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Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation

Abstract

Rationale

Intestinal permeability plays an important role in gut-brain axis communication. Recent studies indicate that intestinal permeability increases in neonate pups during maternal separation (MS).

Objectives

The present study aims to determine whether pharmacological inhibition of myosin light chain kinase (MLCK), which regulates tight junction contraction and controls intestinal permeability, in stressed neonates, protects against the long-term effects of MS.

Methods

Male Wistar rats were exposed to MS (3 h per day from post-natal day (PND)2 to PND14) or left undisturbed and received daily intraperitoneal injection of a MLCK inhibitor (ML-7, 5 mg/kg) or vehicle during the same period. At adulthood, emotional behaviors, corticosterone response to stress, and gut microbiota composition were analyzed.

Results

ML-7 restored gut barrier function in MS rats specifically during the neonatal period. Remarkably, ML-7 prevented MS-induced sexual reward–seeking impairment and reversed the alteration of corticosterone response to stress at adulthood. The effects of ML-7 were accompanied by the normalization of the abundance of members of Lachnospiraceae, Clostridiales, Desulfovibrio, Bacteroidales, Enterorhabdus, and Bifidobacterium in the feces of MS rats at adulthood.

Conclusions

Altogether, our work suggests that improvement of intestinal barrier defects during development may alleviate some of the long-term effects of early-life stress and provides new insight on brain–gut axis communication in a context of stress.

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Acknowledgements

This work was supported by Univ. Bordeaux, the AlimH department of the Institut National de la Recherche Agronomique (INRA), projet inter-régions Aquitaine - Midi-pyrénées, ITMO neurosciences, sciences cognitives, neurologie, psychiatrie. MD was supported by the FFAS (Fond français alimentation santé) and the ANR (Agence Nationale de la Recherche). M.R. and A.L. were supported by a stipend of the French Ministry of Research. AMC was the recipient of a Master fellowship from the Erasmus+ program. The authors acknowledge technical help from Agnès Aubert, Julie Sauvant, and Michèle Nankap for cytokines assay, c-FOS analysis, and genomic bacterial DNA extraction. The authors are grateful to P Costet for his valuable advice for BBB permeability experiment. The authors are grateful to the Get-platform teams (TRIX & PlaGe, Toulouse) for 16S rDNA libraries and sequencing, Genotoul bioinformatics platform Toulouse Midi-Pyrénées, and Sigenae group for providing help and storage resources thanks to Galaxy instance http://sigenae-workbench.toulouse.inra.fr.

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Correspondence to Muriel Darnaudéry.

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The authors declare that they have no conflict of interest.

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This article belongs to a Special Issue on Microbiome in Psychiatry & Psychopharmacology

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Rincel, M., Olier, M., Minni, A. et al. Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation. Psychopharmacology 236, 1583–1596 (2019). https://doi.org/10.1007/s00213-019-05252-w

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  • DOI: https://doi.org/10.1007/s00213-019-05252-w

Keywords

  • Intestinal permeability
  • Myosin light chain kinase
  • Early-life stress
  • Depression
  • Irritable bowel syndrome
  • Animal models
  • Intestinal barrier
  • Blood-brain barrier
  • Female urine sniffing test
  • 16S sequencing