The Influence of Physical Activity on the Gut Microbiome of Pre-Diabetic Adults

在美国，有9180万成年人患有前驱糖尿病（PreD）。PreD高患病率 这是一个突出的公共卫生问题，因为高达70%的PreD患者转化为2型糖尿病 （T2D）。PreD和T2 D患者的心血管疾病（CVD）风险很高，每年近3300亿美元 都花在了治疗T2 D上美国心脏协会和美国糖尿病协会呼吁， 继续研究健康行为与临床前心脏代谢疾病的联系机制 (CMD例如，PreD）。身体活动（PA）是健康的一个关键的可改变的决定因素。文献表明PA 建议的依从性与全因死亡率降低25-35%的剂量依赖性相关， 75分钟/周的常规中等强度PA有益。糖尿病预防计划的数据显示， 建议，在PreD患者中，强调PA和饮食的行为干预至少 作为药物二甲双胍成功预防2型糖尿病。然而，许多人并没有完全意识到心脏代谢 PA的益处以及PA与心脏代谢改善之间的机制性通路仍不完全 明白肠道微生物组被认为是连接健康行为的机械中间体， 作为PA，到CMD开发。事实上，肠道微生物组在免疫学、代谢、 炎症和神经行为过程，其中一些可能部分解释了健康行为 影响CMD风险。然而，有限的证据表明PA对人类肠道微生物组的影响。 到目前为止，大多数研究检查定期慢性PA的潜在影响（即，运动）对肠道微生物组的影响 使用动物模型。动物研究经常报道与运动相关的有益的改变， 群落多样性和短链脂肪酸（SCFA）生产类群。SCFA可能促进增加 能量消耗，并与瘦型有关。虽然有支持这些调查结果在有限的 许多在明显健康的成年人中进行的人体研究，除了一项研究外，所有研究都采用了随机设计，大多数研究都是随机设计。 研究是在小样本中完成的，很少评估肠道微生物组的代谢潜力。 因此，我们建议在30-64岁的个体中进行100名参与者的随机对照双臂平行试验 超重或肥胖并患有PreD的人，检查8周的监督中等强度跑步机 步行运动30-45分钟，每周3次，改变人体肠道微生物组和肠道微生物来源的血清 SCFA。我们将进一步评估肠道微生物组和/或血清SCFAs中观察到的任何变化是否 影响研究参与者心脏代谢特征、体重和身体组成。结果将通知 设计和实施未来的试验，以减少临床前疾病，如PreD， 知情的方式。根据PA-18-720，这项研究还将提供机会，“建立具体的 身体组成或其他表型特征作为肥胖风险的指标，对其治疗的反应，或其 与NIDDK相关的合并症在特征良好的...成人患者中。

PROJECT SUMMARY: In the U.S, 91.8 million adults have prediabetes (PreD). High PreD prevalence represents a prominent public health problem as up to 70% of individuals with PreD convert to type 2 diabetes (T2D). Cardiovascular disease (CVD) risk is high among those with PreD and T2D, and nearly $330 billion/year is spent treating T2D. The American Heart Association and American Diabetes Association have thus called for continued investigation into mechanisms connecting health behaviors to pre-clinical cardiometabolic disease (CMD; e.g., PreD). Physical activity (PA) is a key modifiable determinant of good health. Literature suggests PA recommendation adherence is related to a 25-35% dose-dependent reduction in all-cause mortality, with as little as 75 min/week of regular moderate-intensity PA beneficial. Data from the Diabetes Prevention Program has suggested that, among those with PreD, a behavioral intervention emphasizing PA and diet is at least as successful as the drug metformin in preventing T2D. Yet, many individuals do not fully realize the cardiometabolic benefits of PA, and mechanistic pathways linking PA and cardiometabolic improvements remain incompletely understood. The gut microbiome has been posited as a mechanistic intermediate linking heath behaviors, such as PA, to CMD development. Indeed, the gut microbiome may be important in immunological, metabolic, inflammatory, and neurobehavioral processes, some of which might partially explain how health behaviors influence CMD risk. Yet, limited evidence exists characterizing the effect of PA on the human gut microbiome. To date, most research examining the potential effect of regular chronic PA (i.e., exercise) on the gut microbiome has used animal models. Animal studies often reported exercise-related beneficial alterations to microbial community diversity and short chain fatty acid (SCFA)-producing taxa. SCFAs potentially promote increased energy expenditure and are related to a lean phenotype. While there is support for these findings in a limited number of human studies in apparently healthy adults, all but one study employed a randomized design, most studies were completed in small samples, and the metabolic potential of the gut microbiome was rarely assessed. Therefore, we propose a 100-participant randomized controlled 2-arm parallel trial in individuals 30-64 years old who are overweight or obese and have PreD, to examine how 8 weeks of supervised moderate-intensity treadmill walking exercise for 30-45 min 3 times/week alters the human gut microbiome and gut microbe-derived serum SCFAs. We will further evaluate whether any observed changes in the gut microbiome and/or serum SCFAs impact cardiometabolic profile, body weight, and body composition of study participants. Results will inform the design and implementation of future trials to reduce pre-clinical diseases such as PreD in a mechanistically- informed manner. Pursuant with PA-18-720, this research will also provide the opportunity to “establish specific body composition or other phenotypic features as indicators of risk for obesity, response to its treatment, or its co-morbidities relevant to NIDDK in well characterized…adult patients.”