Maternal vitamin A deficiency impairs cholinergic and nitrergic neurons, leading to gastrointestinal dysfunction in rat offspring via RARβ

Aims: Many gastrointestinal (GI) disorders are developmental in origin and are caused by abnormal enteric nervous system (ENS) formation. Maternal vitamin A deficiency (VAD) during pregnancy affects multiple central nervous system developmental processes during embryogenesis and fetal life. Here, we evaluated whether maternal diet-induced VAD during pregnancy alone can cause changes in the ENS that lead to GI dysfunction in rat offspring. Main methods: Rats were selected to construct animal models of normal VA, VA deficiency and VA supplementation. The fecal water content, total gastrointestinal transmission time and colonic motility were measured to evaluate gastrointestinal function of eight-week-old offspring rats. The expression levels of RAR beta, SOX10, cholinergic (ChAT) and nitrergic (nNOS) enteric neurons in colon tissues were detected through western blot and immunofluorescence. Primary enteric neurospheres were treated with retinoic acid (RA), infection with Ad-RAR beta and siRAR beta adenovirus, respectively. Key findings: Our data revealed marked reductions in the mean densities of cholinergic and nitrergic enteric neurons in the colon and GI dysfunction evidenced by mild intestinal flatulence, increased fecal water content, prolonged total GI transit time and reduced colon motility in adult offspring of the VAD group. Interestingly, maternal VA supplementation (VAS) during pregnancy rescued these changes. In addition, in vitro experiments demonstrated that exposure to appropriate doses of RA promoted enteric neurosphere differentiation into cholinergic and nitrergic neurons, possibly by upregulating RAR beta expression, leading to enhanced SOX10 expression. Significance: Maternal VAD during pregnancy is an environmental risk factor for GI dysfunction in rat offspring.

Automated summary

Maternal vitamin A deficiency during pregnancy can lead to significant reductions in cholinergic and nitrergic enteric neurons density in the colon of rat offspring, resulting in gastrointestinal dysfunction. Interestingly, maternal vitamin A supplementation during pregnancy can rescue these changes. In vitro experiments showed that retinoic acid exposure promoted the differentiation of enteric neurospheres into cholinergic and nitrergic neurons, possibly through upregulating RAR beta expression and enhancing SOX10 expression.