Bacterial modulators of metazoan lipogenesis

项目摘要 细菌生活在我们的肠道中，作为食物消化的媒介，产生必要的维生素，并与 我们的免疫系统允许驻留在我们的组织中。这种“交流”以代谢物的形式出现。 细菌产生的物质与我们的细胞相互作用，改变信号反应和转录机制。 尽管目前的研究已经描绘了生活在我们肠道中的许多细菌物种，并将它们与各种各样的细菌联系在一起 对于正常或病理生理状态，这些对复杂微生物区系的研究不能告诉我们 个别细菌产品会改变我们的细胞功能。如果没有这些知识，我们就不能理解 细胞通路是有针对性的，或者模拟或阻断细菌反应的疗法的效果是什么？ 那就是。 为了解决这个开放的关键问题，我们将两个遗传模型--秀丽隐杆线虫和大肠杆菌--配对，以 确定哪些细菌途径影响了宿主体内的脂肪积累。线虫消耗细菌，但 许多微生物保持完好，居住在肠道中，并在肠道中繁殖，类似于哺乳动物。使用 在线虫的视觉屏幕上，我们发现多个大肠杆菌突变株在柠檬酸甲酯循环中缺乏，这 将丙酸转化为丙酮酸或琥珀酸，刺激生脂记者。这个基因，类固醇Co-A 去饱和酶(SCD1)FAT-7对人类来说是保守的，它的调节是通过类固醇反应元件结合来实现的 蛋白(SREBP)家族转录因子。短链脂肪酸(SCFA)，如丙酸，已被 与影响宿主反应的细菌产物有关。令人惊讶的是，我们发现丙酸盐也能诱发SCD 在人肠源性细胞系中的表达。我们将使用线虫来确定连接的机制 丙酸对致脂基因的表达，测试这是否需要SREBPs，以及其他转录因子， 然后将这些研究扩展到哺乳动物细胞培养。代谢性疾病通常与两个“热门”有关： 脂肪生成和免疫功能。我们之前发现一条保守的代谢途径增加了脂肪-7在 线虫还能刺激先天免疫反应。因此，我们还将确定丙酸是否会发生变化 线虫和哺乳动物细胞的免疫功能。线虫的使用使快速的基因解剖成为可能 造脂和免疫反应，在整个动物模型的背景下确定调控途径。 我们的下一步是评估这些在人类细胞中的高置信度模型，确认与哺乳动物的相关性， 重要的是，它使我们能够在更复杂的哺乳动物环境中研究这些相互作用。

Project Summary Bacteria live in our gut, acting as agents for food digestion, producing essential vitamins and conversing with our immune systems to permit residence in our tissues. This “communication” occurs as the metabolites produced by the bacteria interact with our cells, changing signaling responses and transcriptional mechanisms. Although current studies have profiled many bacterial species living in our gut and linked them to a wide variety of normal or pathological physiological states, these studies of complex microbiota can not tell us how the individual bacterial products change our cellular function. Without this knowledge, we can't understand which cellular pathways are targeted, or what the effects of therapeutics that mimic or block bacterial responses would be. To address this open, critical question, we have paired two genetic models, C. elegans and E. coli, to determine which bacterial pathways affected fat accumulation in the host. C. elegans consume bacteria, but many of the microorganisms remain intact, reside and proliferate in the gut, similar to mammals. Using a visual screen in C. elegans, we found that multiple E. coli mutants deficient in the methylcitrate cycle, which converts propionate to pyruvate or succinate, stimulate a lipogenic reporter. This gene, the sterol Co-A desaturase (SCD1) fat-7, is conserved to humans, as is its regulation by the sterol response element binding protein (SREBP) family of transcription factors. Short chain fatty acids (SCFAs) such as propionate have been implicated as bacterial products influencing host responses. Strikingly, we found propionate also induces SCD expression in human intestine-derived cell lines. We will use C. elegans determine the mechanisms that link propionate to lipogenic gene expression, testing if this requires SREBPs, along with other transcription factors, then expand these studies to mammalian cell culture. Metabolic disease is often linked to two “hits”: lipogenesis and immune function. We previously found that a conserved metabolic pathway increasing fat-7 in C. elegans also stimulated innate immune responses. Therefore, we will also determine if propionate changes immune function in C. elegans and in mammalian cells. Use of C. elegans allows a rapid genetic dissection of lipogenic and immune responses, identifying regulatory pathways in the context of a whole animals model. Our next steps, evaluating these high confidence models in human cells, confirms relevance to mammals and, importantly, allows us to examine these interactions in the more complex mammalian context.