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

项目摘要/摘要 肠道微生物群对全身葡萄糖代谢和胰岛素敏感性有重要贡献 部分，通过生产短链脂肪酸(SCFA)。最近的证据表明，微生物SCFA 运动训练可以增加产量，SCFA可能是重要的积极调节因素 运动成绩与骨骼肌代谢和功能。然而，目前还不知道肠道微生物是如何 可以调节单链脂肪酸的产生，以响应运动。我们的工作确定了乳酸盐利用细菌(LU-Bac)， 它可以将乳酸转化为SCFA，是运动中SCFA的潜在来源。作为循环中的乳酸水平 在中强度到大强度运动中增加，补充LU-Bac和运动可能会导致 循环中SCFA水平较高，从而增强了运动对代谢的益处。有缺陷的个人 糖耐量降低，肠道LU-Bac含量降低，代谢和有氧反应改善迟钝 进行运动训练。因此，除了改善代谢健康，补充LU-Bac可能会增强 通过改善导致训练反应受损的代谢缺陷，运动对健康有好处。我们 假设肌肉在有规律的运动中产生的乳酸被LU-Bac用来产生SCFA，它 然后作用于骨骼肌，改善新陈代谢和功能。我们提出了这种新型的肠道-肌轴导联。 改善新陈代谢健康和运动反应。这项提案的目的之一是测试LU-Bac补充 作为治疗糖耐量受损和运动低反应的代谢模型的小鼠 一种部分反映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水平的特异性贡献 LU-Bac来源的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 单链脂肪酸提高运动能力和代谢的骨骼肌机制 健康。具体地说，我们将确定肌肉中的SCFA受体和转运体是否对 SCFA对肌肉代谢和功能的积极作用。这项工作将对 运动、新陈代谢和微生物学领域，通过确定微生物组 增强肌肉新陈代谢和对运动的适应。我们预计我们的结果将导致开发一种 活的生物疗法，以改善运动反应和代谢健康。

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.