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Lance Baumgard, Sara Kvidera and Erin Horst
Iowa State University
Department of Animal Science
Challenging the paradigm of
metabolic diseases in the fresh period
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Hypothesis
The origin of both heat stress (all farm
animals) and ketosis (dairy cows)
problems is a compromised intestinal
integrity
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Heat Stress Hind Gut AcidosisTransition PeriodFeed Restriction
Leaky Gut
Metabolic Response Endocrine ResponseImmunometabolic Response
Production
Lab Research Priorities: Ruminants and Pigs
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Heat Stress Large Intestine AcidosisTransition Period
Feed Restriction Leaky Gut
Psychological Stress Weaning
Distant Inflammation
Documented Causes of Increased Intestinal Permeability (“leaky gut”)
Large Intestine PTN Fermentation Small Intestine Bacteria Overgrowth
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Feed
BacteriaLacto
se
Propionic
Milk Yield
$$$$$$$$
Glucose is made from propionate
Lactose is made from glucose
Milk yield is determined by the amount of synthesized
lactose
Glucose ATP
Liver
Review of the Importance of Glucose
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Gastro-Intestinal Tract Review
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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 a inhospitable environment
Prevent parasites, pathogens, enzymes, acids,
toxins etc.. From infiltrating “self”
Barrier function
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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
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Intestinal Morphology
Thermal Neutral
Well-fed
Heat Stress Pair-fed
Pearce et al., 2011
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Blood stream
Submucosa
Lumen
ActinMyosin
MLCK
MLCK
Ik
B
P
P65
P6
0
NF
kBTL
R4
PGE2
TNFα
IL-1β
IL-16
INFᵞ
APP
Healthy
TJs
TJs
Compromised
TJs Hypoxia
HIF-1α
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Gut Health…Barrier Dysfunction
Lipopolysaccharide (LPS) stimulates the immune system
LPS promotes inflammation production….catabolic condition
TNF, IL-1 etc.. Reduced appetite
Stimulates fever
Causes muscle breakdown
Induces lethargy
....reduces productivity
LPS causes liver damage
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Cause(s) of Leaky Gut?
Direct affects of heat
Hypoxia
Osmotic stress
Dehydration stress
Oxidative stress
pH stress
Increased intraluminal endotoxin concentration
??
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Leaky Gut and
Ketosis?
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Transition Period Disorders:
Mediated Largely by NEFA
Transition Period
Metabolic shift
NEBAL
Negative effects on future production
Dystocia
Milk fever
Retained placenta
Metritis
Ketosis
Displaced abomasum
Fatty liver
Lameness
Death
Only 50% of cows
complete the transition
period without
experiencing one of these
problems
Drackley, 1999
?
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Dogma
Excess adipose tissue mobilization causes fatty
liver and ketosis
This is exacerbated in high producing cows
Industry Goal: Reduce blood NEFA
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Correlation Studies
Many studies associate NEFA and BHBA with:
Increased risk of ketosis, decreased milk yield, LDA,
metritis, retained placenta, laminitis, or poor
reproduction Chapinal et al., 2011; Huzzey et al., 2011; Ospina et al., 2010a, 2010c;
Duffield et al., 2009; LeBlanc et al., 2005
Plasma NEFA are markedly increased (>700 mEq/L)
following calving in almost all cows
~15-20% get clinical ketosis
What makes these cows more susceptible to ketosis?
Predisposition to developing fatty liver?
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Thought Provoking Observations??
1) Associations and correlations
No cause and effect
2) Infusing ketones or NEFA does not cause negative
outcomes
3) Ketones do not decrease feed intake
Otherwise a starving animal would not have an appetite
4) Infusing ketones do not increase blood ketone levels
In late lactation ketone removal from the circulating pool is very
rapid
5) Cannot recreate ketosis during established lactation
Using a feed-restriction model doesn’t cause fatty liver and ketosis
6) Some females do not consume food after parturition
Ocean mammals
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Maybe its not NEFA’s fault?
Maybe something other than increased NEFA is
responsible for fatty liver?
High NEFA and ketones are a consequence….not the
problem
The “content” of anything is a balance between pool
entry and pool removal.
Maybe something is preventing efficient hepatic lipid
export?
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Human Intestinal Disorders
Diseases associated with increased intestinal permeability
(leaky gut)
Crohn’s disease
Irritable bowel syndrome
Inflamatory bowel syndrome
Celiac disease
Alcoholism
Post-absorptive phenotype
Increased circulating lipopolysaccharide (LPS)
Circulating acute phase proteins
Fatty liver: without affiliated rise in blood non-esterified fatty acids (NEFA)
Inflammation can compromise the liver’s ability to export lipid and increases
NEFA incorporation into hepatic triglycerides (Lanza-Jacoby and Tabares, 1990;
Ma et al., 2008)
Copyright © 2004 Pearson Education, Inc., publishing as
Benjamin Cummings
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Humans with
intestinal barrier
dysfunction have
fatty liver….but do
not have increased
[NEFA]
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Peculiar Observations?
