Inflammation in the transition dairy cow Huw R McConochie Zinpro RNS
Is Inflammation the milk thief?
Effect of LPS infusion on milk productionaz 24 Milk production (kg)
Reduction in DMI only accounts 16 Saline for half of the reduction in milk 8 LPS production 0
-‐4 -‐3 -‐2 -‐1 0 1 2 3 Milking relative to infusion
§ aCows were milked 2x/d § zTreatment by time effect P<0.01 § Waldron, et.al., 2006. J. Dairy Sci. 89:596
DG - 1417
Innate Immune Response Endotoxins
Pathogens
Trauma
Immune Ac7va7on Muscle Catabolism
Leukocytes Cytokines
Macrophages
IL-1, 2, 6, TNFα, COX
Activation
Bone Marrow
Hepatocytes Acute phase proteins
Hypothalmus Fever Anorexia
Niewold 2007. Poultry Science 86:605-609
Leukopoiesis
Adipose tissue mobilisation
Contreras et al., 2017. Journal of Animal science and Biotechnology: 8:41.
What is the energetic cost of inflammation?
1 KG GLUCOSE EVERY 12 HOURS FOR INFLAMMATION/ IMMUNE SYSTEM ACTIVATION Kvidera et al., 2014
Ini7a7on of Estrous Cycle and New Pregnancy
Excess Energy Reserves
Replenish Energy Reserves Maintain Previously Established Pregnancy
Immunity and Inflammation
Growth Lacta7on
Basal Metabolism Feed
Chebel, R.C. 2009. Proc. MN. Nutrition Conf.
So how does inflammation steal the milk?
GLUCOSE Â
Inflammation affects glucose absorption by the mammary gland
Source: CAST Animal health
Glucose sparing § During LPS induced mas??s and when glucose supply is limited the mammary gland aligns its metabolism to saving glucose for the immune system. Gross et al., 2014. J, Anim. Phys. and Anim. Nutr., 99:747-‐756. § Intra-‐perineal LPS infusion downregulates genes associated with glucose uptake in the mammary gland of rats. Ling and Alcorn 2010. Research in Veterinary Science 89(2):200-‐2
Controlled inflammation is a normal part of transition
Uncontrolled inflammation is the gateway to transition failures
Adipose tissue mobilisation
Contreras et al., 2017. Journal of Animal science and Biotechnology: 8:41.
The risk of transition diseases increases with severity of Inflammation
Liver Ac7vity Index HIGH INTERMEDIATE LOW Acute Phase Protein
Bertoni et al., 2008
Increased Risk of Transition Disease
Longer to Rebreed
Less Milk
Lower Plasma Calcium
Transition diseases
Transition breakpoint model
immunosuppression Oxidative stress
Mitochondrial stress
Traumatic episodes
Fatty liver
Degree of Inflammation
Adipose mobilisation
Hypo-calcaemia Drop in plasma calcium
Glucose consumption
Elevated Inflammation
Macrophages Inflammation
Tissue repair
Normal Inflammation
Placental Expulsion Tissue mobilisation
Calving
LACTATION
Circulating LPS Compromised epithelium
Inflammation driven adipose tissue mobilisation is self perpetuating Adipose tissue mobilisation
Normal inflammation
Traumatic episode
Elevated inflammation
Increased energy demand
Return to Homeostasis
Plasma Insulin (ng/ml)
Inflammation increases plasma insulin during a LPS challenge 0,8 0,6 0,4 0,2 0 0
120 240 360 Hours post LPS Infusion Saline
LPS
Waldron, et.al., 2006. J. Dairy Sci. 89:596 Means were adjusted by analysis of covariance using the mean insulin concentra?on for each treatment group from −240 through 0 min rela?ve to intramammary infusion. **Treatment by ?me effect, P < 0.01.
