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

• 批准号: 10595023
• 负责人: Aleksandar David Kostic
• 金额: $ 63.5万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 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/10595023
• 关键词: Acute; Aerobic; Aerobic Exercise; Affect; Bacteria; Biological Response Modifier Therapy; Blood Glucose; Carbon; Chronic; Coupled; Couples; Data; Defect; Development; Diabetes Mellitus; Diet; Disease model; Exercise; FFAR2 gene; Fermentation; Fiber; GTP-Binding Proteins; Glycogen; Gnotobiotic; Health; Health Benefit; Human; Hyperglycemia; Impairment; In Vitro; Individual; Injections; Insulin Resistance; Lead; Measures; Mediating; Mediator; Metabolic; Metabolic Diseases; Metabolism; Microbiology; Modeling; Molecular; Mus; Muscle; Muscle Mitochondria; Muscle function; Nonesterified Fatty Acids; Pathology; Performance; Persons; Physical Exercise; Play; Prediabetes syndrome; Production; Propionates; Role; Running; Serum; Signal Transduction; Site; Skeletal Muscle; Source; Supplementation; Testing; Time; Tissues; Training; Veillonella; Volatile Fatty Acids; Work; blood glucose regulation; calmodulin-dependent protein kinase II; exercise capacity; exercise intensity; exercise training; exhaustion; experience; glucose metabolism; glucose uptake; 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; probiotic therapy; receptor; response; sedentary; skeletal muscle metabolism; treadmill; type I and type II diabetes

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.

项目概要/摘要 肠道微生物组对全身葡萄糖代谢和胰岛素敏感性做出了重大贡献， 部分是通过生产短链脂肪酸（SCFA）。最近的证据表明微生物 SCFA 运动训练可能会增加产量，并且 SCFA 可能是重要的正向调节剂 运动表现和骨骼肌代谢和功能。然而，目前尚不清楚肠道微生物如何 可以根据运动调节 SCFA 的产生。我们的工作鉴定了乳酸利用细菌 (LU-Bac)， 它可以将乳酸转化为 SCFA，作为运动期间 SCFA 的潜在来源。随着循环乳酸水平 在中度至高强度运动期间增加，将 LU-Bac 补充剂与运动相结合可能会导致 更高水平的循环 SCFA，从而增强运动的代谢益处。身体有障碍的人士 葡萄糖耐量降低肠道 LU-Bac 含量，并减弱代谢和有氧反应的改善 进行运动训练。因此，除了改善代谢健康之外，补充 LU-Bac 还可以增强 通过改善导致训练反应受损的代谢缺陷，锻炼对健康有益。我们 假设 LU-Bac 使用定期运动的肌肉产生的乳酸来生成 SCFA， 然后作用于骨骼肌，改善新陈代谢和功能。我们提出这种新颖的肠肌轴引导 改善代谢健康和运动反应。该提案的目的之一是测试 LU-Bac 补充剂 作为代谢小鼠模型中糖耐量受损和运动反应低的治疗 部分反映 1 型和 2 型糖尿病病理的疾病。第二个目标是确定 LU-Bac 乳酸发酵对运动时循环和组织 SCFA 水平的具体贡献，以及 LU-Bac 衍生的 SCFA 是否有助于运动训练的健康益处。我们的第三个目标是定义 SCFA 增强运动表现和代谢的骨骼肌机制 健康。具体来说，我们将确定肌肉中的 SCFA 受体和转运蛋白是否是必需的 SCFA 对肌肉代谢和功能的积极影响。这项工作将产生广泛的影响 运动、新陈代谢和微生物学领域通过确定微生物组可以发挥作用的机制 增强肌肉新陈代谢和运动适应能力。我们预计我们的成果将导致开发 活体生物疗法可改善运动反应和代谢健康。