Microbial Regulation of Host Nutrient Metabolism

描述(由申请人提供)：当前肥胖和相关健康问题的流行对公共卫生构成了重大挑战。因此，确定调节能量摄入、吸收和储存的新治疗策略是一个重要的目标。近年来，消化道微生物群落(微生物区系)被认为是调节宿主营养代谢和能量储存的重要环境因素。肠道微生物群的存在导致体内脂肪显著增加，部分原因是微生物抑制肠道上皮细胞表达禁食诱导的脂肪因子(FIAF/ANGPTL4；一种循环中的脂蛋白脂肪酶抑制物)。在肠道中控制Fiaf表达的微生物信号和宿主转录调控机制仍然完全未知。我的研究计划的长期目标是了解消化道内宿主-微生物相互作用的分子机制。我们已经建立了一个斑马鱼诺生菌模型，并用它来揭示斑马鱼微生物区系在宿主营养代谢中的进化保守作用，包括斑马鱼Fiaf同源基因的肠道上皮抑制。发育中的斑马鱼的光学透明度，以及斑马鱼对遗传屏幕的适应性，为研究微生物区系在宿主生物学中的作用提供了新的机会。这项应用的总体目标是利用斑马鱼模型的优势来识别调节Fiaf表达的细菌和宿主因素。这项拟议的研究将解决这一中心假设，即肠道细菌通过宿主转录调控机制发出信号来抑制Fiaf，从而改变宿主能量平衡。这项研究的基本原理是，识别控制Fiaf合成的细菌和宿主机制将为操纵宿主能量储存提供新的靶点。在具体目标1中，我们将使用细菌遗传学方法来鉴定抑制Fiaf所需的细菌基因。在具体目标2中，我们将使用斑马鱼转基因和基因测试来确定控制肠道中Fiaf表达的宿主转录调控机制。这项研究的结果有望有助于对调节FIAF肠道表达的细菌基因和宿主转录调控机制有新的理解。这一贡献意义重大，因为它有望垂直推进肠道宿主-微生物互惠关系领域，并导致开发新的治疗策略来调节人类的能量储存。与公众健康相关：脂肪储存受到肠道中复杂的微生物群落的影响。这项拟议的研究的目标是了解肠道微生物是如何向宿主发出信号来调节脂肪储存的。这一新知识可能导致预防和治疗肥胖症及相关疾病的新的治疗方法。

DESCRIPTION (provided by applicant): The current epidemic of obesity and associated health problems is presenting significant public health challenges. The identification of new therapeutic strategies for regulating energy intake, absorption, and storage is therefore an important goal. The complex community of microorganisms residing within the digestive tract (microbiota) has recently been identified as an important environmental factor that regulates host nutrient metabolism and energy storage. The presence of the gut microbiota leads to a significant increase in body fat, caused in part by microbial suppression of intestinal epithelial expression of Fasting-induced adipose factor (Fiaf/Angptl4; a circulating inhibitor of lipoprotein lipase). The microbial signals and host transcriptional regulatory mechanisms that control Fiaf expression in the intestine remain completely unknown. The long-term goal of my research program is to understand the molecular mechanisms underlying host-microbial interactions in the digestive tract. We have established a gnotobiotic zebrafish model and used it to reveal evolutionarily-conserved roles for the zebrafish microbiota on host nutrient metabolism, including intestinal epithelial suppression of the zebrafish Fiaf ortholog. The optical transparency of the developing zebrafish, as well as the amenability of the zebrafish to genetic screens, provide new opportunities for investigating the roles of the microbiota in host biology. The overall objective of this application is to exploit the advantages of the zebrafish model to identify bacterial and host factors that regulate Fiaf expression. The proposed research will address the central hypothesis that intestinal bacteria signal through host transcriptional regulatory mechanisms to suppress Fiaf and thereby alter host energy balance. The rationale underlying the proposed research is that the identification of bacterial and host mechanisms that control Fiaf synthesis will provide new targets for the manipulation of host energy storage. In Specific Aim 1, we will use a bacterial genetic approach to identify bacterial genes required for suppression of Fiaf. In Specific Aim 2, we will use zebrafish transgenesis and genetic tests to identify host transcriptional regulatory mechanisms that control Fiaf expression in the intestine. The results of this research are expected to contribute a new understanding of the bacterial genes and host transcriptional regulatory mechanisms that regulate intestinal expression of Fiaf. This contribution is significant because it is expected to vertically advance the field of host-microbial mutualism in the intestine, and lead to the development of new therapeutic strategies for regulating energy storage in humans. PUBLIC HEALTH RELEVANCE: Fat storage is influenced by the complex community of microorganisms residing in the intestine. The goal of the proposed research is to understand how intestinal microorganisms signal to their host to regulate fat storage. This new knowledge could lead to novel therapeutic approaches for prevention and treatment of obesity and related diseases.