Eberly Gari L, Manthey Marie, Pang Karen K L, Hussein Heba, Vargas Paniagua Emmanuel, Machen Scott, Klingensmith Sara Maeve, Anikeeva Polina
MIT-Harvard Graduate Program in Health Sciences and Technology, Boston, MA, United States.
K. Lisa Yang Brain-Body Center, Massachusetts Institute of Technology, Cambridge, MA, United States.
Front Neurosci. 2025 Apr 17;19:1552369. doi: 10.3389/fnins.2025.1552369. eCollection 2025.
Gastrointestinal (GI) comorbidities are common among those with Autism Spectrum Disorder (ASD), but their etiology is not well understood. This study aimed to characterize gastrointestinal morphology and function in Shank3B mutant mice, a common genetic model of ASD, to identify potential alterations to the GI tract that could underlie ASD-associated GI comorbidities.
GI and enteric nervous system morphology was characterized using Hematoxylin and Eosin staining and immunohistochemistry. GI permeability was measured using the FITC-Dextran paracellular permeability assay. Whole-GI tract motility time was measured using the carmine dye motility assay. Colonic contractions were characterized by tracking motility using an motility assay.
Homozygous knock-out (KO) mice exhibit significantly altered epithelial morphology and increased GI permeability. An increased myenteric plexus density and a higher number of HuC/D-expressing neurons in myenteric ganglia are observed in the colon of mice. These mice exhibit slowed whole-GI tract transit and reduced velocity and propagation length of colonic contractions. Compared to mice, heterozygous mice exhibit milder epithelial, neuronal, and functional alterations.
mice exhibit altered GI morphology and function, while mice exhibit a partial phenotype. These results indicate that whose mutation is associated with ASD, is critical for function of the GI tract and its mutation may contribute to the etiology of GI comorbidities.
胃肠道（GI）合并症在自闭症谱系障碍（ASD）患者中很常见，但其病因尚不完全清楚。本研究旨在描述ASD常见遗传模型Shank3B突变小鼠的胃肠道形态和功能，以确定可能是ASD相关胃肠道合并症基础的胃肠道潜在改变。
使用苏木精和伊红染色及免疫组织化学对胃肠道和肠神经系统形态进行表征。使用异硫氰酸荧光素-葡聚糖（FITC-Dextran）跨细胞通透性测定法测量胃肠道通透性。使用胭脂红染料运动测定法测量全胃肠道运动时间。通过使用运动测定法跟踪运动来表征结肠收缩。
纯合敲除（KO）小鼠表现出明显改变的上皮形态和增加的胃肠道通透性。在KO小鼠的结肠中观察到肌间神经丛密度增加以及肌间神经节中表达HuC/D的神经元数量增加。这些小鼠表现出全胃肠道转运减慢以及结肠收缩速度和传播长度降低。与野生型小鼠相比，杂合KO小鼠表现出较轻的上皮、神经元和功能改变。
KO小鼠表现出改变的胃肠道形态和功能，而杂合KO小鼠表现出部分表型。这些结果表明，其突变与ASD相关的Shank3B对胃肠道功能至关重要，其突变可能导致胃肠道合并症的病因。
