How amino acid may help to support a protective immune system

(1)

HAL Id: hal-02786409

https://hal.inrae.fr/hal-02786409

Submitted on 5 Jun 2020

HAL is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Copyright

How amino acid may help to support a protective immune system

Nathalie Le Floc’H, Elodie Merlot

To cite this version:

Nathalie Le Floc’H, Elodie Merlot. How amino acid may help to support a protective immune system.

The first amino acid academy. Amino acid nutrition and sustainability, Sep 2017, Paris, France.

�hal-02786409�

(2)

N Le Floc’h, E Merlot

INRA PEGASE, SAINT GILLES 35590 FRANCE

How amino acids may help to support a protective immune system ?

Amino Acid Academy, Paris, September 28-29, 2017

(3)

.02

Amino Acid Academy, Paris, September 28-29, 2017

LE FLOC’H/ Paris 2017

Outline

A brief introduction of immune system

AA dietary supplies and immune system maintenance and functioning

Does maintening a protective immune system require nutritional adjustments?

(4)

.03

Outline

(5)

.04

Pathogens Injury

Contaminants

• Prevents « nonself » entry

• Eliminates « nonself »

• Repairs lesions Environment

What is expected from the immune system ?

Individual

A major contribution to health preservation and restoration Immune system

(6)

.05

Immune system

Pathogens Injury

Contaminants

Individual

Neuro‐endocrine and nutritional regulations

How AA interact with the immune system?

(7)

.06

Immune system

Pathogens Injury

Contaminants

Individual

Neuro‐endocrine and nutritional regulations

• Nutrients for the immune system

• Molecules with specific immune‐

related bioactivity

Roles of AA

(8)

.07

• Maintaining immune functions Environment

Pathogens Injury

Contaminants

Individual

• Nutrients for the immune system

• Regulation of the immune system

Roles of AA

Immune system

• Mounting an immune response

• Supporting recovery

(9)

SKIN MUCOSA

Innate immune system

= non specific immune response

Physical barriers

Local inflammatory response

Macrophages

Polynuclears (= Granulocytes) Natural killer cells (NK)

Ig Adaptive immune

system

=

Specific immune response

T and B Lymphocytes Antigen processing

proliferation T Lymphocytes

cytotoxic B Lymphocytes Plasmocytes

Immune memory

Antigen « clearance »

A simplified overview of the immune system

Systemic inflammatory response

Oxidative burst phagocytosis

cytokines

09 Cytokines

(10)

.09

 Feed intake

Sickness behaviour Fever

 Protein breakdown

 Protein synthesis

The systemic inflammatory response

INFLAMMED

TISSUE LIVER

Pro‐inflammatory cytokines (IL‐1, IL‐6, TNF‐α)

 Acute phase proteins

 Energy production (gluconeogenesis)

MUSCLE

Hormones (cortisol, insulin) Tissue

injury

Metabolic cost

Common response to many diseases (infectious or not), stressful events,

management …

BRAIN

(11)

.010

And its consequences on AA and protein metabolism

Hormones Cytokines

↘ feed intake fever

↗ protein synthesis

↘ protein synthesis

↗ protein breakdown

proliferation activation

cortisol

insulin

TNF-α

IL-6

IL-1β INF-γ

AA

↗ energy production

AA re allocation towards immune functions

(12)

SKIN MUCOSA

Innate immune system non specific

Physical barriers

Local inflammatory response

Macrophages

Polynuclears (= Granulocytes) Natural killer cells (NK)

Ig Adaptive immune

system

=

Specific immune response

T and B Lymphocytes Antigen processing

proliferation T Lymphocytes

cytotoxic B Lymphocytes Plasmocytes

Immune memory

Antigen « clearance » Systemic inflammatory

response

What means a protective immune system ?

integrity

Less harmful as possible

cooperation efficacy

efficacy

(13)

.012

Outline

(14)

.013

Which AA and for what purposes ?

