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Investigating Metabolically Protective Members of the Microbiota that Modulate Ceramides

研究调节神经酰胺的微生物群的代谢保护成员

基本信息

批准号：
10425287
负责人：
Kendra Alyse Klag
金额：
$ 4.56万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10425287
关键词：
Adipose tissue Affect Animals Bacteria Binding CD36 Antigens CD36 gene Ceramides Chloroform Clinical Research Clostridium difficile Communities Complex Data Defect Deposition Desulfovibrio Diabetes Mellitus Disease Fatty Acids Fatty Liver Fatty acid glycerol esters Feces Firmicutes Food Hypersensitivity Genes Genome Germ-Free Glucose Gnotobiotic Goals Health Health Benefit High Fat Diet Human Immunoglobulin A In Vitro Individual Inflammatory Inflammatory Bowel Diseases Insulin Resistance Intake Intestines Knockout Mice Laboratory Research Lipids Liver Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Molecular Monitor Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathway interactions Population Primary Cell Cultures Probiotics Production Regulation Research Role Small Intestines Sphingolipids Supplementation Taxonomy Testing Therapeutic Thinness Weight Gain Work absorption colonization resistance enteric infection epidemiology study fasting glucose fatty liver disease gastrointestinal epithelium gut bacteria gut colonization gut inflammation gut microbes gut microbiota host microbiota improved in vivo insight insulin sensitivity member metabolic abnormality assessment metagenome metagenomic sequencing microbial microbiota mouse model neonate novel novel therapeutics obesogenic pathogen prevent response tool underserved community uptake

项目摘要

Project Summary The number of individuals with metabolic diseases like obesity and type 2 diabetes is growing at overwhelming rates globally, increasingly affecting younger populations, and disproportionally affect under-served communities. Emerging clinical, epidemiological, and laboratory research has demonstrated an essential role for gut bacteria in the regulation of metabolism. Another key contributor to the pathogenesis of these metabolic diseases are the sphingolipids ceramides. Ceramides are produced in response to increased fat intake and mediate many of the molecular pathways that cause increased lipid uptake, insulin resistance, and fatty liver disease. A few studies have begun to investigate the relationship between the gut microbiota, ceramides, and metabolic diseases, and have shown that the microbiota can regulate ceramide production. Despite these studies, it remains unclear which bacteria and how these bacteria impact ceramide production and ultimately host metabolism. Our lab has identified a community of Clostridia Class bacteria that provide metabolic protection from a high-fat diet in the form of decreased weight gain, improved leanness, and lower fasting glucose. Furthermore, we have found that Clostridia reduce the rate of ceramide production. The objective of this proposal is to understand which bacteria are essential to providing metabolic protection and determine how these bacteria are impacting ceramide synthesis and overall host metabolism. We hypothesize that select Clostridia bacteria can protect from features of metabolic disease through decreasing ceramides and reducing lipid absorption in the gut epithelium. We will test this hypothesis in two aims: 1) defining the community of Clostridia that protect from features of metabolic disease induced by a high-fat diet, and 2) determining if Clostridia decrease ceramides and lipid absorption in the gut epithelium. Aim 1 will continue to culture, genetically characterize, and define the most limited community of Clostridia that provides metabolic protection. Aim 2 will use in vitro and in vivo approaches with germ-free (GF) and gnotobiotic mouse models to assess the relationship between Clostridia and ceramides in the context of lipid absorption. This proposed work will have a significant impact on the study of the metabolic disease and the microbiota by providing novel insight into microbiota-driven mechanisms that can be leveraged for therapeutic benefit.

项目总结