Microbial Regulation of Host Nutrient Metabolism

描述（由申请人提供）：目前肥胖症和相关健康问题的流行正在提出重大的公共卫生挑战。因此，确定用于调节能量摄入、吸收和储存的新的治疗策略是一个重要的目标。消化道内复杂的微生物群落（微生物群）最近被确定为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身体脂肪的显著增加，这部分是由禁食诱导的脂肪因子（Fiaf/Angptl 4;脂蛋白脂肪酶的循环抑制剂）的肠上皮表达的微生物抑制引起的。控制肠道中Fiaf表达的微生物信号和宿主转录调节机制仍然完全未知。我的研究计划的长期目标是了解消化道中宿主-微生物相互作用的分子机制。我们已经建立了一个gnotobiotic斑马鱼模型，并用它来揭示斑马鱼微生物群对宿主营养代谢的进化保守作用，包括斑马鱼Fiaf直系同源物的肠上皮抑制。发育中的斑马鱼的光学透明度以及斑马鱼对遗传筛选的顺从性为研究微生物群在宿主生物学中的作用提供了新的机会。本申请的总体目标是利用斑马鱼模型的优势来鉴定调节Fiaf表达的细菌和宿主因子。拟议的研究将解决核心假设，即肠道细菌通过宿主转录调控机制发出信号，以抑制Fiaf，从而改变宿主能量平衡。拟议研究的基本原理是，控制Fiaf合成的细菌和宿主机制的鉴定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遗传测试来识别控制肠道中Fiaf表达的宿主转录调控机制。本研究的结果有望有助于对调控肠道表达的Fiaf的细菌基因和宿主转录调控机制的新认识。这一贡献是重要的，因为它有望垂直推进肠道中宿主-微生物互利共生的领域，并导致开发用于调节人类能量储存的新治疗策略。公共卫生相关性：脂肪储存受到肠道内复杂微生物群落的影响。这项研究的目的是了解肠道微生物如何向宿主发出信号来调节脂肪储存。这一新的知识可能会导致预防和治疗肥胖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.