 AA as contituent of immune proteins

Immunoglobulins, Acute phase proteins

Energy, cell proliferation

 AA as nutrients for immune cells

 AA as bioactive molecules (or precursor)

Cytotoxic and antioxidant compounds

Thr, Val

Trp, Phe

Ala, Gln

Arg, Cys, Trp

(15)

.014

 BCAA deficiency (50% of the Control) reduced lymphoid organ weights (spleen, BF, thymus) in broilers

- Impact on maintenance of immune system -

Konashi et al 2000

 Val deficiency (4 vs 15 g/kg) upregulated the expression of gene coding for inflammatory response (TNF, IL‐8 and NFkB) while downregulated antiinflammatory response (IL‐10) in the gut in carps

 Thr deficiency (70% of the Control) in primiparous sows reduced

plasma total IgG Cuaron et al 1984

Luo et al 2014

AA deficiency

(16)

.015

 Gut explants from birds fed a Thr deficient diet had no response

(mucin, IgA and IL‐8 mRNA) to ex vivo LPS treatment

Zhang et al 2017

Le Floc’h et al 2008

 Pigs fed a moderate Trp deficient diet had higher inflammatory response (haptoglobin, fever)

Pigs fed a moderate Thr deficient diet had lower serum specific anti BSA and swine fever Ig G Defa et al 1999

- Impact on stimulated immune functions -

AA deficiency

(17)

.016

Threonine is a major component of

glycoproteins : mucins and immunoglobulins

Mucins  420 % Fogg et al. 1997

 Thr confers specific properties to these proteins : post‐

traductional glycosylation

Thr/Lys : Immunoglobulins 150 % Basset et al. 1965

 Postprandial plasma [Thr] are lower in co infected pigs ^(Mh+H1N₁)

Plasma total Ig G content 8‐8.3 g/L

2.8 g/L µM

Carcass  54 % Bikker et al. 1997



(18)

.017

 Threonine supply above recommendations

Mao et al 2014

Trevisi et al 2015

Threonine supplementation enhances immunoglobulins

 total IgG and  inflammatory response (sera cytokine concentrations, tissue expression of TLR) induced by pseudorabies vaccination, but depressed FCR

 IgM in ETEC challenged pigs susceptible to ETEC

(19)

.018

0 100000 200000 300000

0 0,5 1 1,5 2 2,5

Gln,mM

cpm

0 40 80 120 160

pg/ml

Proliferation IL-2 production

Glutamine is essential for lymphocyte activity

Yaqoob et al 1997

Gln supplied in vitro

Rodent spleen lymphocyte T stimulated in vitro by ConA

[Gln] in culture medium

50 100 150 200

x 1.8

C 19 g/kg

Gln 55 g/kg

ala + gly 13 g/kg

Gln supplied in vivo

0 10 20 30

x 3

diet Kew et al. 1999

proliferation

IL-2

(20)

.019

Dietary Gln supplementation preserves lymphocyte proliferation capacity in infected pigs

Piglets weaned at 21d, fed a diet supplemented with 4% of Gln, inoculated with E coli at 26 d

 Gln supplementation restored lymphocyte proliferation capacity in infected pigs

 but did not modify growth rate and hyperthermia

0 1 2 3 4 5

- E coli - Gln

- E coli+Gln

+E coli-Gln +E coli+Gln Lymphocyte proliferation (ConA)

Yoo et al 1997 b

ab

b

a

(21)

.020

Gln dietary supplementation (1% of the diet) during 3 wks resulted in higher intestinal Ig A and blood IgG (+ better growth rate) but 4% of Gln did not

Bartell & Batal 2007

With contrasted results in broilers

Gln+Glu dietary supplementation (0,5% of the diet) during 3 or 6 wks had no beneficial effect on growth performance, intestinal morphology, and inflammatory response of broiler chickens

raised under hot and humid tropical environment

Shakeri et al 2014

(22)

.021

ROS

Ahr receptor

Aryl hydrocarbon receptor Islam et al 2017

Munn & Mellor 2016 Badawy et al 2016

“Antiinflammatory” effects of Trp and Cys



+

Trp

IDO

Trp metabolites INF‐ɣ

+

Immune tolerance

Antioxidant activity

Immune regulation

Christen et al 1990



 ^GSH

Glu‐Cys‐Gly

Cys

Tau Met



Wu et al 2004 Malmezat et al 2000

(23)

.022

Trp and Cys exert therapeutic function and limit gut inflammation

0 5 10 15 20 25 30

0 20 40 60 80 100 120

0 10 20 30 40 50 60 70 80

Colitis total score Tissue [IL‐6]

pg/g

Tissue [TNF]

pg/g

Kim et al. 2009 and 2010

Piglets 2‐5 kg; model of DSS‐induced colitis 5 d later : AA were infused intragastically

control DSS DSS+

Trp

DSS+

Cys

control DSS DSS+

Trp

DSS+

Cys

control DSS DSS+

Trp

DSS+

Cys L‐TRP 80% of recommended daily feed intake

L‐Cys 60% of recommended daily feed intake

 less severe diarheas

(24)

.023

Outline

(25)

