Modulatory Effects of the Functional Gut Microbiome in Relation to Cassava Associated Motor and Neurocognitive Deficits

翻译后摘要：木薯（Manihot esculenta Crantz）作为一种主食作物，超过6亿人， 世界的热带地区。两种类型的木薯传统上种植在地球仪上，"甜"和 “苦”品种，后者是一种环境耐受性植物，含有极高至致命剂量的 有毒的氰化合物长期饮食依赖有毒木薯与氰化物有关 神经毒性，导致不可逆的，非进行性运动神经元疾病称为konzo，并可能， 神经认知缺陷在撒哈拉以南非洲的易发地区， 受影响的儿童的原因和机制尚待充分阐明。虽然几乎大多数科目 在受konzo影响的村庄，严重依赖生氰木薯作为主食，目前只有约5%至10% 有明显的痉挛性下肢瘫痪这表明接触水平、营养和环境成分 例如肠道微生物组的解毒能力可能是疾病的促成因素， 易感性我们已经表明，肠道植物群配置文件之间的青少年谁依赖显着不同， 在刚果民主共和国的木薯上进行了低-高毒性试验。即使在刚果民主共和国的一个地区， 易受疾病爆发的影响，未受影响的细菌之间的细菌组成存在显着差异。 个人取决于他们是否居住在历史上konzo患病率高或低的村庄， 增加了通过肠道微生物组调节疾病的可能性。根据我们的洞察力， 初步和发表的数据，我们将调查是否有功能差异，在肠道菌群之间， 性别匹配的同胞对谁是不一致的疾病，通过利用宏基因组和转录组学 粪便标本的测序方法（目的1）。使用相同的研究人群，我们还将确定 如果代谢生物标志物是可识别的，其指示疾病状态或易感性， 代谢应用，如超高效液相色谱与质谱联用 （UHPLC-MS/MS）（目的2）。从这两种方法产生的数据将使我们不仅能够评估 与疾病状态相关的肠道微生物组的特征和功能，但将提供动力， 确定宿主-微生物组在下游代谢过程中的相互作用。鉴于 世界卫生组织估计，非传染性疾病造成的负担和死亡人数 非传染性疾病的发病率将超过疟疾和艾滋病毒的总和，在未来几年里，我们已经嵌入了一个 全面的高级培训计划，以扩大对非传染性疾病相关专题的了解， 营养学、毒理学、神经流行病学等相关学科。总的来说，这项建议和培训 该计划将大大扩展我们对与木薯神经毒性相关的疾病调节剂的理解 这可能用于监测和预防战略，同时提供足够的学术和 以研究为基础的培训，为独立的全球卫生科学事业。

Abstract: Cassava (Manihot esculenta Crantz) serves as a staple crop for more than 600 million people in tropical regions of the world. Two types of cassava are traditionally grown across the globe, the “sweet” and “bitter” varieties, the latter being an environmentally tolerant plant, harboring extremely high to lethal doses of toxic cyanogenic compounds. Chronic dietary reliance on toxic cassava is associated with cyanide neurotoxicity, causing an irreversible, non-progressive motor neuron disease known as konzo and possibly, deficits in neurocognition. Within prone regions of sub-Saharan Africa, there are a disproportionate number of children affected for reasons and mechanisms that have yet to be fully elucidated. While nearly most subjects in konzo-affected villages rely heavily on cyanogenic cassava as a staple food, only about 5 to 10% present with a visible spastic paraparesis. This suggests that exposure levels, nutrition, and environmental components such as the detoxification capabilities of the gut microbiome are likely contributing factors in disease susceptibility. We have shown that the gut flora profiles are significantly different between adolescents who rely on cassava with low-high levels of toxicity in the DRC. Even within a region of the DRC that is highly susceptible to outbreaks of disease, there are marked differences in bacterial composition between unaffected individuals depending on whether they reside in villages with historically high or low konzo prevalence, again adding to the likelihood of disease modulation through the gut microbiome. Based on insight from our preliminary and published data, we will investigate if there are functional differences in the gut-flora between sex-matched sibling pairs who are discordant for disease, by utilizing metagenomic and transcriptomic sequencing approaches on stool specimens (Aim 1). Using the same study population, we will also determine if metabolic biomarkers are identifiable that indicate a disease state or susceptibility using state-of-the-art metabolic applications, such as ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS/MS) (Aim 2). The data generated from both approaches will enable us to not only assess the profiles and functionality of the gut microbiome in relation to disease status, but will provide the power to determine the host-microbiome interaction in regards to downstream metabolic processes. Given that the World Health Organization estimates that the burden and deaths resulting from non-communicable diseases (NCDs) will surpass those from malaria and HIV combined, in the coming years, we have embedded a comprehensive advanced training plan to expand knowledge on pertinent topics relating to NCDs, such as nutrition, toxicology, neuroepidemiology and other relevant disciplines. Collectively, this proposal and training plan will significantly expand our understanding of disease modulators associated with cassava neurotoxicity that can be potentially used for monitoring and prevention strategies, while providing adequate academic and research-based training for an independent global health scientific career.