Contribution of sweet taste receptors (STRs) to saccharin-induced alterations of gut microbiota

甜味受体（STR）对糖精诱导的肠道微生物群改变的贡献

基本信息

批准号：
9376608
负责人：
George Kyriazis
金额：
$ 12.93万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9376608
关键词：
Ablation Acute Address Affect Artificial Sweeteners Aspartame Bacteria Bacteroides Cell surface Cells Chronic Clinical Protocols Clostridium Consumption Data Development Diabetes Mellitus Diet Dietary Sugars Endocrine Enterocytes Esthesia Etiology Functional disorder Future Gastrointestinal tract structure Genetic Genotype Germ-Free Glucose Glucose Intolerance Growth Human Ingestion Insulin Intervention Studies Intestines Knock-out Knockout Mice Lead Ligands Light Link Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Oral Outcome Participant Pathway interactions Permeability Pharmacology Phylogenetic Analysis Play Process Proteins Public Health Randomized Receptor Signaling Recombinant DNA Risk Role Saccharin Sensory Signal Transduction Supplementation Taste Buds Techniques Testing Therapeutic Intervention Thinness Tissues Transplantation Transport Process Volatile Fatty Acids Weaning Weight Gain Wild Type Mouse blood glucose regulation detection of nutrient energy balance epidemiologic data feeding glucose transport gut microbiota in vivo intestinal epithelium metabolic profile metagenomic sequencing microbial community microbiota microbiota transplantation new therapeutic target novel novel therapeutics nutrient metabolism obesity management post intervention prevent receptor response sugar sweet taste perception translational impact

项目摘要

PROJECT SUMMARY Sweet taste receptors (STRs) are expressed in a variety of tissues including the gastrointestinal tract. Intestinal STRs play a role regulating metabolic responses to the ingestion of sugars and non-caloric artificial sweeteners (NCASs). Paradoxically, consumption of NCASs is associated with metabolic dysregulation and obesity although the tissues do not metabolize these nutrients. The underlying pathophysiological mechanisms responsible for these observations are largely unknown, but it has been suggested that NCAS consumption alters gut microbiota to cause glucose intolerance. Considering that STR-mediated chemosensation in the gut is likely relevant to the metabolic effects of NCASs, we hypothesize that intestinal STRs provide a mechanistic link between NCAS- induced metabolic dysfunction and gut microbiota. Towards this end, we show that elimination of STR signaling in mice, through genetic ablation of the T1R2 protein (T1R2-knock out; KO), protects against metabolic derangements induced by the overconsumption of saccharin. Notably, basal (chow diet) T1R2-KO gut microbiota composition displays marked alterations compared to T1R2-wild type (WT), followed by elevated concentrations of fecal short-chain fatty acids (SCFAs). These changes are most notable in genera (Clostridium, Bacteroides and Blautia) that are known to influence host metabolism and are pertinent to human gut microbiota. Finally, to begin addressing the direct role of intestinal STRs in humans, we tested the effects of acute pharmacological inhibition (lactisole) of STRs in the gut and found that it alters the glycemic and insulin response to an oral glucose load. Taken together, these data emphasize the translational impact of our studies and suggest that chemosensory input involving STRs is likely relevant to nutrient metabolism and the development of metabolic diseases. Thus, we propose comprehensive studies that investigate the contribution of STRs in NCAS-induced glucose intolerance. We will explore potential causative mechanisms associated with gut microbiota and glucose transport/metabolism in enterocytes. We will perform a) qualitative phylogenetic (16S rDNA) and meta-genomic sequencing (RNA-Seq) analyses of gut microbiota, b) assessment of in vivo metabolic profiling and energy balance, c) assessment of targeted metabolites of intestinal epithelium and fecal SCFAs, and d) ex vivo assessment of intestinal glucose transport (Ussing Chamber). We expect that STR-mediated chemosensory signaling interacts with gut microbiota to alter the absorptive capacity of the gut and it is required for the development of glucose dysregulation induced by NCASs. Finally, to establish causality between host-microbiota pathways, we will conventionalize germ-free mice with microbiota from T1R2-KO mice subjected to NCAS feeding. The proposed studies will a) explore interactions of novel host chemosensory mechanisms with gut microbiota, b) define the role of STRs in the gut, and c) identify causative mechanisms that link NCAS consumption and the development of metabolic diseases. Understanding the nature of these regulatory mechanisms could lead to gut-restricted therapeutic interventions for the treatment of metabolic diseases.

项目摘要甜味受体（Strs）在包括胃肠道在内的多种组织中表达。肠 Strs在调节对糖摄入糖和非含量人造甜味剂的代谢反应中扮演角色（ncass）。矛盾的是，NCASS的消费与代谢失调和肥胖有关组织不会代谢这些养分。负责的基本病理生理机制这些观察结果在很大程度上是未知的，但有人提出NCAS消费会改变肠道菌群引起葡萄糖不耐症。考虑到肠道中的str介导的化学一致化可能与 NCASS的代谢作用，我们假设肠道STR提供了NCAS-之间的机械联系诱导代谢功能障碍和肠道微生物群。为此，我们表明消除了STR信号传导在小鼠中，通过T1R2蛋白的遗传消融（T1R2-knock ut; KO）预防代谢糖精的过度消费引起的危险。值得注意的是，基础（Chow Diet）T1R2-KO肠道微生物群与T1R2-wild类型（WT）相比，组成显示出明显的变化，然后浓度升高粪便短链脂肪酸（SCFA）。这些变化在属（梭状芽胞杆菌，细菌下最为明显）已知会影响宿主代谢，与人类肠道菌群有关的蓝脂蛋白）。最后，到开始解决肠道中肠道中的直接作用在人类中，我们测试了急性药理的影响肠道中StR的抑制（乳酸），发现它会改变口服的血糖和胰岛素反应葡萄糖负荷。综上所述，这些数据强调了我们的研究的翻译影响，并建议涉及Strs的化学感觉输入可能与营养代谢和代谢的发展有关疾病。因此，我们提出了全面的研究，以研究NCAS诱导的STR的贡献葡萄糖不耐症。我们将探索与肠道菌群和葡萄糖相关的潜在因果机制肠细胞中的运输/代谢。我们将执行a）定性系统发育（16S rDNA）和元基因组测序（RNA-SEQ）肠道菌群分析，b）评估体内代谢分析和能量平衡，c）评估肠上皮和粪便的靶向代谢产物，d）评估肠葡萄糖转运（USSING COMELL）。我们期望STR介导的化学感应信号传导与肠道菌群相互作用以改变肠的吸收能力，并且需要 NCASS诱导的葡萄糖失调的发展。最后，建立宿主 - 微生物之间的因果关系途径，我们将用来自NCAS的T1R2-KO小鼠的微生物群常规化细菌小鼠进食。拟议的研究将a）探索新型宿主化学感应机制与肠道的相互作用微生物群，b）定义str在肠道中的作用，c）确定将NCAS连接起来的致病机制消费和代谢疾病的发展。了解这些监管的性质机制可能导致肠道限制的治疗干预措施，以治疗代谢疾病。