MIA mice exhibit enteric nerve defects and are more susceptible to dextran sulfate sodium-induced colitis

Abstract

Maternal immune activation (MIA) during pregnancy impairs the development of the central nervous system as well as the peripheral nervous system. Emerging evidence indicates that individuals with MIA suffer more from gastrointestinal disorders. The present study aims to test the hypothesis that MIA-induced susceptibility to inflammatory bowel disease is due to defects in the innervation of mucosal sensory nerves. Acute dextran sulfate sodium (DSS) colitis was induced in MIA and control adult mice. Body weight loss, disease activity index and colonic histological changes were measured during colitis. The study found that MIA mice were hypersusceptible to DSS-induced colitis and that macrophage infiltration and cytokine production were elevated in the colon of MIA mice. In vitro experiments also demonstrated that colonic macrophages from MIA mice presented hyperinflammatory responses to LPS stimulation. Sensory nerve-secreted calcitonin gene-related peptide (CGRP) is an important neuropeptide in modulating enteric inflammation. Intriguingly, we found that CGRP-positive nerves were sparsely distributed in the colon of MIA mice regardless of DSS treatment. And the protein level of CGRP was significantly reduced in colon of MIA mice. However, there was no decrease in the number of CGRP-positive cell bodies in either the DRG or vagal ganglion, suggesting that innervation defects of CGRP mucosal sensory nerves exist in the colon of MIA mice. Critically, administration of recombinant CGRP to MIA mice during DSS colitis significantly reversed their hyperinflammatory pathology. Additionally, the hyperinflammatory phenotype of colonic macrophages of MIA mice could also be reversed by CGRP treatment in vitro. Collectively, these findings suggested that the sensor nerve innervation defect-induced CGRP deficiency in MIA mice participates in their increased susceptibility to colitis. Thus, sensor nerve-secreted CGRP may be a new therapeutic target for autism combined with inflammatory bowel disease.

Keywords: CGRP; Inflammatory bowel disease; Macrophage; Maternal immune activation; Mice.