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

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，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，SCFA可能是重要的正调节因子， 运动能力和骨骼肌代谢和功能。然而，目前尚不清楚肠道微生物 可以调节SCFA的产生以响应运动。我们的工作鉴定了乳酸利用细菌（LU-Bac）， 其可以将乳酸盐转化为SCFA，作为运动期间SCFA的潜在来源。循环乳酸水平 在中到高强度运动期间增加，结合LU-Bac补充与运动可能导致 在更高水平的循环SCFA，从而提高运动的代谢效益。受损的个体 葡萄糖耐量降低了肠道LU-Bac含量，并减弱了代谢和有氧改善的反应， 进行锻炼训练。因此，除了改善代谢健康外，LU-Bac补充剂还可以增强 通过改善导致训练反应受损的代谢缺陷来改善运动对健康的益处。我们 假设LU-Bac利用肌肉在规律运动中产生乳酸盐来产生SCFA， 然后作用于骨骼肌以改善新陈代谢和功能。我们提出了这种新型的肠肌轴导线 改善代谢健康和运动反应。该提案的一个目的是测试LU-Bac补充剂 作为代谢性疾病小鼠模型中葡萄糖耐量受损和对运动低反应的治疗 1型糖尿病和2型糖尿病的发病机制第二个目标是确定 LU-Bac乳酸发酵对运动循环和组织SCFA水平的特定贡献，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在骨骼肌中的机制导致增强的运动表现和代谢 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 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，代谢和微生物学领域，通过确定微生物组可以 增强肌肉新陈代谢和对运动的适应。我们预计我们的研究结果将导致发展一个 live biofilm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.