480
Adipose tissue remains insulin resistant • Interleukin-‐6 • Resis?n
• More pronounced in high yielding cows
• TNF⍺
• High rates of lipolysis
• Increase during transi?on
• High BCS cows
• Ensures adequate energy during –ive energy balance
Contreras et al., 2017
So why are NEFA and BHB not elevated? § BHB used as an alterna?ve energy source § NEFA converted to BHB in the liver § Suppresses glucose § Glucose supply to immune system compromised § Immune suppression
Zarrin et al., 2014. J. Dairy Sci. 97:3531-‐3541
Mitochondrial health • 80% of the cells ATP requirements are produced by the MIT
Murphy 2009. Biochemical Journal 417 (1) 1-‐13
Source: www.frontiersin.org
Oxidative stress is associated with inflammation TransitionIncreased Metabolic Demands
Increased Glucose Demand
ROS
AO
Increased NEFA And BHB Levels
Oxidative Stress
Immune Suppression
§ Abuello et al., 2015. J. of Anim. Physiol. and Anim. Nutr. 99(6):1003-‐16
Transition Diseases
Hepatic oxidative stress in healthy and ketotic cows
MDA = malondialdehyde. A Marker for oxida7ve stress, CAT = Catalase,,SOD = Superoxide dismutase, GSH-‐p = Glutathione Peroxidase – Endogenous an7oxidants Du et al., 2017. J. Cellular Phys, 43:568-‐578
Inflammation is everywhere
Ini7a7on of Estrous Cycle and New Pregnancy
Excess Energy Reserves
Replenish Energy Reserves Maintain Previously Established Pregnancy
Immunity and Inflammation
Growth Lacta7on
Basal Metabolism Feed
Chebel, R.C. 2009. Proc. MN. Nutrition Conf.
Milk loss is only the tip of the iceberg
Image: Romolo Tovani
•
Loss of production
• • • • •
Herd removals Transition diseases Replacement costs Efficiency Repro performance
Is inflammation the driver of herd removals?
Source: Milkproduction.com
Traumatic episodes may originate from the GIT
70% of the ruminants immune system resides in the GIT
Fibre deprivation in the colon compromises gut epithelial integrity
Mahesh et al., 2016. Cell 167, 1339–1353
Interesting observations § Compromised DMI associated with increased incidence of transi?on diseases § High fibre controlled energy transi?on diets reduce the risk of transi?on diseases. Jim Drackley § In vitro, LPS and pathogenic bacteria can cross GIT epithelium – Emmanuel et al., 2007. J. Dairy Sci. 90(12): 5552-‐5557 § High starch diets disrupt colonic ?ght junc?on integrity and cause inflamma?on. Huimin et al., 2016. Sci. Reports. 6, 20329 § Feed restric?on disrupts rumen epithelium integrity and causes inflamma?on – No Fibre. Hu et al., 2018. J. Anim. Science. 29;96(10):4293-‐4305
Feed restriction
What Happens During Heat Stress Hyperthermia Reduced GIT Blood Flow
Reduced Feed Intake GIT Oxida7ve Stress
GIT Hypoxia
Tight Junc7on
ATP Deple7on Depolariza7on Of Enteroendocrine Cells
Altered Morphology
Reduced Livestock Produc7vity SwG -‐ 401
•
Heat Shock Proteins (Hsp)
Permeability Endotoxin Immune Ac7va7on & Inflamma7on
Baumgard et al. 2012. Impact of climate change on livestock produc?on. Pages 413-‐468. Chapter 15. Environmental Stress and Ameliora?on in Livestock Produc?on. Eds. V. Sejian, et al., Springer-‐Verlag Berlin Heidelberg.
Uterine infections as a source of inflammation
Manifestation of disease and inflammation are related to trauma and metabolic stress!!!! Sheldon, Â 2014 Â
Existing and new intra-mammary infections
http://qualitymilkpays.blogspot.nl/2012/04/recommended-mastitis-control-program.html
Epithelium
Compromised epithelium causes inflammation
Summary § Inflamma?on is the link between management and transi?on diseases § Uncontrolled inflamma?on is the gateway to transi?on diseases § Opportunity – Good management can mi?gate the risk of excessive inflamma?on § Minimising trauma?c episodes is the key to efficiency – Transi?on breakpoint model § Crea?ng maintaining robust epithelium can reduce inflamma?on