Abnormal enteric nervous system organization and gastrointestinal motility in mice with valproic acid-induced neural tube defects

2026 · doi:10.64898/2026.02.26.708353
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This study investigated the structural and functional alterations of the enteric nervous system in mouse embryos exposed to valproic acid, a model for neural tube defects. Researchers utilized immunohistochemistry and ex vivo motility assays to observe that these embryos exhibited thinner enteric neuronal stripes with narrower interstripe distances in the duodenum and jejunum. Consequently, the gastrointestinal tracts displayed abnormal motility characterized by increased contraction frequency and longer contractile segments. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Background Neurogenic bowel is a major cause of morbidity in patients affected by neural tube defects (NTDs) such as spina bifida, but the underlying reasons for bowel dysfunction are unknown. An absolute requirement for gastrointestinal (GI) motility is the enteric nervous system (ENS) located within the walls of the GI tract. Enteric neurons coalesce into circumferential stripes throughout embryonic and early postnatal development, and this gradual organization of the ENS into enteric neuronal stripes correlates with the emergence of neurogenic GI motility. We hypothesized that NTDs are associated with changes in ENS organization that correlate with specific GI motility defects. Methods We used prenatal valproic acid (VPA) exposure as a model for NTDs in embryonic mice. We used immunohistochemistry, high resolution confocal imaging, and ex vivo motility assays to assess enteric neuronal stripes and gastrointestinal motility in embryos with a VPA-induced neural tube defect. Key results GI tracts from embryos with a VPA-induced NTD contain blood. Structurally, the enteric neuronal stripes are thinner with a narrower interstripe distance, leading to an increased number of stripes. Functionally, GI motility is abnormal, with increased contraction frequency and increased length of contractile segments. Conclusions and inferences ENS organization and GI motility are disrupted in mouse embryos with a VPA-induced NTD. This has important implications for our understanding of neurogenic bowel in central nervous system diseases such as spina bifida. Key Points - VPA exposure is a reliable model of neural tube defects with variable intralitter susceptibility - Embryos with a VPA-induced neural tube defect have blood in the amniotic sac and within the lumen of the gastrointestinal tract - Enteric nervous system organization is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, with thinner enteric neuronal stripes and narrower interstripe distance - Ex vivo gastrointestinal motility is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, including increased contraction frequency and increased length of the contractile segment
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Abstract

Background Neurogenic bowel is a major cause of morbidity in patients affected by neural tube defects (NTDs) such as spina bifida, but the underlying reasons for bowel dysfunction are unknown. An absolute requirement for gastrointestinal (GI) motility is the enteric nervous system (ENS) located within the walls of the GI tract. Enteric neurons coalesce into circumferential stripes throughout embryonic and early postnatal development, and this gradual organization of the ENS into enteric neuronal stripes correlates with the emergence of neurogenic GI motility. We hypothesized that NTDs are associated with changes in ENS organization that correlate with specific GI motility defects.

Methods

We used prenatal valproic acid (VPA) exposure as a model for NTDs in embryonic mice. We used immunohistochemistry, high resolution confocal imaging, and ex vivo motility assays to assess enteric neuronal stripes and gastrointestinal motility in embryos with a VPA-induced neural tube defect. Key results GI tracts from embryos with a VPA-induced NTD contain blood. Structurally, the enteric neuronal stripes are thinner with a narrower interstripe distance, leading to an increased number of stripes. Functionally, GI motility is abnormal, with increased contraction frequency and increased length of contractile segments.

Conclusions

and inferences ENS organization and GI motility are disrupted in mouse embryos with a VPA-induced NTD. This has important implications for our understanding of neurogenic bowel in central nervous system diseases such as spina bifida. Key Points - VPA exposure is a reliable model of neural tube defects with variable intralitter susceptibility - Embryos with a VPA-induced neural tube defect have blood in the amniotic sac and within the lumen of the gastrointestinal tract - Enteric nervous system organization is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, with thinner enteric neuronal stripes and narrower interstripe distance - Ex vivo gastrointestinal motility is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, including increased contraction frequency and increased length of the contractile segment Competing Interest Statement The authors have declared no competing interest.

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