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

摘要：木薯是我国6亿多人的主要粮食作物。 世界上的热带地区。全球传统上种植的木薯有两种，一种是“甜的”，另一种是 “苦味”品种，后者是一种耐环境的植物，含有极高到致命剂量的 有毒的生氰化合物。长期饮食依赖有毒木薯与氰化物有关 神经毒性，导致一种不可逆转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，有不成比例的 儿童受到影响的原因和机制尚未完全阐明。虽然几乎大多数受试者 在受魔芋影响的村庄，严重依赖氰化木薯作为主食，目前只有5%到10%。 伴有明显的痉挛麻痹。这表明，暴露水平、营养和环境成分 例如肠道微生物群的解毒能力可能是导致疾病的因素 敏感度。我们已经证明了肠道菌群分布在依赖于 关于刚果民主共和国低-高毒性水平的木薯。即使在刚果民主共和国的一个地区，也是高度 易受疾病暴发的影响，未受影响的细菌组成存在显著差异 同样，取决于他们居住在历史上魔芋流行程度较高或较低的村庄的个人 增加了通过肠道微生物群调节疾病的可能性。基于我们从我们的 初步和已发表的数据，我们将调查是否在肠道菌群之间的功能差异 性别匹配的兄弟姐妹对，通过利用后基因组学和转录组技术，对疾病有不一致的反应 粪便标本测序方法(目标1)。使用相同的研究人群，我们还将确定 如果使用最先进的技术识别出指示疾病状态或易感性的代谢生物标记物 代谢应用，如超高效液相色谱与质谱仪联用 (UHPLC-MS/MS)(目标2)。这两种方法生成的数据将使我们不仅能够评估 肠道微生物组的概况和功能与疾病状态有关，但将提供动力 确定与下游代谢过程有关的宿主-微生物组相互作用。考虑到 世界卫生组织估计，非传染性疾病造成的负担和死亡 (非传染性疾病)将超过疟疾和艾滋病毒的总和，在未来几年，我们已经嵌入了 全面的高级培训计划，以扩大关于非传染性疾病相关主题的知识，例如 营养学、毒理学、神经流行病学等相关学科。总而言之，这项建议和培训 PLAN将显著扩展我们对与木薯神经毒性相关的疾病调节因子的理解 有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，以实现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.