L.H. Baumgard1, N.K. Gabler1, J.W. Ross1, A.F. Keating1,,

J.F. Patience1, and R.P. Rhoads2

1ISU, 2Virginia Tech

baumgard@iastate.edu

Department of Animal Science

Gut Integrity – Implications for health and

performance

Heat Stress (HS) is Not a Fever

When ambient temperature approaches body

temperature, cooling mechanisms are impaired.

Fever vs. Hyperthermia

Key Biological Differences

Heat Stress is a Global Problem

January 2003, NASA

July 2003, NASA

Heat Stress: Animal Agriculture

Industry Loss

American Dairy Industry 897 million - $1.5 billion

American Swine Industry >$350 million annually(St-Pierre et al., 2003 J. Dairy Sci. E52-E77)

Grow - Finishing $450 million/year(Dr. Steve Pollmann)

Sow - Repro $450 million/year(Dr. Steve Pollmann)

Almost double the economic impact of PRSS

Largest impediment to

food security:Chinese Government

Heat Stress: Economics and Food Security

Cost: (lost productivity, mortality, product quality, health care etc.)

American Agriculture: > $3 billion/year

Global Agriculture: > $100 billion/year

Heat abatement is the primary strategy to mitigate

heat stress

But production remains suboptimal during the summer

Heat stress one of the largest impediments to efficient

animal agriculture (even in developed countries)

Threatens global food security

Regionalizes animal agriculture

St. Pierre et al., 2003; Baumgard and Rhoads, 2013

HS will Become More an Issue in the Future if:

Climate change continues as predicted

Genetic selection continues to emphasis heat

generating processes

Lean tissue accretion

Increased muscle mass increases basal heat

production

Piglets/litter

Gestational heat

Lactation heat

Increased basal heat increases susceptibility

to heat stressBaumgard and Rhoads, 2013

Heat Stress and Industry Issues

Don’t “finish”

Increased variability in market weight

Packing issues with “seam fat”/“flimsy fat”/”watery fat”

Seasonal infertility

Wean to estrous; Failure to express estrous; Conception rate

Failure to maintain pregnancy… “slipped liters”

Mortality

Especially late gestation

The pig with the biggest investment

Farrowing parameters

Pigs born alive, birth weight, weaning weight

Decreased Efficiency

Feed

Production/Facility/Barn (decreased market weights or increased time to

market weight)

Etiology of Heat Stress Symptoms

Heat Stress and Gut Health

Marked diversion of blood flow to skin and extremities….in an attempt to maximize radiant heat dissipation

Coordinated vasoconstriction in intestinal tissues

Reduced nutrient and oxygen delivery to enterocytes

Hypoxia increases reactive oxygen species (ROS)

Reduced nutrient uptake increases intestinal osmolarity Multiple reasons for increased osmotic stress

Etiology of Heat Stress

(Intestine, Hepatic, Renal, Endothelium, Brain, Muscle, Heart)

Heat Storage

Cytokine Release

(IL-1,IL-6,IL-10, TNF)NO

Ischemia,

ROS & RNS

Cardiovascular Responses

Skin

Dilates

Gut

ConstrictsMuscle

Dilates

Increased

Intestine

Permeability

Endotoxemia

DeathApoptosis

Necrosis

Cell Heat Shock & Ischemia

Heat StrokeCNS & multi-organ damage via

fever, shock, hemorrhage,

stroke & muscle breakdown

InjuryInflammation

Sawka & Young Adv. Exerc. Physiol 2006

Heat Stress and Gut Integrity

Endotoxin (aka. Lipopolysaccharide: LPS)

Component of bacteria cell wall

When bacteria die, LPS is released into

intestine

Normally LPS is prevented from entering

through GIT tight junctions

During HS some LPS enters blood stream

Blood stream

Submucosa

Lumen

ActinMyosin

MLCK

MLCK

IkB

P

P65P60

NFkB

TL

R4

PGE2

TNFα

IL-1β

IL-16

INFᵞ

APP

Healthy TJs

TJs

Compromised TJs

Hypoxia

HIF-1α

LPS

Gut

Lumen

LPS/LBP

Complex

LBP

Portal

Circulation

Immune

Cell

TL

R4

Liver

↑ Immune response

↑ Inflammatory response

↑ Acute Phase Proteins:

•Serum Amyloid A

•Haptoglobin

•LBP

Heat Stress and Gut Health

LPS causes liver damage

May impair gluconeogenesis capability

May impair ability to export VLDL (fatty liver)

May impair ability to secrete anabolic hormones

LPS stimulates the immune system and inflammatory cytokine production

TNF, IL-1 etc.. Reduced appetite

Stimulates fever

Causes muscle breakdown

Induces lethargy

....reduces productivity

Heat Stress and Bioenergetics

Heat Stress Increases Lipid and Decreases

Carcass Lean Content

Pigs

Close et al., 1971; Verstegen et al., 1978; Stahly et al., 1979;

Heath, 1983, 1989; Bridges et al., 1998; Collin et al., 2001

Chickens

Geraert et al., 1996; Yunianto et al., 1997

Rodents

Schmidt and Widdowson, 1967; Katsumata et al., 1990

But, normally growing animals on a restricted-diet

prioritize lean tissue accretion and deemphasize fat

synthesis (Le Dividich et al., 1980; Oresanya et al., 2008)

Heat Stress alters the nutrient partitioning hierarchy

Pig Heat Stress Questions

Direct vs. Indirect Effects of Heat

Indirect effects mediated by reduced feed intake

Production

Metabolism

Leaky Gut?