.024

The question of the nutritional cost of immunity

2 ways to get and provide energy and nutrients for immune functions

acquisition (= feed intake)

allocation (= metabolism)

Derting & Compton 2003

- the theory -

Feed intake Nutrients

Production

Immune functions Acquisition

α1

α2

Nutrient Allocation

(26)

.025

The question of the nutritional cost of immunity

• If the cost of IS is small compared to the other functions

 the animal could increase nutrient acquisition or/and change nutrient allocation towards immune functions

• If the cost of IS is (very) high compared to other functions

the animal won’t be able to maintain its immune functions

Derting & Compton 2003

- the theory -

Competition between functions when AA are limiting nutrients

Limiting AA

Limiting capacity of the organism to use AA

(27)

.026

Why dietary AA (as exogenous supply) may help to support immune system in livestock species?

 Rapidly growing young and immature animal : meats High productive animals : milk, eggs

 competition for AA utilisation, low acquisition (digestive capacity)

 Because of changes in AA allocation induced by immune system activation (systemic inflammatory response)

 high cost, low acquisition (sickness behaviour)

 Inadequate AA supplies : low protein diet, unbalanced protein

 low acquisition

(28)

.027

AA and maintenance of immune functions

- Lysine -

Klasing & Calvert 1999

Lysine intake, µmol/kg BW 9 520

mg tissue/kg µmol Lys /kg BW

Weight gain 85 000 5 950

Immune functions

Leucopoïesis 650 45.5

Ig synthesis 114 65.3

APP synthesis 0 0

Total 764 111

% of lysine intake

Use for growth 62.5%

Use for immune functions 1.2%

(29)

.028

AA and maintenance of immune functions

Bikker et al 2007

No antibiotic Antibiotic

Threonine in the feed

Antibiotics in feed reduced the maintenance cost of immune functions

- Threonine -

More Thr is required to maximize growth

More Thr for immune maintenance ?

(30)

.029

AA adjustment for mounting an immune response

AA

Limit the impact of inflammation on productive functions

(growth)

anti inflammatory and anti oxidant

effects Support immune functions

Immune cell activity

Synthesis of immune related proteins

Limit or prevent the the negative consequences

(31)

.030

Lys requirement for growth during immune system activation

Williams et al 1997 0

20 40 60 80 100 120 140

0..45 0,6 0,75 0,9 1,05

% dietary Lysine

Proteindeposition, g/d High sanitary status

Low sanitary status

Webel et al 1998

15 20 25 30 35 40

1.5

DIS Lys, mg/d

Proteindeposition, g/j

LPS Control

150 200 250 300 350 400

2.0 2.5 3.0

1.5 LPS Control

(32)

.031

Trp requirement for growth during immune activation

300 400 500 600

15 18 21 24

+ 15%

+ 6%

Dietray SID Trp/Lys %

Average daily gain, g/d 10‐35 kg

Control

Moderate inflammation

• no growth restoration with Trp

• greater response of growth to additional Trp

In pigs suffering from inflammation :

(33)

.032

Do dietary AA (as exogenous supply) may help to support immune system in livestock species?

But the question should be …

Do dietary AA (as exogenous supply) mays help to support HEALTH in livestock species?

(34)

.033

 Arg supplementation (up to 0.8%) in a milk based diet

enhanced spleen weigh, blood granulocytes and IgG and IL‐8 in piglets

Interpretation of immune indicators

Tan et al 2008

Does it reflect a protective immune response or does it result from a « toxic » effect?

(35)

.034

Conclusion (1)

 The nutritional cost of maintaining the immune system is probably not so high (# AA)

 BUT « basal »immune functions are affected by AA deficiency

 Does it really impact on health?

 Evidences showing that immune capacities compromised by AA deficiency may affect health are still scarce in

livestock

(36)

.035

Conclusion (2)

 The metabolic effort for mounting an immune response is high

+++ for inflammatory response

 Not all but some AA support immune functions and limit the negative effect on performance

 Two major limits for efficacy of nutritional adjusments reduced feed intake

catabolic state associated with inflammation

(37)

.036

Conclusion (3)

 AA may be used for their physiological role

• Antiinflammatory and antioxidant

• To limit the negative consequences of inflammation

 May require AA be supplied far above current nutritional recommandations

• Safety issue : side effects? toxicity?

• Economic issue

• Regulation issue : health allegation, drugs or nutrients?

(38)

.037

How amino acid may help to support a protective immune system

Conclusion (1)

Conclusion (2)

Conclusion (3)

Thank you for your

attention