Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, 95616, USA.
Mol Psychiatry. 2022 Dec;27(12):4959-4973. doi: 10.1038/s41380-022-01752-y. Epub 2022 Aug 26.
Epidemiological evidence implicates severe maternal infections as risk factors for neurodevelopmental disorders, such as ASD and schizophrenia. Accordingly, animal models mimicking infection during pregnancy, including the maternal immune activation (MIA) model, result in offspring with neurobiological, behavioral, and metabolic phenotypes relevant to human neurodevelopmental disorders. Most of these studies have been performed in rodents. We sought to better understand the molecular signatures characterizing the MIA model in an organism more closely related to humans, rhesus monkeys (Macaca mulatta), by evaluating changes in global metabolic profiles in MIA-exposed offspring. Herein, we present the global metabolome in six peripheral tissues (plasma, cerebrospinal fluid, three regions of intestinal mucosa scrapings, and feces) from 13 MIA and 10 control offspring that were confirmed to display atypical neurodevelopment, elevated immune profiles, and neuropathology. Differences in lipid, amino acid, and nucleotide metabolism discriminated these MIA and control samples, with correlations of specific metabolites to behavior scores as well as to cytokine levels in plasma, intestinal, and brain tissues. We also observed modest changes in fecal and intestinal microbial profiles, and identify differential metabolomic profiles within males and females. These findings support a connection between maternal immune activation and the metabolism, microbiota, and behavioral traits of offspring, and may further the translational applications of the MIA model and the advancement of biomarkers for neurodevelopmental disorders such as ASD or schizophrenia.
流行病学证据表明，严重的母体感染是神经发育障碍（如 ASD 和精神分裂症）的风险因素。因此，模拟怀孕期间感染的动物模型，包括母体免疫激活（MIA）模型，会导致后代出现与人类神经发育障碍相关的神经生物学、行为和代谢表型。这些研究大多在啮齿动物中进行。我们试图通过评估 MIA 暴露后代的全局代谢谱变化，在与人类更密切相关的灵长类动物猕猴（Macaca mulatta）中更好地理解 MIA 模型的分子特征。在此，我们展示了来自 13 名 MIA 和 10 名对照后代的六个外周组织（血浆、脑脊液、三个肠黏膜刮取部位和粪便）的全局代谢组，这些后代被证实存在非典型神经发育、免疫特征升高和神经病理学。脂质、氨基酸和核苷酸代谢的差异区分了这些 MIA 和对照样本，特定代谢物与行为评分以及血浆、肠道和脑组织中的细胞因子水平之间存在相关性。我们还观察到粪便和肠道微生物群谱的轻微变化，并确定了雄性和雌性体内的差异代谢组学图谱。这些发现支持母体免疫激活与后代的代谢、微生物群和行为特征之间的联系，并可能进一步推进 MIA 模型的转化应用和神经发育障碍（如 ASD 或精神分裂症）的生物标志物的发展。