Incidence of clinical ketosis in Southwest vs
Midwest and Northeast ~0.5% vs. 10-15%
Heat Stress cows have increased incidence of
fatty liver
Rumen acidosis:
Ground grain: systemic inflammation
Alfalfa pellets: no inflammation
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Subacute Rumen Acidosis (SARA)
and Systemic Inflammation
Rumen Blood
SARA
Inducer
pH < 5.6
(min/d)
∆ LPS
(EU/mL)
∆ LPS
(EU/m
L)
∆
SAA
(µg/m
L)
∆
Haptoglobi
n
(µg/mL)
∆ LBP
(µg/m
L)
Alfalfa
Pellet268 + 60,139 0 - 15.3 - 29 - 3.8
Grain
Pellet279 + 47,579 + 0.52
+
269.2+ 476 + 34.9
Adapted from Khafipour et al., 2009a,b
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Grain Acidosis
↓ pH
CHO
CHO↓ pH
CH
O ↓ pH
Alfalfa Pellet Acidosis
CHO ↓ pH
CHO
Cartoon created from comments made within Dr. Kees Plazier’s papers
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Transition Period: Acute Phase Protein
Response & Inflammation
Associated with or partly responsible for
transition period issues?
Hailemariam et al., 2014
Homeorhetic adaptation to lactation?
Farney et al., 2013
Inflammation source???
General
Uterus
Mammary
Gastrointestinal tract?
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GIT Permeability and Hepatic NEFA
Intolerance?
Reasons for increased likelihood of leaky gut
in transition dairy cows???
Dietary shift to increased concentrates
Rumen acidosis with grain compromises GIT barrier
and increases blood LPS
Starch delivery to the hind-gut
Rumen acidosis with alfalfa pellets does not increase
blood LPS
Plaizier et al., 2012; 2009
Distally derived cytokines Paibomesai et al., 2013
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LPS
Gut
Lumen
LPS/LBP
Complex
L
BP
Portal
Circulation
Immune
Cell
TLR4
Liver
↑ Inflammatory response
↑ Acute Phase Proteins:
•Serum Amyloid A
•Haptoglobin
•LBP
Sara Stoakes
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Objectives
Measure biomarkers of leaky gut in cows that
were retrospectively classified as ketotic (only
diagnosed problem) and healthy herd mates
n = 8 ketotic cows
n = 8 “healthy” cows
Initial experiment had non-ketotic objectives
Nayeri et al., 2015
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Increased LBP in Ketotic Cows
0
5000
10000
15000
20000
25000
30000
35000
40000
-21 3 10 21 56
ng/m
l
DIM
Healthy vs. Ketotic Transition CowsLipopolysaccharide Binding Protein
(LBP)
Healthy Ketotic
*
*Trt: P = 0.047
DIM: P < 0.01
Trt X DIM: P < 0.01
Nayeri et al., 2013
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Objectives
Confirm that the biomarkers of leaky gut
increase during the transition period for
clinically ketotic cows
A compromised GIT barrier and subsequent
endotoxin (LPS) infiltration may play a
causative key role in ketosis development
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0
500
1000
1500
2000
2500
3000
3500
4000
-7 3 7 10 14
EU
/ml
Days relative to calving
Healthy
Ketotic
Trt: P=0.40
Day: P=0.26LPS
Abuajamieh et al., 2015
Trt: P = 0.02
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1000
2000
3000
4000
5000
6000
7000
-7 3 7 10 14
ng/m
l
Days relative to calving
Healthy
Ketotic
Trt: P=0.06
Day: P<0.01LBP
Abuajamieh et al., 2015
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Still not causative data
Same “associative” problem that NEFA
and ketones have with ketosis
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Objectives
Determine if intentionally induced
gastrointestinal permeability reduces
productivity and alters energetic and
inflammatory indices…..
