The role of the gut mycobiota in regulating host lipid absorption and obesity

肠道菌群在调节宿主脂质吸收和肥胖中的作用

• 批准号: 10453363
• 负责人: Kristina Brooke Martinez-Guryn
• 金额: $ 16.53万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10453363
• 关键词: 16S ribosomal RNA sequencing; Adult; Antibiotics; BODIPY; Bacteria; Binding; Biological Assay; Body Composition; Body Weight; C Type Lectin Receptors; CD36 gene; Candida; Candida albicans; Carbohydrates; Communities; Consumption; Data; Diabetes Mellitus; Diet; Digestion; Disease; Epithelial; Esterification; Eukaryota; Fat-Restricted Diet; Fatty Acids; Fatty acid glycerol esters; Fluorescent in Situ Hybridization; Gene Expression; Genes; Genetic; Germ-Free; Gnotobiotic; Goals; Health Care Costs; High Fat Diet; Human; Impairment; In Vitro; Insulin Resistance; Intestines; Knock-out; Knockout Mice; Knowledge; Length; Lipids; Literature; Macronutrients Nutrition; Mediating; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic dysfunction; Metabolism; Microbe; Molecular; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Organoids; Physiological Processes; Plasma; Play; Quality of life; Radiolabeled; Regulation; Research; Role; Saline; Shapes; Signal Transduction; Site; Small Intestines; Stains; Supplementation; Testing; Up-Regulation; Weight Gain; Work; Yeasts; absorption; bacterial community; base; diet-induced obesity; feeding; fungal microbiota; fungus; gastrointestinal; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; innovation; jejunum; member; microbial; microbiome; microbiota; mycobiome; neglect; novel; novel strategies; obesity development; oral glucose tolerance; receptor; response; saturated fat; small molecule; sugar; targeted treatment; therapeutic development; transcriptome sequencing; translocase; uptake; western diet

PROJECT SUMMARY A leading cause of obesity and diabetes is consumption of a Western-style diet rich in saturated fat and simple sugars. Recent research shows that high fat (HF)-high sugar diets alter the microbial composition of the gut. Interestingly, we previously showed that HF diets have a strong impact on the small bowel microbiota specifically in the jejunum, the major site of nutrient digestion and absorption. Moreover, jejunal HF microbes increased lipid absorption in adult germ-free mice compared to low fat (LF) diet microbes collected from the jejunum. However, in this study, we focused on the bacterial taxa as opposed to fungal taxa. A critical gap exists in the literature regarding the role of fungi in regulating the absorptive capacity of the gut in response to HF diets. Our long-term goal is to elucidate the mechanisms by which candidate fungi such as Candida regulate lipid absorption, fat transport and adiposity. The objective of this application is to determine the impact of Candida, in yeast or hyphal form, on lipid digestive and absorptive capacity and obesity development. In addition, we will examine the localization of Candida along the length of the gut. Our preliminary data demonstrate that C. albicans in yeast and hyphal form triggers the upregulation of genes involved in fat absorption. Weekly supplementation of heat- killed C. albicans also increased body weight gain in mice fed a HF diet and induced fatty acid translocase (Cd36) expression in the jejunum. As emerging evidence suggests that diet-gut microbe interactions have the potential to promote disease, we developed our central hypothesis that the gut mycobiota contributes to lipid absorptive and digestive capacity in the small intestine. Two specific aims are proposed to test this hypothesis: Aim 1) Test the localization and morphology of C. albicans and impact on host lipid uptake and obesity, Aim 2) Determine the molecular mechanisms involved in C. albicans-mediated lipid absorption. We have only reached the precipice of understanding how bacteria regulate nutrient digestion and absorption and even less is known regarding the role of intestinal fungi. The proposed research is innovative and significant because it will better define the small intestinal mycobiota, regional localization of Candida and better define the mechanisms of host-microbe interactions that regulate absorption contributing to the development of obesity.

项目摘要 肥胖和糖尿病的主要原因是食用富含饱和脂肪和简单的西式饮食 糖。最近的研究表明，高脂肪（HF） - 高糖饮食会改变肠道的微生物组成。 有趣的是，我们以前表明，HF饮食对小肠微生物群具有很大的影响 在空肠中，养分消化和吸收的主要部位。此外，空肠HF微生物增加了脂质 与从空肠收集的低脂肪（LF）饮食微生物相比，成年无菌小鼠的吸收。然而， 在这项研究中，我们专注于细菌分类单元，而不是真菌类群。文献中存在关键的差距 关于真菌在调节肠道饮食中肠道吸收能力中的作用。我们的长期 目标是阐明候选真菌（如念珠菌）调节脂质吸收的机制 运输和肥胖。本应用的目的是确定念珠菌，酵母或 菌丝形式，以脂质消化和吸收能力和肥胖的发展。此外，我们将检查 念珠菌沿着肠道的长度进行定位。我们的初步数据表明酵母中白色念珠菌 菌丝形式触发了与脂肪吸收有关的基因的上调。每周补充热量 杀死的白色念珠菌还增加了喂养HF饮食和诱导脂肪酸易位酶的小鼠体重增加（CD36） 在空肠中的表达。正如新兴的证据表明，饮食中的微生物相互作用具有潜力 为了促进疾病，我们提出了肠道霉菌群有助于脂质吸收性的中心假设 和小肠的消化能力。提出了两个具体目的来检验这一假设：目标1） 测试白色念珠菌的定位和形态以及对宿主脂质摄取和肥胖的影响，目标2） 确定白色念珠菌介导的脂质吸收的分子机制。我们只有 达到理解细菌如何调节营养消化和吸收的悬崖，甚至更少 关于肠道真菌的作用已知。拟议的研究具有创新性和意义 将更好地定义小肠菌根，念珠菌的区域定位，并更好地定义 调节吸收有助于肥胖的吸收的宿主 - 微生物相互作用的机制。