Lance BaumgardJacobson Professor

baumgard@iastate.edu

Department of Animal Science

Causes of leaky gut and the metabolic and production consequences of it

Heat Stress Hind Gut AcidosisTransition PeriodFeed Restriction

Leaky Gut

Metabolic Response Endocrine ResponseImmuno-metabolic Response

Production

Baumgard Research Group Priorities: Ruminants and Pigs

Mycotoxins

Blood stream

Submucosa

Lumen

TLR4

TJs

NFĸB

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: Animal Agriculture

Industry Loss

American Dairy Industry $1.5 billion

American Swine Industry >$900 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 PRRS

Largest impediment tofood security: Chinese Government

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/litterGestational heat Lactation heat

Increased basal heat increases susceptibility to heat stress

Baumgard 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 (gross feed efficiency vs. carcass efficiency vs lean tissue accretion efficiency)

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

Heat Stress and Production

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 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

PFTN46% Decrease

Pearce et al., 2013

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

Plasma Insulin 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

Increased insulin is a metabolic paradox???

Heat stress is catabolic and insulin is a potent anabolic hormone

Gastro-Intestinal Tract Review

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

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

Etiology of Heat Stress Symptoms

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

GutConstricts

Muscle Dilates

Increased Intestine

Permeability

Endotoxemia

DeathApoptosisNecrosis

Cell Heat Shock & Ischemia

Heat StrokeCNS & multi-organ damage via

fever, shock, hemorrhage,stroke & muscle breakdown

InjuryInflammation

Sawka & Young Adv. Exerc. Physiol 2006

Blood stream

Submucosa

Lumen

ActinMyosin

MLCK

MLCK

IkB

P

P65P60NFkB

TLR

4

PGE2TNFαIL-1βIL-16INFᵞAPP

Healthy TJs

TJs

Compromised TJs

Hypoxia

HIF-1α

LPS

Gut Lumen

LPS/LBP

Complex

LBP

Portal Circulation

Immune

Cell

TL

R4

Liver

↑ Inflammatory response↑ Acute Phase Proteins:

•Serum Amyloid A•Haptoglobin•LBP

Heat Stress and Gut Health

Lipopolysaccharide (LPS_ causes liver damage Impairs gluconeogenesis capability Impair ability to export VLDL (fatty liver)

LPS stimulates the immune system and inflammatory cytokine production TNF, IL-1 etc.. Reduced appetite Stimulates fever Causes muscle breakdown Induces lethargy ....reduces productivity

Intestinal Morphology

Thermal Neutral Heat Stress Pair-fed

Pearce et al., 2013

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., 2013

Feed Restriction or Out of Feed Events and Gut Health

12 hours of feed restriction (40% of ad libitum intake) causes leaky gut in the pig

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

aLipopolysaccharide (LPS) LPS-BP

Pearce et al., 201512 TN: 12 hours of thermal neutral ad libitum fed conditions12 PF: 12 hours of pair-feeding in thermal neutral conditions12 HS: 12 hours of heat stress and ad libitum feed intake12 HS-Zn: 12 hours of heat stress and fed Availa-Zn

The GIT is enervated by both the CNS and ENS

https://www.lumennatura.com/2013/01/30/study-craniosacral-therapy-and-the-digestive-system/

http://gut.bmj.com/content/65/1/155

Why does heat stress and leaky gut 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

Professor Otto Warburg

First recognized the unique metabolism of cancer cells (1927) Large glucose consumers Switch from oxidative phosphorylation aerobic glycolysis 1931 Noble Prize

Also observed activated lymphocytes become highly glycolytic (1958)

Mentored Hans Krebs

Drinking buddy with Albert Einstein

Translation: “Metabolism of “Leukocytes

GLU GLUGLUGLUResting Immune Cell Activated

Immune Cell

G-6-P

Pyr Pyr

TCA

ETCATPATP

GLU

G-6-P

Pyr Pyr

TCA

ETC

LPS

Lac

ATPATP

Lac

Shouse and Baumgard, 2017

Warburg Effect

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

LPS Challenge & Blood Glucose

LPS

Bolus

Glu

cose

Time

> immune system utilization

Immune system glucose utilization >

Hepatic Glucose output &Peripheral Insulin Resistance

Hepatic Glucose output &Peripheral Insulin Resistance

LPS Challenge & Blood Glucose

LPS

Bolus

Glu

cose

Time

Can we quantify this amount of glucose?

Stoakes et al., 2015

LPS-euglycemic Clamp: Pigs

600 g glucose/day!

8.4 Mcal of energy!

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

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, 2018)

$$ Billion Dollar Question $$

Can the Feed or Animal Health Industry do anything about leaky gut????

Targets: Direct action at intestine Indirect via: Increased feed intake

Heat Stress

Leaky Gut

Immune System Nutrient Utilization

Immuno-activation

↑Insulin↑ LPS

↓Performance

↓Feed Intake

Hind Gut Acidosis Ketosis

Psychological Stress

Mycotoxins Shipping

Stress Umbrella

Tissue Trauma Over-crowding

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

Seminar Summary

Heat stress markedly alters metabolism

Decreases productivity

Costs everyone in the industry

Origin of the problem is at the GIT

Acknowledgments

• USDA NRI/AFRI/NIFA• # 2005-35203-16041 • # 2008-35206-18817• # 2010-65206-20644• # 2011-67003-30007• # 2014-67015-21627• # 2015-10843• # 2017- 05931• # 2017-10843

• Alltech• Zinpro Inc.• FormAFeed• TechMix• Elanco Animal Health• Kemin Inc.• ADM• Diamond V• ASCUS• Novus

Funding Support

Questions?

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