Transcript The Nexus Between Nutrition, Microbiology and

The far-reaching impacts of
immunity and inflammation during
the transition to lactation
Barry Bradford
June 2015
Large dairies
Overview
• Early lactation – a unique challenge
• Infection and metabolic disease links
• Long-lasting effects of early lactation
problems
• Current research – novel solutions
The transition period
First lactation
Third lactation
~ 40% metabolic
~ 60% infectious
Ingvartsen, 2006
Transition cows have decreased
immune function
Lymphocyte function
Neutrophil function
Goff and Horst,1997
Transition immune cells
• Enhanced inflammatory
response
All talk!
• Impaired chemotaxis
• Decreased phagocytosis
• Reduced killing ability
Sordillo et al., 1995; Contreras et al., 2012; Kehrli et al., 1989; Nonnecke et al., 2003
Immunosuppression coincides with
greater risk of infection
Østergaard et al, 2005
Monocyte proliferation response
to endotoxin
Immune function predicts
infection risk
Infections
n=7
0%
16%
n = 19
100%***
n=5
Catalani et al, 2013
Infections increase ketosis risk
3.0
Odds ratio, subsequent risk of ketosis
2.5
2.0
1.5
1.0
0.5
0.0
Early metritis
Acute mastitis
Chronic mastitis
Gröhn et al., 1989
Ketosis increases infection risk
4.0
Odds ratio, relative risk following ketosis
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Risk of metritis
Risk of mastitis
Duffield et al., 2009; Doohoo and Martin, 1984
Long-term consequences
of transition problems
Whole-lactation production losses (L)
500
400
300
200
100
Risk of leaving herd
3X
1.5 X
3.5 X
Metritis
Ketosis
0
Mastitis
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
Inflammation
Chronic inflammation
• No outward signs
• Slightly elevated
inflammatory mediators
• Alterations in signaling
Inflammation is associated with
transition disorders
% of cows with one or more transition disorders
50
a
a
Int. High
High
40
a
30
20
b
10
0
Low
Int. Low
Degree of inflammation
Bertoni et al., 2008
Subacute, liver inflammation is
common in postpartum cows
Day relative to calving
Sabedra, 2012 (thesis)
What causes transition inflammation?
Systemic inflammation
Systemic inflammation
Systemic inflammation
Systemic inflammation
Systemic inflammation
Systemic inflammation
Dry matter intake (kg/d)
Inflammation promotes ketosis
16
Subclinical
Ketosis
Control
9%
1.5 µg/kg TNF 27%
3.0 µg/kg TNF 27%
14
12
10
8
P = 0.02, TNFα vs. control
(18% decrease)
6
0
1
2
3
4
5
6
7
Day of lactation
Yuan et al., 2013
Milk yield (kg/d)
…and decreases milk yield
40
35
30
25
20
15
0
1.5
3.0
P = 0.03, TNFα vs. control
(15% decrease)
0
1
2 3 4 5 6
Day of lactation
7
Yuan et al., 2013
A vicious cycle
Metabolic disorders
promote
Infections
promote
Metabolic disorders
Should we block inflammation?
Anti-inflammatories in early lactation
(not currently approved)
305-day ME milk yield (kg)
14000
11,411
11,205
6000
+9%
P < 0.05
+7%
P < 0.05
4000
3 doses
1 dose
Salicylate
Meloxicam
12000
10,472
10000
8000
2000
0
Placebo
Culling Rate
C vs. M: P = 0.04
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
A new possibility
RNA interference:
• A mechanism whereby small RNA molecules can promote
degradation of a specific transcript to knock down expression
of a certain gene.
The discovery of RNAi
Craig Mello and Andrew Fire, 2006 Nobel Prize
The central dogma
How does it work?
Protection and delivery
Silencing (knockdown)
The central dogma
The problem?
Calving
Poor appetite
Ketosis
Displaced abomasum
Cull
How this could work
Calving
Small
Interfering
RNA
Increasing appetite
Decreased NEFA
Milk!
Why is this exciting
• One dose should be effective for at least a week
Why is this exciting
• Off target effects can be avoided
–Liver only
–Single gene target
• No genetic engineering involved
• RNA is a very safe “drug residue”
Hopefully….
CSIRO Australian Animal Health Laboratory
Thank you!
Questions/comments:
Barry Bradford
Kansas State University
[email protected]
@AnimNutr