Transition cows have decreased immune function. The transition period. Inflammation, Immune Function, and the Transition Cow.

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1 Overview Inflammation, Immune Function, and the Transition Cow Barry Bradford Kansas State University Herd Health & Nutrition Conferences April 2016 Immunity and inflammation in the transition cow Long lasting effects of early lactation problems Predicting transition train wrecks Disrupting pathology The transition period Transition cows have decreased immune function Lymphocyte function First lactation Third lactation ~ 40% metabolic ~ 60% infectious Neutrophil function Ingvartsen, 2006 Goff and Horst,1997

2 Transition immune cells Enhanced inflammatory response Impaired chemotaxis Decreased phagocytosis Reduced killing ability All talk! Immunosuppression coincides with greater risk of infection Sordillo et al., 1995; Contreras et al., 2012; Kehrli et al., 1989; Nonnecke et al., 2003 Østergaard et al, 2005 Immune function predicts infection risk 3.0 Infections increase ketosis risk Odds ratio, subsequent risk of ketosis Monocyte proliferation response to endotoxin n = 7 n = 19 n = 5 Infections 0% 16% 100%*** Early metritis Acute mastitis Chronic mastitis Catalani et al, 2013 Gröhn et al., 1989

3 Ketosis increases infection risk Odds ratio, relative risk following ketosis Long term consequences of transition problems Whole lactation production losses (L) Risk of leaving herd 3 X 1.5 X 3.5 X 0.0 Risk of metritis Risk of mastitis 0 Mastitis Metritis Ketosis Duffield et al., 2009; Doohoo and Martin, 1984 Seegers 2003; Deluyker 1991; Wittrock 2011; Ospina 2010; Seifi 2011 Suppressed immune function contributes to infectious disorders Infections promote metabolic disorders Metabolic problems increase infection risk Does inflammation provide a mechanistic link? Inflammation Acute inflammation Associated with immune activation or tissue damage Swelling Pain Fever

4 Innate immune response The cytokine storm Tisoncik J R et al. Microbiol. Mol. Biol. Rev. 2012;76: Inflammation Chronic inflammation No outward signs Slightly elevated inflammatory mediators Alterations in signaling

5 Inflammation is associated with transition disorders % of cows with one or more transition disorders a a a Subacute, liver inflammation is common in postpartum cows b 0 Low Int. Low Int. High High Degree of inflammation Day relative to calving Bertoni et al., 2008 Sabedra, 2012 (thesis) What causes transition inflammation? Systemic inflammation

6 Systemic inflammation Systemic inflammation Systemic inflammation Systemic inflammation

7 Stress hormones Physiological levels of glucocorticoids, epinephrine, and norepinephrine may promote liver inflammation Handling stress induces an acute phase response in cattle Chida et al., 2006 Lomborg et al., 2008 Systemic inflammation Hypothetical impacts of unresolved inflammation

8 How does this impact cows? Dry matter intake (kg/d) Inflammation promotes ketosis Day of lactation Subclinical Ketosis Control 9% 1.5 µg/kg TNF 27% 3.0 µg/kg TNF 27% P = 0.02, TNFα vs. control (18% decrease) Yuan et al., 2013 Milk yield (kg/d) and decreases milk yield Day of lactation P = 0.03, TNFα vs. control (15% decrease) A vicious cycle Metabolic disorders promote Infections promote Metabolic disorders Yuan et al., 2013

9 Should we block inflammation? Immediate postpartum NSAID Flunixin meglumine given 2 h and 24 h after calving Over 1,300 cows enrolled Blocking inflammation on the day of calving may interfere with inflammatory signals needed to expel the placenta Odds ratio relative to placebo *** Retained placenta *** Metritis Duffield et al., 2009 Delayed Treatment: On farm NSAID study 1. Na salicylate 2. Meloxicam Administered orally starting 24 h postpartum 51 multiparous cows per treatment 305 day ME milk yield (kg) Anti inflammatories in early lactation (not currently approved) ,472 11,411 11,205 +9% P < doses +7% P < dose Placebo Salicylate Meloxicam Carpenter et al., 2016 Carpenter et al., 2016

10 Too much milk? Time to Leave Herd Con vs. Melox: P = 0.06 Days in milk Carpenter et al., 2016 Time to Pregnancy Nutrition can directly influence: Gut health Microbial ecology Metabolic health Immune function Carpenter et al., 2016

11 Plasma NEFA, μm Polyphenol source improves the transition Control NEFA Polyphenol NEFA Control milk Polyphenol milk * * * * 600 * Week of lactation Winkler et al., 2015 Energy corrected milk, kg/d 60% 50% 40% 30% 20% 10% 0% Unexpected benefits? Control Choline P = 0.01 Ketosis Cows were fed 15 g choline per day from 25 days before calving to 80 days in milk. Lima et al., % Unexpected benefits? P = Best practices to support immunity? 50% 40% 30% 20% 10% Control Choline P = 0.01 P = % Ketosis Mastitis Total morbidity Lima et al., 2012

12 Best practices to support immunity? Prevent heat stress during the dry period Calve with a BCS 3.5 Supplement with antioxidants during the dry period Work to maintain postpartum total serum calcium concentrations near 9 mg/dl Work to keep postpartum blood BHBA and NEFA concentrations below 1 mm The Big Picture There is much crosstalk between metabolic and immune systems Inflammatory signals, driven by a wide variety of stimuli, are a key link Not always a negative The physiological milieu in the first week can have long term impacts Strong immune function can help to prevent unresolved inflammation and long term problems Thank you! Questions/comments: Barry Bradford