Pharmacological Restoration of Gut Barrier Function in Stressed Neonates Partially Reverses Long-Term Alterations Associated With Maternal Separation

Psychopharmacology (Berl). 2019 May;236(5):1583-1596. doi: 10.1007/s00213-019-05252-w. Epub 2019 May 23.

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.

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Azepines / pharmacology*
  • Azepines / therapeutic use
  • Corticosterone / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Gastrointestinal Microbiome / drug effects*
  • Gastrointestinal Microbiome / physiology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism*
  • Male
  • Maternal Deprivation*
  • Myosin-Light-Chain Kinase / pharmacology
  • Myosin-Light-Chain Kinase / therapeutic use
  • Naphthalenes / pharmacology*
  • Naphthalenes / therapeutic use
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism*
  • Stress, Psychological / psychology
  • Time Factors

Substances

  • Azepines
  • Naphthalenes
  • ML 7
  • Myosin-Light-Chain Kinase
  • Corticosterone