PDF(Pubmed)
Abstract：
Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut-immune interactions in GWI.
摘要：
数十年来，研究人员一直未能解开多种症状的海湾战争疾病（GWI）病理并找到有效的治疗方法。在小鼠模型中研究病因的慢性症状持续性和局限性与人类的病因显着不同，这对药物发现和寻找有效的治疗方案构成了挑战。GWI暴露在研究队列中存在显着差异，以上情况使得很难重建与GWI症状病理学非常相似的模型。我们已经使用双重植入策略来重建人类免疫系统以及人类微生物组转移，以创建GWI的人源化小鼠模型。采用全基因组鸟枪测序和血液免疫细胞因子酶联免疫吸附试验(ELISA),我们表明，我们用海湾战争（GW）化学物质处理的双人化小鼠显示出显着改变的肠道微生物组，与GWI的退伍军人队列中报道的相似。结果还显示了相似的细胞因子谱，如IL-1β水平升高，双人源化模型中的IL-6和TNF-R-1，正如以前在人类队列中发现的那样。Further,我们利用一种新型GWI退伍军人粪便微生物群转移方法创建了第二种替代模型,该模型与GWI退伍军人的微生物组和免疫系统相关病理非常相似.在人源化小鼠中的GWI退伍军人微生物群移植显示了人类微生物组重建和全身性炎症病理，正如白细胞介素1β的增加所反映的那样，6，8（IL-1β，IL-6,IL-8),肿瘤坏死因子受体1（TNF-R-1），和内毒素血症。总之,虽然是初步的，我们报道了一种新的体内模型,该模型具有人类微生物组重建和移植的人类免疫表型,可能有助于更好地了解GWI中的肠道-免疫相互作用.
