Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Nutrition and Health, China; Ministry of Education Key Laboratory of Child Development and Disorders, China; National Clinical Research Center for Child Health and Disorder, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, China.
Children's Nutrition Research Center, Children's Hospital of Chongqing Medical University, Chongqing Key Laboratory of Child Nutrition and Health, China; Ministry of Education Key Laboratory of Child Development and Disorders, China; National Clinical Research Center for Child Health and Disorder, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, China.
Life Sci. 2021 Jan 1;264:118688. doi: 10.1016/j.lfs.2020.118688. Epub 2020 Oct 29.
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.
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 RARβ, 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-RARβ and siRARβ adenovirus, respectively.
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 RARβ expression, leading to enhanced SOX10 expression.
Maternal VAD during pregnancy is an environmental risk factor for GI dysfunction in rat offspring.
许多胃肠道（GI）疾病源于发育异常，是由肠神经系统（ENS）形成异常引起的。妊娠期间母体维生素 A 缺乏（VAD）会影响胚胎发生和胎儿期的多个中枢神经系统发育过程。在这里，我们评估了妊娠期间母体饮食引起的 VAD 是否单独引起 ENS 变化，从而导致大鼠后代的 GI 功能障碍。
选择大鼠构建正常 VA、VA 缺乏和 VA 补充的动物模型。通过测量粪便含水量、全胃肠道传递时间和结肠蠕动，评估 8 周龄子代大鼠的胃肠道功能。通过 Western blot 和免疫荧光检测结肠组织中 RARβ、SOX10、胆碱能（ChAT）和氮能（nNOS）肠神经元的表达水平。分别用维甲酸（RA）、Ad-RARβ 和 siRARβ 腺病毒处理原代肠神经球。
我们的数据显示，VA 缺乏组成年子代的结肠中胆碱能和氮能肠神经元的平均密度明显降低，并且出现 GI 功能障碍，表现为轻度肠胀气、粪便含水量增加、全胃肠道传递时间延长和结肠蠕动减少。有趣的是，妊娠期间母体 VA 补充（VAS）可以挽救这些变化。此外，体外实验表明，适当剂量的 RA 暴露促进肠神经球分化为胆碱能和氮能神经元，可能通过上调 RARβ 表达，从而增强 SOX10 表达。
妊娠期间母体 VAD 是大鼠子代 GI 功能障碍的环境风险因素。
