2 Human GIT Surface Area: That’s an enormous amount of area to defend! No wonder 70% of the immune system resides in GIT
- 4. Feed Restriction What Causes Leaky Gut? Transition Period Heat Stress Rumen Acidosis Psychological Stress LEAKY GUT Metabolic Response Immuno-metabolic Response Endocrine Response ↓ Production (Meat, Milk, Eggs, etc.)
- 5. Psychological Stress- Likely Augments Stress Insults STRESS Cascade of Stress Hormones (CRF → ACTH → Cortisol) IgE CRF-1 CRF-2 TLR-4 IgG IL-1 Mast Cells Chemokines Growth factors Eicosanoids Proteases Cytokines Histamine Heparin Dr. Johana Mayorga CRF LEAKY GUT Feed Restriction Heat Stress Overcrowding Rough Handling New Social Hierarchies Predators Not the only mode of action…. but likely contributes to many insults!
- 6. Many potential sources of inflammation: Lung Uterus Mammary gland Gastrointestinal tract Stress Causes Leaky Gut Healthy gut epithelium Bacteria/LPS Gut lumen Portal Blood Circulation STRESS Leaky gut epithelium Nutrients Nutrients Tight Junctions Immune cell Inflammation ↓ Production Nutrients/energy Psychological stress Heat stress Feed restriction Rumen acidosis
- 7. Lactose Liver Immune system Feed Propionate Ruminants Monogastrics Glucose Amino Acids Bacteria Milk Yield $$$$$$$$ Meat Synthesis $$$$$$$$ STRESS Immune Activation Insulin Egg Production $$$$$$$$ Amino Acids Gluconeogenesis & Acute Phase Proteins
- 8. Heat Stress and Production (Dairy) Rhoads et al., 2009 10 11 12 13 14 15 16 17 18 19 20 1 2 3 4 5 6 7 8 9 DMI (kg) Day Heat-stressed Pair-fed Heat stress feed intake by ~30% 20 25 30 35 40 45 50 0 1 2 3 4 5 6 7 8 9 Milk Yield (kg) Day Heat-stressed Pair-fed Heat stress yield ~45% Pair-feeding yield by ~19% Thus, feed intake only accounts for ~50% of the reduction in milk yield… other 50% immune system?
- 9. Heat Stress, Production, and Intestinal Integrity (Pigs) Thermoneutral Heat Stress Heat Stress and Growth in Swine Pearce et al., 2013 Mayorga et al., 2019 Heat stress ↑ gut permeability and ↓ growth in pigs
- 10. Feed Restriction Causes Intestinal Hyperpermeability and Production Losses in Cattle 2000 2500 3000 3500 4000 4500 5000 P1 2 5 Cr AUC: μg/L × h Day of Feed Restriction AL FR Trt: P = 0.01 Day: P = 0.12 Trt × Day: P = 0.09 ↑ 17% P = 0.09 ↑ 32% P = 0.01 Horst et al., 2019 0 2 4 6 8 10 12 Pre-Trt 6 12 Milk Yield (kg) Fasting Time (h) 22% 39% How often are cows without feed for ≥ 6 hours on farms?
- 11. 12 h of Feed Restriction Causes Leaky Gut in Pigs Pearce et al., 2015 0 1 2 3 4 5 6 7 12 TN 12 PF 12 HS 12 HS-Zn Serum Endotoxin (AU) Pair-fed “Feed Restriction” 12 TN: 12 h of thermal neutral ad libitum fed conditions 12 PF: 12 h of pair-feeding in thermal neutral conditions 12 HS: 12 h of heat stress and ad libitum feed intake 2.3 kg BW loss in 12 h 0.88 kg less feed intake than CON ~1.4 kg BW loss (including lost gain)… part immune response? ~83% less feed intake than TN Psychological Stress?
- 12. Costs of Immune Activation
- 13. Professor Dr. Otto Warburg First recognized the unique metabolism of cancer cells (1927) Large glucose consumers Switch from oxidative phosphorylation aerobic glycolysis Also observed activated lymphocytes become highly glycolytic (1958) Mentored Hans Krebs Drinking buddy with Albert Einstein Translation: “Metabolism of “Leukocytes
- 14. Immuno-Metabolism Immune cells become obligate glucose utilizers when activated Called “The Warburg Effect” Leukocytes are insulin sensitive Palsson-McDermott and O’Neill, 2013 Advantages of Warburg effect: Rapid production of ATP Synthesis of biomolecules (nucleotides, reducing equivalents, etc.) Adaptation to hypoxic environment Inflammatory signaling GLUCOSE Insulin
- 15. GLU GLU GLU GLU Resting Immune Cell Activated Immune Cell G-6-P Pyr Pyr TCA ETC ATP ATP GLU G-6-P Pyr Pyr TCA ETC LPS Lac ATP ATP Lac Shouse and Baumgard, 2017 Warburg Effect Acetate Amino Acids NEFA Insulin
- 16. How much glucose is the entire body using?? 80 years later and we still not know how much glucose the immune system needs in vivo? Prerequisite for developing mitigation strategies What’s the Problem?: Dynamic and ubiquitous distribution of the immune system throughout tissues Allows for quasi tissue/organ quantification but…. Complicates whole-body quantification
- 17. LPS Challenge and Blood Glucose LPS Bolus Glucose Time Can we quantify this amount of glucose?
