nutriFORUM 2019 - Ponencia sobre el impacto negativo de la inflamación sobre la producción de leche

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