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Homoectoine Protects Against Colitis by Preventing a Claudin Switch in Epithelial Tight Junctions

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Abstract

Background

Inflammatory bowel diseases (IBD) are multifactorial disorders affecting millions of people worldwide with alarmingly increasing incidences every year. Dysfunction of the intestinal epithelial barrier is associated with IBD pathogenesis, and therapies include anti-inflammatory drugs that enhance intestinal barrier function. However, these drugs often have adverse side effects thus warranting the search for alternatives. Compatible solutes such as bacterial ectoines stabilize cell membranes and proteins.

Aim

To unravel whether ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and homoectoine (4,5,6,7-tetrahydro-2-methyl-1H-(1,3)-diazepine-4-carboxylic acid), a synthetic derivative of ectoine, have beneficial effects during dextran sulfate sodium (DSS)-induced colitis in mice.

Methods/Results

We found that the disease activity index was significantly reduced by both ectoines. DSS-induced edema formation, epithelial permeability, leukocyte recruitment and tissue damage were reduced by ectoine and homoectoine, with the latter having stronger effects. Interestingly, the claudin switch usually observed during colitis (decreased expression of claudin-1 and increased expression of the leaky claudin-2) was completely prevented by homoectoine, whereas ectoine only reduced claudin-2 expression. Concomitantly, only homoectoine ameliorated the drop in transepithelial electrical resistance induced by IFN-γ and TNF-α in Caco-2 cells. Both ectoines inhibited loss of ZO-1 and occludin and prevented IFN-γ/TNF-α-induced increased paracellular flux of 4 kDa FITC-dextran in vitro. Moreover, both ectoines reduced expression of pro-inflammatory cytokines and oxidative stress during colitis.

Conclusion

While both ectoine and homoectoine have protective effects on the epithelial barrier during inflammation, only homoectoine completely prevented the inflammatory claudin switch in tight junctions. Thus, homoectoine may serve as diet supplement in IBD patients to reach or extend remission.

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Abbreviations

AJ:

Adherens junction

APJ:

Apical junction complex

CD:

Crohn’s disease

DAI:

Disease activity index

DSS:

Dextran sulfate sodium

IBD:

Inflammatory bowel diseases

IFN-γ:

Interferon-γ

IL:

Interleukin

KO:

Knock-out

MPO:

Myeloperoxidase

ROS:

Reactive oxygen species

TEER:

Transepithelial electrical resistance

TJ:

Tight junction

TNBS:

2,4,6-Trinitrobenzenesulfonic acid

TNF-α:

Tumor necrosis factor alpha

UC:

Ulcerative colitis

ZO:

Zonula occludens

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Acknowledgment

We thank Angélica Silva Olivares for expert technical assistance.

Funding

This work was supported by grants of the Mexican Council for Science and Technology (CONACyT, 233395 and 207268 to MS).

Author information

Author notes

  1. Alfonso Felipe-López

    Present address: Molecular Biology Division, Navy Medical Center, Ministry of Marine and Army, Av. Heroica Escuela Naval Militar, 04470, Mexico-City, Mexico

Authors and Affiliations

  1. Department of Molecular Biomedicine, CINVESTAV, Avenida IPN 2508, San Pedro Zacatenco, 07360, Mexico-City, Mexico

    Karla F. Castro-Ochoa, Hilda Vargas-Robles, Sandra Chánez-Paredes, Alfonso Felipe-López, Rodolfo I. Cabrera-Silva & Michael Schnoor

  2. Department of Infectomics and Molecular Pathogenesis, CINVESTAV, Avenida IPN 2508, San Pedro Zacatenco, 07360, Mexico-City, Mexico

    Mineko Shibayama & Abigail Betanzos

  3. Conacyt, Av. Insurgentes Sur 1582, 03940, Mexico-City, Mexico

    Abigail Betanzos

  4. Department of Physiology, Biophysics and Neurosciences, CINVESTAV, Avenida IPN 2508, San Pedro Zacatenco, 07360, Mexico-City, Mexico

    Porfirio Nava

  5. Institute of Microbiology and Biotechnology, University of Bonn, 53115, Bonn, Germany

    Erwin A. Galinski

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  1. Karla F. Castro-Ochoa
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Correspondence to Michael Schnoor.

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Castro-Ochoa, K.F., Vargas-Robles, H., Chánez-Paredes, S. et al. Homoectoine Protects Against Colitis by Preventing a Claudin Switch in Epithelial Tight Junctions. Dig Dis Sci 64, 409–420 (2019). https://doi.org/10.1007/s10620-018-5309-8

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  • DOI: https://doi.org/10.1007/s10620-018-5309-8

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