in otherwise healthy dairy cows
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Gamma-Secretase Inhibitor
(GSI)
Reduces crypt cell differentiation
Decreases enterocyte migration on the
microvilli
Decreased differentiation likely
compromises intestinal integrity
Potential model for natural causes of
“leaky gut”
(van Es et al., 2005)
Guilmeau, 2012
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Control
PF GSI
Stoakes et al., 2014
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PF GSI
0
2
4
6
8
10
12
P1 2 3 4 5 6 7
µg/m
L
Day
LPS-Binding Protein
Day: P < 0.01
0
500
1000
1500
2000
2500
3000
P1 2 3 4 5 6 7
µg/m
L
Day
Haptoglobin
PF
GSI
Day: P < 0.01
0
200
400
600
800
1000
1200
1400
P1 2 3 4 5 6 7
µg/m
L
Day
Serum Amyloid A
Day: P
0
5
10
15
20
25
30
P1 1 2 3 4 5 6 7
kg
Day
Dry Matter Intake
Day: P <0.01
Stoakes et al., 2014
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0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
P1 2 3 4 5 6 7
μg/L
Insulin
Trt: P = 0.07
0
200
400
600
800
1,000
1,200
P1 1 2 3 4 5 6 7
mE
q/L
NEFA
Treatment: P = 0.06
Day: P < 0.01
*
*
40
50
60
70
80
90
P1 1 2 3 4 5 6 7
mg
/dL
Day
Glucose
Day: P =
02468
10121416
P1 1 2 3 4 5 6 7
mg
/dL
Day
BHBA Day: P = 0.08
Trt x Day: P = 0.09
Stoakes et al.,
2014
PF GSI
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Summary
GSI morphologically altered villi architecture and
biomarkers of the acute phase protein response:
characteristics consistent with leaky gut.
Induced leaky gut markedly affected production and
metabolism: responses similar to ketosis.
Feed restriction (by itself) negatively affected intestinal
barrier function.
Feed restriction may be a useful tool to test molecules
targeting leaky gut mitigation.
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Feed
BacteriaLacto
se
Propionic
Milk Yield
$$$$$$$$
Glucose is made from propionate
Lactose is made from glucose
Milk yield is determined by the amount of synthesized
lactose
Glucose ATP
Liver
Review of the Importance of Glucose
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Evolution of the
Immunometabolic Field
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Me
tab
olic
Pri
ori
ty
CNS
Immune
System
Reproduction
Lactation
Muscle
Adipose
Review: Coordination of Nutrient Partitioning
Nutrient Flux Hierarchy
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Proffesor 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
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GLUGLU
GLU
GLU
Resting Immune Cell
Activated Immune Cell
G-6-P
Pyr Pyr
TCA
ETCATP
ATP
GLU
G-6-P
Pyr
Pyr
TCA
ETC
LPS
Lac
ATP
ATP
Lac
Carrie Shouse
Warburg Effect
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Glucose and the Immune System
At rest, immune cells can oxidize multiple fuels
Once activated, immune cells become obligate
glucose utilizers
How much glucose does the immune system
use?
Milk synthesis is regulated by lactose
synthesis….glucose is precursor to lactose
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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
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Etiology of Our Hypothesis
All leukocytes become obligate glucose utilizers
Adipocytes, myocytes and hepatocytes reduce
glucose utilization
Liver glucose output increases
……but hypoglycemia still occurs
Hmmmmmm????????
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LPS Challenge & Blood Glucose
LPS
Bolu
s
Glu
cose
Time
> immune system utilization
Immune system glucose utilization >
Hepatic Glucose output &
Peripheral Insulin Resistance
Hepatic Glucose output &
Peripheral Insulin Resistance
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LPS Challenge & Blood
Glucose
LPS
Bolus
Glu
cose
Time
Can we quantify this amount of glucose?
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Stoakes et al., 2015
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8
5
%
8
5
%
0
2
4
6
8
10
12
Pre-Trt 6 12
Mil
k Y
ield
(k
g)
Time Relative to Bolus (hr)
Control LPS LPS-EuTrt: P<0.01
Stoakes et al., 2015
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483 1259 15530
200
400
600
800
1000
1200
1400
1600
1800
To
tal
Glu
cose
Def
icit
(g
)
Control LPS LPS-Eu
P=0.06
Trt: P<0.01
1553 g – 483 g = 1070 g
glucose/12 h
Stoakes et al., 2015
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Study Limitations
Glucose uptake by other tissues
↓ insulin sensitivity in adipose (Song et al., 2006, Shi et al., 2006, Poggi et al., 2007)
↓ insulin sensitivity in muscle (White et al., 1987, Lang et al., 1989, 1990, 1992, Liang
et al., 2013)
Glucose output by liver
Increased (Lang et al., 1993, McGuinness et al., 1993, Ling et al.,
1994)
Conclusion: 1 kg/12 h is underestimated!
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8.4 Mcal of energy!
