Westmark Cara J
Department of Neurology, University of Wisconsin, Madison, WI, United States.
Molecular Environmental Toxicology Center, University of Wisconsin, Madison, WI, United States.
Front Mol Neurosci. 2025 Mar 21;18:1520211. doi: 10.3389/fnmol.2025.1520211. eCollection 2025.
Gastrointestinal problems including vomiting, reflux, flatulence, diarrhea, constipation and colic are common comorbidities in fragile X syndrome. There is accumulating evidence suggesting that leaky gut syndrome causes neurological phenotypes. Although fragile X messenger ribonucleoprotein is ubiquitously expressed, there is a dearth of knowledge regarding its role outside of the brain including effects on gut dysfunction in fragile X. The aim of this study was to generate novel data on gastrointestinal barrier function and the gut microbiome in response to genotype, sex and diet in mice.
male mice and littermate controls in an FVB background were maintained on two purified ingredient diets (AIN-93G with casein protein versus soy protein isolate) versus two standard chows (Teklad 2019 with wheat, corn and yeast protein versus Purina 5015 with wheat, soy, corn, yeast and whey protein sources). Gut permeability was quantified by FITC-dextran levels in blood plasma. The cecal microbiome was identified by 16S rRNA sequencing. In addition, gut permeability was tested in mice in the C57BL/6 J background maintained on casein- and soy protein isolate-based AIN-93G versus Teklad 2019.
Knockout of the gene in FVB mice did not affect gut permeability. Soy protein isolate-based AIN-93G increased gut permeability. Beta-diversity of the cecal microbiome was significantly altered as a function of the four test diets. was increased in mice fed AIN-93G while unnamed species within the genus and family Ruminococcaceae were increased and the order Clostridales decreased in mice fed AIN-93G/soy. mice in the C57BL/6 J background exhibited increased gut permeability in response to soy protein.
These findings regarding the effects of diet on gut permeability and the microbiome have important implications for experimental design. Single-source diets are ubiquitously used to maintain laboratory animals for medical research and feed details are frequently not reported in publications. Diet/phenotype interactions could have a large impact on inter-laboratory replicability in premedical research. For infants with fragile X, early-life diet could impact the severity of disease outcomes.
胃肠道问题，包括呕吐、反流、肠胃胀气、腹泻、便秘和腹绞痛，是脆性X综合征常见的共病。越来越多的证据表明，肠道渗漏综合征会导致神经表型。尽管脆性X信使核糖核蛋白在全身广泛表达，但对于其在大脑之外的作用，包括对脆性X患者肠道功能障碍的影响，我们知之甚少。本研究的目的是生成关于小鼠胃肠道屏障功能和肠道微生物群对基因型、性别和饮食反应的新数据。
以FVB为背景的雄性小鼠及其同窝对照，分别喂食两种纯化成分饮食（含酪蛋白的AIN-93G与大豆分离蛋白）和两种标准饲料（含小麦、玉米和酵母蛋白的Teklad 2019与含小麦、大豆、玉米、酵母和乳清蛋白来源的普瑞纳5015）。通过血浆中异硫氰酸荧光素标记的葡聚糖水平来量化肠道通透性。通过16S rRNA测序鉴定盲肠微生物群。此外，还对以酪蛋白和大豆分离蛋白为基础的AIN-93G与Teklad 2019喂养的C57BL/6J背景小鼠的肠道通透性进行了测试。
FVB小鼠中该基因的敲除不影响肠道通透性。以大豆分离蛋白为基础的AIN-93G增加了肠道通透性。盲肠微生物群的β多样性因四种测试饮食而发生显著变化。喂食AIN-93G的小鼠中[未提及具体物质]增加，而喂食AIN-93G/大豆的小鼠中[未提及具体属名]属内未命名物种增加，梭菌目减少。C57BL/6J背景的小鼠对大豆蛋白的反应是肠道通透性增加。
这些关于饮食对肠道通透性和微生物群影响的发现对实验设计具有重要意义。单一来源的饮食被广泛用于饲养用于医学研究的实验动物，而出版物中往往不报告饲料细节。饮食/表型相互作用可能对医学前期研究中的实验室间可重复性产生重大影响。对于脆性X婴儿，早期饮食可能会影响疾病结局的严重程度。
