Molecular Mechanisms of Reelin in the Enteric Nervous System and the Microbiota-Gut-Brain Axis: Implications for Depression and Antidepressant Therapy

Abstract

Current pharmacological treatments for depression fail to produce adequate remission in a significant proportion of patients. Increasingly, other systems, such as the microbiome-gut-brain axis, are being looked at as putative novel avenues for depression treatment. Dysbiosis and dysregulation along this axis are highly comorbid with the severity of depression symptoms. The endogenous extracellular matrix protein reelin is present in all intestinal layers as well as in myenteric and submucosal ganglia, and its receptors are also present in the gut. Reelin secretion from subepithelial myofibroblasts regulates cellular migration along the crypt-villus axis in the small intestine and colon. Reelin brain expression is downregulated in mood and psychotic disorders, and reelin injections have fast antidepressant-like effects in animal models of depression. This review seeks to discuss the roles of reelin in the gastrointestinal system and propose a putative role for reelin actions in the microbiota-gut-brain axis in the pathogenesis and treatment of depression, primarily reflecting on alterations in gut epithelial cell renewal and in the clustering of serotonin transporters.

Keywords: antidepressant; crypt–villus axis migration; depression; enteric nervous system; gut–brain axis; microbiota; reelin.

Figure 1

Avenues of communication between the gut and the brain. The four primary avenues of microbiota–gut–brain communication. Damaged epithelium leads to increased translocation of gut bacteria into circulation (A). Microbial metabolites like short-chain fatty acids (SCFAs), neurotransmitters, and cytokines enter circulation to affect central structures (B). The vagus nerve provides a bidirectional communication pathway for the gut and brain (C). Activation of the hypothalamus–pituitary–adrenal (HPA) axis leads to the production of cortisol, which increases intestinal permeability and alters microbial composition (D).

Figure 2

Crypt–villus axis migration in the small intestine and colon. A schematic delineating crypt–villus axis migration in the small intestine (left panel) and colon (right panel). Reelin is released from subepithelial myofibroblasts to aid in migration processes. Intestinal stem cells of the crypts differentiate into enterocytes, goblet cells, tuft cells, enteroendocrine cells, and Paneth cells (small intestine only). Migrating cells “push” adjacent cells above to encourage cell death and lining regeneration. Additionally, cell death on the villi facilitates proliferative and migratory processes in the crypts. Following migration to villus tips and differentiation, cells live for 3–5 days before being shed into the lumen of the gut. Paneth cells can live for close to 60 days.