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Practical Implications: Growth
Immune System Glucose: ~1000 g/d
1000 g of CHO x 4.1 kcal/g = 4,100 kcal
Protein synthesis: 10 kcal/g (Patience, 2012)
4,100 kcal ÷ 10 kcal/g = 410 g of protein
410 g PTN ÷ ~30% dm = ~1,366 g of lean tissue
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Conserved Response
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, unpublished)
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Calcium and Immune System
Inflammation plays a key role in hypocalcemia (Zebeli et al., 2013;
Hendy and Canaff, 2016)
Ca is involved in immune system activation (Hendy and Canaff,
2016)
Immunoactivation/inflammation can be induced
experimentally by infusing lipopolysacchride (LPS)
LPS is a cell wall component of gram-negative bacteria which
elicits a robust immune response (Waldron et al., 2003; Kvidera et al., 2017)
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Ca and Immune System
I.V. LPS decreases circulating Ca in late lactation (Kvidera et al.,
2017; Horst et al., 2017)
Kvidera et al., 2017 Horst et al., 2017
46
% 39
%
39
%
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Immuno-activation and Hypocalcemia?
Maybe pathogen/antigen exposure during the
periparturient period also contributes to milk
fever.
LPS is toxic to developing follicles (Hansen et
al., U of FL)
..??? maybe the reason why negative
outcomes during the transition period are all
correlated with each other is because most of
them can be causal connected with LPS.
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Can “leaky gut” explain suboptimal production
frequently observed in animal agriculture?
Heat Stress
Inadequate feed intake
“off-feed event”
The negative effects on growth and milk yield are
bioenergetically unexplainable by reduced feed intake
Transition period
Cause of ketosis?
Weaning
Shipping
Overcrowding
Unpalatable feed
Drought
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$$ Billion Dollar Question $$
Can the Feed or Animal Health Industry
do anything about leaky gut????
Targets:
Direct action at intestine
Indirect via:
Increased feed intake
Rumen acidosis prevention
Hind gut acidosis prevention
Improved immune function
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Target Mitigation Strategies
Prevent infection (obvious)
Encourage feed intake
Maximize digestion prior to large intestine
Dietary strategies
Prevent rumen acidosis
Dietary Strategies
Enhance intestinal permeability
Dietary strategies
Immunomodulation
Minimize psychological stress
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Potential nutritional strategies to
ameliorate intestinal permeability
Supplement Presumed Mechanism of Action
Bicarbonate
Glutamine
Zinc
Dairy Products
Vitamin A
Vitamin C
Vitamin E
Selenium
Dexamethasone
Betaine
Conjugated Linoleic Acid
Chromium
Yeast, yeast extract/DFM
Ionophores
β-glucan
Mannanoligosaccharide
Rehydration therapy
Butyrate
Mycotoxin binders
OmniGen-AF
Organic acids
Plant botanicals
Acidosis prevention
↑ intestine integrity
↑ intestine integrity, antioxidant
↑ intestine integrity
Antioxidant
Antioxidant
Antioxidant
Antioxidant
↑ intestine integrity
Osmotic regulation; CH3 bdonor
↑ Energy balance
↑ Feed Intake, enhance immune cell function
Acidosis prevention & ↑ Feed Intake
Acidosis prevention
Immune modulation
↑ intestine integrity
↑ intestine integrity & ↑ Feed Intake
↑ intestine integrity
↑ intestine integrity
Immune modulation
↑ intestine integrity
↑ intestine integrity
Baumgard et al., 2014
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Dairy Cow
Maladaptation to Lactation
Summary
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Metabolic Flexibility:
Decreased Insulin Sensitivity
Baumgard and Rhoads, 2013
Successful Transition
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Metabolic Flexibility:
Decreased Insulin Sensitivity
Glucose redirected to immune system
Baumgard and Rhoads, 2013
Unsuccessful Transition
LPS
Fatty Liver, Excessive Ketone Synthesis
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Ketosis: When to intervene?
Treat:
High ketones
Not coming into milk
Not aggressively eating
Looks lethargic and melancholic
Has a mild fever
Don’t mess with
High ketones….but she’s
Eating like a champ
Milking like a world-record holder
Looks great
No fever
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Summary
High NEFA and ketones are needed to support
maximum milk production
In a “crashing cow”, NEFA and ketones are a
“reflection” of the underlying insult
Ketosis appears to be an immuno-metabolic
event
Leaky gut…and other sources of inflammation could
be etiological origin
The activated immune system utilizes an
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Conclusions
Leaky gut and endotoxin infiltration may play
important roles (if not the origin) in suboptimal
productivity commonly observed in animal
agriculture, and ketosis in particular
Strategies that can improve intestinal integrity
need to be researched…in a “stressed model”
If leaky gut is the fundamental cause of many
typical on-farm problems….then it is a financial
problem that dwarfs all others combined
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Acknowledgments
• USDA NRI/AFRI
• # 2005-35203-16041
• # 2008-35206-18817
• # 2010-65206-20644
• # 2011-67003-30007
• # 2014-67015-21627
• Zinpro Inc.
• Elanco Animal Health
• Kemin Inc.
• ADM
• Diamond V
• ASCUS
• TecMix
Funding Support
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