In Utero Heat Stress

Future body temperature

Future performance

Body composition

Pig Heat Stress Experiments

Utilized pair-feeding model

Eliminates the confounding effect of dissimilar feed intake

Need to appreciate the difference between direct and indirect

effects of heat stress in order to develop mitigation strategies.

Daily Feed Intake

0

0.5

1

1.5

2

2.5

3

-1 1 2 3 4 5 6 7

kg

Day

TN

HS

PFTN

46% Decrease

Pearce et al., 2013

Rectal Temperature

36

38

40

42

44

-1 1 2 3 4 5 6 7

°C

Day

TN

HS

PFTN

Pearce et al., 2013

39.3 vs. 40.9 °C

Pigs: Change in Body Weight

-5

-3

-1

1

3

5

7

9

7

kg

Day

TN

HS

PFTN

a

b

c

P<0.01

Pearce et al., 2013

Pigs: Plasma Energetics

0

0.1

0.2

0.3

0.4

7

mm

ol/

L

TN

HS

PFTN

a

NEFAP<0.01

a

b

0

0.1

0.2

0.3

7

ng

/mL

TN

HS

PFTN

50

75

100

125

150

7

mg

/dL

Day

TN

HS

PFTN

Glucose

0

3

6

9

12

7

mg

/dL

Day

TN

HS

PFTN

BUN

a

b

c

InsulinP<0.01

Pearce et al., 2013

Insulin Secretion Variables

0.2

0.4

0.6

0.8

1.0

1.2

0 1 2 3 4 5 6 7

AU

Day

Trt*Day P < 0.01

C-peptide

0.2

0.4

0.6

0.8

1.0

1.2

0 1 2 3 4 5 6 7

AU

Day

Trt*Day P = 0.03

Insulin

Sanz-Fernandez et al., 2013

Intestinal Morphology

Thermal Neutral Heat Stress Pair-fed

Pearce et al., 2013

The effects are rapid!

Plasma LPS & LBP

0

1

2

3

4

5

6

7

0

3

6

9

12

15

18

0 2 4 6 12

Seru

m E

nd

oto

xin

, AUP

lasm

a L

BP

, u

g/m

L

Time of heat stress (h)

LBP Endotoxina

b b

bc

c

x

xyxy

y

z

Pearce et al., 2015

LPS

Macrophage

Inflammatory

cytokines

Inflammatory

cytokines

Brain

GIT

Liver

Muscle

Appetite

Fever

Lethargy

diarrhea

Alter insulin action

Proteolysis

Insulin

PancreasFatty liver

Almost all of these metabolic/physiological effects occur

during heat stress

LPS and the Immune System

Marked activation of the innate immune system.

Activated immune has a large nutrient requirement

Energy and amino acids

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?

LPS can Induce Lethal Hypoglycemia

0

20

40

60

80

100

120

-20 -10 0 15 30 45 60 75 90 105 120 135 150

Glu

cose

(m

g/d

L)

Time Relative to LPS Infusion (min)

Stoakes, Abuajamieh, and Baumgard, 2012 unpublished data

LPS

Bolus

LPS Challenge & Blood Glucose

LPS

Bolus

Glu

co

se

Time

Can we quantify this amount of glucose?

Stoakes et al., 2015

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: 78 g/h or 1880 g/d is underestimated!

Why does heat stress increase insulin??

Why increase the most anabolic hormone during a

hypercatabolic condition?

Direct or Indirect effects?

Indirect: associated/caused by heat compromised

gastrointestinal track barrier function?

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.1

0

20

40

60

80

100

120

-20 -10 0 10 20 30 40 50 60 70

Insu

lin C

on

cen

trat

ion

(n

g/m

L)

Glu

cose

Co

nce

ntr

atio

n (

mg/

dL)

Time (min)

I.V. LPS Challenge to Pigs

Glucose

Tr

Insulin

101.8˚F

103.2˚FInsulin

Baumgard unpublished

LPS and Insulin

LPS stimulates or at least augments glucose stimulated insulin

secretion….

LPS activates the immune system

Insulin promotes adipose tissue accretion

Partitions nutrients away from muscle and lactation

$$ Billion Dollar Question $$

Can the Feed or Animal Health Industry do

anything about leaky gut????

