Alteration of intestinal permeability and effect of drugs on...

Alteration of intestinal permeability and effect of drugs on postoperative ileus in a guinea pig model

Young Min Kim, Zahid Hussain, Young Ju Lee, Hyojin Park

Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea

Introduction (1)

Related to alteration of intestinal permeability• Inflammatory bowel disease

• Functional gastrointestinal disease

• Malignancy

• Obesity-associated with metabolic diseases

• Allergic disease

Mechanisms• Gut inflammation

• Dysregulation for tight junction (TJ) proteins

• Gut dysbiosisGut 2007;56:61-72

Intest Res 2016;14:297-304Front Med 2018;5:349

Introduction (2)

Postoperative ileus (POI)

: Transient cessation of coordinated bowel motility after surgical procedure

Hypothesis I

: POI is associated with alteration of intestinal permeability.

J Neurogastroenterol Motil 2018;24:147-158

Mosapride Glutamine

Gut 2011;60:638-647Int J Mol Sci 2017;12:18

Introduction (3)

Introduction (4)Ketotifen

Hypothesis II: Mosapride, glutamine, and ketotifen have an effect on intestinal permeability.

Block the release of mast cell granules (tryptase, histamine, PG) following activation

Front Immunol 2015;6:238

Aims

Characterize the alteration of intestinal permeability in POI

Investigate whether mosapride, glutamine, and ketotifen have an effect on intestinal permeability in POI

Experimental POI model

Mosapride (0.3 and 1mg/kg, per oral)

POI 3H POI 6H

-1hr +1hr

Adult male guinea pigs, 250-350g

Harvest tissue (ileum & proximal colon)

Method

Glutamine (500mg/kg, per oral)

Ketotifen (1mg/kg, per oral)

-4D -1D-2D-3D

Measurements• Permeability

: Ussing chamber (differences in optical translucency)• Inflammatory markers

: Leukocyte count, calprotectin level• Tight junction proteins

: Claudin-1, 2 level

Analyses• Control vs. POI group • POI vs. Drug group

OP

Leukocyte count (POI 3H)

* P < 0.05

POI 3H

Ileum Proximal colon

Result

0

20

40

60

80

100

Control POI 3H MOS0.3mg

MOS 1mg GLN500mg

KET 1mg

Leu

kocy

tes/

fie

ld (

x40

0)

POI 3H

0

20

40

60

80

100


MOS 1mg GLN500mg

KET 1mg

Leu

kocy

tes/

fie

ld (

x40

0)

Leukocyte count (POI 6H)

* P < 0.05

POI 6H POI 6H


0

20

40

60

80

100


MOS 1mg GLN500mg

KET 1mg

Leu

kocy

tes/

fie

ld (

x40

0)

0

20

40

60

80

100


MOS 1mg GLN500mg

KET 1mg

Leu

kocy

tes/

fie

ld (

x40

0)

Result

Calprotectin level (POI 3H)

* P < 0.05

POI 3HPOI 3H


Result

0

5000

10000

15000

20000

25000

30000

35000


MOS 1mg GLN500mg

KET 1mg

Ave

rage

inte

nsi

ty (

x20

0)

0

5000

10000

15000

20000

25000

30000

35000


MOS 1mg GLN500mg

KET 1mg

Ave

rage

inte

nsi

ty (

x20

0)

Calprotectin level (POI 6H)

* P < 0.05

POI 6H POI 6H


Result

0

5000

10000

15000

20000

25000

30000

35000


MOS 1mg GLN500mg

KET 1mg

Ave

rage

inte

nsi

ty (

x20

0)

0

5000

10000

15000

20000

25000

30000

35000

Control POH 6H MOS0.3mg

MOS 1mg GLN500mg

KET 1mg

Ave

rage

inte

nsi

ty (

x20

0)

Claudin-1 level

* P < 0.05

POI 6H POI 6H


0

10

20

30

40

50

60

70

80

90

Control POI 6H MOS 0.3mg GLN 500mg KET 1mg

Ave

rage

inte

nsi

ty (

x10

6)

0

10

20

30

40

50

60

70

80

90


Ave

rage

inte

nsi

ty (

x10

6)

Result

Claudin-2 level

* P < 0.05

POI 6H POI 6H


0

10

20

30

40


Ave

rage

inte

nsi

ty (

x10

6)

0

10

20

30

40


Ave

rage

inte

nsi

ty (

x10

6)

Result

Mast cell tryptase

* P < 0.05

POI 6HPOI 6H

Proximal colon

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

Control POI 3H KET 1mg POI 6H KET 1mg

Ave

rage

inte

nsi

ty (

x20

0)

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

Control POI 3H KET 1mg POI 6H KET 1mg

Ave

rage

inte

nsi

ty (

x20

0)

POI 3HPOI 3H

Ileum

Result

Permeability (POI 3H)

* P < 0.05


0

100

200

300

400

500

600


MOS 1mg GLN500mg

KET 1mg

% c

han

ge f

rom

co

ntr

ol

0

100

200

300

400

500

600


MOS 1mg GLN500mg

KET 1mg

% c

han

ge f

rom

co

ntr

ol

POI 3H POI 3H

Result

Permeability (POI 6H)

* P < 0.05


0

100

200

300

400

500

600


MOS 1mg GLN500mg

KET 1mg

% c

han

ge f

rom

co

ntr

ol

0

100

200

300

400

500

600


MOS 1mg GLN500mg

KET 1mg

% c

han

ge f

rom

co

ntr

ol

POI 6H POI 6H

Result

Alteration of intestinal permeability and change ofinflammatory markers, claudin level, and mast cell tryptasewere observed in the POI guinea pig model.

Mosapride, glutamine, and ketotifen have an anti-inflammatory effect, thereby, modulates intestinal permeability.

Notably, glutamine had an effect on tight junction proteins,and ketotifen had an effect on mast cells.

Conclusions

Thank You for Your Attention

Alteration of intestinal permeability and effect of drugs on...

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