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Gut microbial fermentation products of muscle-derived lactate as mediators of exercise and metabolism

肌肉来源的乳酸的肠道微生物发酵产物作为运动和代谢的介质

基本信息

批准号：
10443495
负责人：
Aleksandar David Kostic
金额：
$ 58.87万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443495
关键词：
Acute Aerobic Aerobic Exercise Affect Bacteria Biological Response Modifier Therapy Blood Glucose Carbon Coupled Couples Data Defect Development Diabetes Mellitus Diet Disease model Exercise FFAR2 gene Fermentation Fiber GTP-Binding Proteins Glucose Glycogen Gnotobiotic Health Health Benefit Human Hyperglycemia Impairment In Vitro Individual Injections Insulin Resistance Insulin-Dependent Diabetes Mellitus Lead Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolism Microbiology Modeling Molecular Mus Muscle Muscle Mitochondria Muscle function Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Oxides Pathology Performance Persons Physical Exercise Play Prediabetes syndrome Probiotics Production Propionates Role Serum Signal Transduction Site Skeletal Muscle Source Supplementation Testing Tissues Training Veillonella Volatile Fatty Acids Work calmodulin-dependent protein kinase II exercise capacity exercise intensity exercise training exhaustion experience glucose metabolism glycemic control gut bacteria gut microbes gut microbiome gut microbiota impaired glucose tolerance improved in vivo insulin secretion insulin sensitivity knock-down microbial microbiome mouse model muscle metabolism novel oxidation receptor response sedentary skeletal muscle metabolism treadmill

项目摘要

PROJECT SUMMARY/ABSTRACT The gut microbiome makes significant contributions to whole-body glucose metabolism and insulin sensitivity, in part, through production of short chain fatty acids (SCFA). Recent evidence suggests that microbial SCFA production may be increased by exercise training, and that SCFA may be important positive regulators of exercise performance and skeletal muscle metabolism and function. However, it is not known how gut microbes could regulate SCFA production in response to exercise. Our work identifies lactate utilizing bacteria (LU-Bac), which can convert lactate to SCFA, as potential sources of SCFA during exercise. As circulating lactate levels increase during moderate to high intensity exercise, combining LU-Bac supplementation with exercise may result in higher levels of circulating SCFA, thus enhancing the metabolic benefits of exercise. Individuals with impaired glucose tolerance have lower gut LU-Bac content, and blunted metabolic and aerobic improvements in response to exercise training. Thus, in addition to improving metabolic health, LU-Bac supplementation may enhance the health benefits of exercise by ameliorating the metabolic defects that lead to impaired training response. We hypothesize that lactate produced by muscle with regular exercise is used by LU-Bac to generate SCFA, which then act on skeletal muscle to improve metabolism and function. We propose this novel gut-muscle axis leads to improved metabolic health and exercise response. One aim of this proposal is to test LU-Bac supplementation as a treatment for impaired glucose tolerance and low response to exercise in mouse models of metabolic disease that partially reflect the pathologies of type 1 and type 2 diabetes. A second aim is to determine the specific contribution of lactate fermentation by LU-Bac to circulating and tissue SCFA levels with exercise, and whether LU-Bac-derived SCFA contribute to the health benefits of exercise training. Our third aim is to define the mechanisms in skeletal muscle by which SCFA lead to enhanced exercise performance and metabolic health. Specifically, we will determine whether SCFA receptors and transporters in muscle are necessary for the positive effects of SCFA on muscle metabolism and function. This work will have a broad impact on the fields of exercise, metabolism, and microbiology by determining the mechanisms by which the microbiome can enhance muscle metabolism and adaptation to exercise. We anticipate our results will lead to development of a live biotherapeutic to improve exercise response and metabolic health.

项目总结/文摘