Targets:

Direct action at intestine

Indirect via:

Increased feed intake

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

Acidosis prevention

↑ intestine integrity

↑ intestine integrity, antioxidant

↑ intestine integrity

Antioxidant

Antioxidant

Antioxidant

Antioxidant

↑ intestine integrity

Osmotic regulation; CH3 donor

↑ Energy balance

↑ Feed Intake

Acidosis prevention & ↑ Feed Intake

Acidosis prevention

Immune modulation

↑ intestine integrity

↑ intestine integrity & ↑ Feed Intake

↑ intestine integrity

↑ intestine integrity

Human Gut Health and Zinc

Alam et al., 1994. Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation

Rodriguez et al., 1996. Intestinal paracellular permeability during malnutrition in guinea pigs: effect of high dietary zinc. Gut. 39:416-422.

Sturniolo et al., 2001. Zinc supplementation tightens “leaky gut” in Crohn’s disease. Inflamm. Bowel Dis. 7:94-98.

Finamore et al., 2008. Zinc deficiency induces membrane barrier damage and increases neutrophil transmigration in Caco-2 cells. J. Nutr. 138:1664-1670

Peterson et al., 2008. Moderate zinc restriction affects intestinal health and immune function in lipopolysaccharide-challenged mice. J. Nutr. Biochem. 19:193-198.

Mahmood et al., 2009. Zinc carnosine, a health food supplement that stabilizes small bowl integrity and stimulates gut repair processes. Gut 56:168-175

Results: Ileum Permeability

0

10

20

30

40

50

60

70

1 7

Ilea

l F

ITC

-Dex

tra

n A

PP

,

µg

/ml/

min

/cm

2

Day of Heat Stress

Trt: P = 0.14

PF

ZnC

Zn220

Zn320

0

20

40

60

80

100

120

140

160

1 7

Ilea

l T

ER

, Ω

/cm

2

Day of Heat Stress

Trt: P ≤ 0.10

PF

ZnC

Zn220

Zn320

San Fernandez et al., 2014

Summary

Previous experiment evaluated just increasing amounts of Zinc.

Objectives of next experiment: compare Zinc source

Treatments:

Control: 120 ppm ZnSO4

Treated: 120 ppm Zn: 50% ZnSO4 & 50% Zn-Amino Acid Complex

Zn and Intestinal Integrity

0

1

2

3

4

5

6

7

12 TN 12 PF 12 HS 12 HS-Zn

Seru

m E

nd

otx

on

, A

U

0

2

4

6

8

10

12

14

16

18

12 TN 12 PF 12 HS 12 HS-Zn

ug

/ml

a

b

b,c

a,c

a

a,b

b

a

Lipopolysaccharide (LPS) LPS-BP

Pearce et al., 2015

Zinc Amino Acid Complex Summary

Feeding Zn-AA complex improved the intestinal integrity during

heat stress (in pigs)

Sanz-Fernandez et al., 2014;

Pearce et al., 2015

Baumgard unpublished (in steers)

Mechanism unknown

Likely due to up-regulation of HSP prior to heat load?

Seminar Summary

Heat stress causes leaky gut

Reduced feed intake causes leaky gut

off feed events, weaning etc.

Increased insulin and decreased adipose tissue breakdown

Explains fatter carcasses in late summer

Leaky gut and endotoxin infiltration

Potential dietary strategies

Primary objective is to control environment

Adrenal

Proteolysis

LPS

Lactate

Pancreas

GIT

Prolactin

Thyroid

Somatotropin

TRH

Pyruvate Alanine

Urea

Lactate

ROS

InflammationLiver

StomachGIT

Macrophage

Adipose Glycogenolysis

Glycogenolysis

GluconeogenesisIGF-

1

Insulin

Muscle

Catecholamines

Feed intake

T4; T3

NEFA

Heat Stress: Metabolic

and Physiological

Summary

Baumgard et al., 2014

Acknowledgments

• USDA NRI/AFRI

• # 2005-35203-16041

• # 2008-35206-18817

• # 2010-65206-20644

• # 2011-67003-30007

• # 2014-67015-21627

• Zinpro Inc.

• Elanco Animal Health

• Midwest Dairy Association

• National Pork Board

• Iowa Pork Producers

• TechMix

• Kemin Industries

• Murphy Brown

• Victoria Sanz-Fernandez

• Sarah Pearce

• Jay Johnson

• Rebecca Boddicker

• Amir Nayeri

• Nathan Upah

• Anna Gabler

• Sam Lei

Funding Support

Questions?

http://www.oildrumpigroasterdesigns.com/

Can “leaky gut” explain suboptimal production

frequently observed in animal agriculture?

Heat Stress

Inadequate feed intake

“off-feed event”

The negative effects on growth are bioenergetically unexplainable by

reduced feed intake

Transition period

Cause of ketosis?

Weaning

Shipping

Overcrowding

Unpalatable feed

http://www.sciohealth.co.za

Thermal NeutralHeat Stress