- 18. Kvidera et al., 2015
- 19. 483 1259 1553 0 200 400 600 800 1000 1200 1400 1600 1800 Total Glucose Deficit (g) Control LPS LPS-Eu P = 0.06 Trt: P < 0.01 1553 g – 483 g = 1070 g glucose/12 h in a lactating dairy cow Kvidera et al., 2015
- 20. 35.1 MJ of energy!
- 21. LPS-Euglycemic Clamp: Steer Calves and Pigs Stoakes et al., 2015
- 22. Euglycemic Clamp in Steer Calves 0 10 20 30 40 50 60 70 80 0 50 100 150 200 250 300 350 -60 0 60 120 180 240 300 360 420 480 540 600 660 720 780 Rate of Glucose Infusion (g/h) Blood Glucose (mg/dL) Time Relative to Bolus (min) Control LPS-C LPS-Eu ROGI ~515 g of glucose over 12 h Stoakes et al., 2015
- 23. 0 5 10 15 20 25 30 -30 0 15 30 45 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 480 Rate of Glucose Infusion (g/h) Time Relative to Bolus (min) 116 g or 16 g/h or 400 g/d Kvidera et al., 2017 Euglycemic Clamp in Pigs Almost ½ a Kg of glucose per day!
- 24. Conserved Response Across Species Species: Immune glucose utilization Steers: 1.0 g/kg BW0.75/h (Kvidera et al., 2016) Pigs: 1.1 g/kg BW0.75/h (Kvidera et al., 2015) Cows: 0.7 g/kg BW0.75/h (Kvidera et al., 2017) Cows: 1.0 g/kg BW0.75/h (Horst et al, 2020)
- 25. What does this mean for production? Dairy Cow 1. ~2,000 g glucose in 24 h 2. 72 g glucose/ 1 liter milk synthesis (Kronfield et al., 1982) ~ 28 L of milk lost in 24 h 120 kg hog 1. ~ 960 g glucose in 24 h 2. 960 g x 0.017 MJ/g = 16.3 MJ 3. Protein synthesis: 0.04 MJ/g 4. 16.3/0.04 = 408 g PTN 5. 408 ÷ ~30% DM = 1,358 g lean tissue! ~1.4 kg lean tissue lost in 24 h 1. ~3,200 g glucose in 24 h 2. 3,200 g x 0.017 MJ/g = 54.4 MJ 3. Protein synthesis: 0.04 MJ/g (Patience, 2012) 4. 54.4 MJ/0.04 MJ = 1,360 g 5. 1,360 g ÷ ~30% DM = 4,533 g of lean tissue! 680 kg steer ~4.5 kg lean tissue lost in 24 h
- 26. Can the feed industry do anything about leaky gut? Prevent infection (obvious) Encourage feed intake Ensure 100% feed availability Minimize psychological stress Maximize digestion prior to large intestine Dietary strategies Prevent rumen acidosis Dietary Strategies Manage intestinal permeability Dietary strategies Immunomodulation Producer’s Responsibility Nutritionist and Producer’s Responsibility Nutritionist’s Responsibility
- 27. Conclusions Immune activation, regardless of origin, is energetically and nutrient expensive and compromises production (i.e., milk yield, growth) 28 L milk 1.4 - 4.5 kg lean tissue loss (pigs and steers) Many different stressors can cause leaky gut, and ergo, inflammation Heat stress Feed restriction Rumen acidosis Psychological stress Management and nutrition practices should prioritize the prevention of immune activation
- 28. Acknowledgments • USDA NRI/AFRI/NIFA • # 2005-35203-16041 • # 2008-35206-18817 • # 2010-65206-20644 • # 2011-67003-30007 • # 2014-67015-21627 • # 2015- 10843 • # 2017- 05931 • # 2017- 10843 • # 2019- 07859 • # 2020- 02716 • # 2021- 09507 •Industry Partners • ADM Alltech • ASCUS BASF • Biomin Cargill • Diamond V DPI Global • Elanco Grain States Soya • Idemitzu Kemin Inc. • Micronutrients Microaid Novus • Phileo Lesaffre Sherring Plough • TechMix Zinpro Inc. • Zoetis Funding Support
Editor's Notes
- Here are a couple pictures that hopefully help to illustrate what we did. You can see here there are two jugular lines coming out of this cow. Here we are taking a sample from the cows right catheter while glucose is being infused via a hospital infusion pump through her left jugular catheter. Every 10 minutes, we took a small blood sample from the catheter and measured it using a glucometer. We would record this data and compare it to her baseline in order to adjust the pump rate of infusion, which we also recorded every 10 minutes.
- So, using the methods I described earlier, we calculated the total glucose deficit for each cow and we saw a treatment difference with the LPS cows displaying a much higher glucose deficit than the control treatment. There was a tendency for a greater glucose deficit in the euglycemic clamped cows relative to the LPS-only cows. However, it is apparent that reduction in milk glucose output is a major strategy to spare glucose for the immune system. Remember all animals were consuming the same amount of feed, so 483 g of the glucose deficit were due to reduction in feed intake, therefore we estimate that approximately a little over 1 kg of glucose was used by the immune system during this challenge.