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GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats

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Abstract

Background

Circulating endotoxin (lipopolysaccharide, LPS) increases the gut paracellular permeability. We hypothesized that glucagon-like peptide-2 (GLP-2) acutely reduces LPS-related increased intestinal paracellular permeability by a mechanism unrelated to its intestinotrophic effect.

Methods

We assessed small intestinal paracellular permeability in vivo by measuring the appearance of intraduodenally perfused FITC-dextran 4000 (FD4) into the portal vein (PV) in rats 1–24 h after LPS treatment (5 mg/kg, ip). We also examined the effect of a stable GLP-2 analog teduglutide (TDG) on FD4 permeability.

Results

FD4 movement into the PV was increased 6 h, but not 1 or 3 h after LPS treatment, with increased PV GLP-2 levels and increased mRNA expressions of proinflammatory cytokines and proglucagon in the ileal mucosa. Co-treatment with a GLP-2 receptor antagonist enhanced PV FD4 concentrations. PV FD4 concentrations 24 h after LPS were higher than FD4 concentrations 6 h after LPS, reduced by exogenous GLP-2 treatment given 6 or 12 h after LPS treatment. FD4 uptake measured 6 h after LPS was reduced by TDG 3 or 6 h after LPS treatment. TDG-associated reduced FD4 uptake was reversed by the VPAC1 antagonist PG97-269 or L-NAME, not by EGF or IGF1 receptor inhibitors.

Conclusions

Systemic LPS releases endogenous GLP-2, reducing LPS-related increased permeability. The therapeutic window of exogenous GLP-2 administration is at minimum within 6–12 h after LPS treatment. Exogenous GLP-2 treatment is of value in the prevention of increased paracellular permeability associated with endotoxemia.

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Abbreviations

DPP4:

Dipeptidyl peptidase-4

GLP-2:

Glucagon-like peptide-2

GLP2R:

GLP-2 receptor

LPS:

Lipopolysaccharide

GPCR:

G protein-coupled receptor

PV:

Portal vein

IGF-1:

Insulin-like growth factor-1

EGF:

Epidermal growth factor

NO:

Nitric oxide

NOS:

NO synthase

VIP:

Vasoactive intestinal peptide

L-NAME:

Nω-nitro-l-arginine methyl ester

PACAP:

Pituitary adenylate cyclase-activating peptide

TDG:

Teduglutide

VPAC1:

VIP/PACAP receptor-1

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Acknowledgment

This work was supported by a Department of Veterans Affairs Merit Review Award (Grant No. 5I01BX001245-08), NIH R01 DK54221, and an investigator-initiated Grant from Shire Pharmaceuticals/Takeda Pharmaceuticals USA (Grant Nos. IIR-USA-001851, IIR-USA-000857).

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    Authors and Affiliations

    1. Greater Los Angeles Veterans Affairs Healthcare System, West Los Angeles VA Medical Center, Bldg. 114, Suite 217, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA

      Yasutada Akiba, Emi Irie & Jonathan D. Kaunitz

    2. Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

      Koji Maruta, Takeshi Takajo, Yasutada Akiba, Hyder Said & Jonathan D. Kaunitz

    3. Department of Surgery, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

      Jonathan D. Kaunitz

    4. Brentwood Biomedical Research Institute, Los Angeles, CA, USA

      Yasutada Akiba & Jonathan D. Kaunitz

    5. Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan

      Ikuo Kato

    6. Research Unit for Epithelial Physiology, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan

      Atsukazu Kuwahara

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    Contributions

    Y.A. and J.D.K. were responsible for the study concept and design and for drafting article. K.M., T.T., Y.A., H.S., and E.I. were responsible for collection, assembly, and analysis of data. I.K and A.K provided the essential chemicals for the experiments. Y.A. and J.D.K. were responsible for data interpretation.

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    Correspondence to Jonathan D. Kaunitz.

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    Maruta and Takajo have equally contributed to this work.

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    Maruta, K., Takajo, T., Akiba, Y. et al. GLP-2 Acutely Prevents Endotoxin-Related Increased Intestinal Paracellular Permeability in Rats. Dig Dis Sci 65, 2605–2618 (2020). https://doi.org/10.1007/s10620-020-06097-6

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    • DOI: https://doi.org/10.1007/s10620-020-06097-6

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