Treatment effect and functional characterization of Fecal Microbiota Transplantation (FMT) from RYGB-operated versus lean donors on metabolic outcome in obese recipients - a proof-of-concept exploratory study

肥胖和相关的代谢性疾病，如2型糖尿病(T2D)，是主要的全球健康问题，目前的药物治疗和生活方式改变并不能阻止疾病的进展或死亡率的降低。减肥手术干预，特别是Roux-en-Y胃旁路手术(RYGB)和袖状胃切除术，已被证明在持续减脂和改善代谢方面有效，尽管潜在的机制尚未完全了解。由于其侵入性和不可逆转性，对于许多患有肥胖相关疾病的患者来说，减肥手术仍然是一个不具吸引力的治疗选择，如果其他侵入性较小的治疗方法失败，减肥手术仅限于病态肥胖患者的最后治疗手段。因此，确定手术诱导的体重减轻和T2D缓解的分子机制对于以较小的侵入性方式靶向潜在的途径具有科学和临床上的必要性。一些临床前和临床研究表明，肥胖、糖耐量受损和肠道微生物群之间存在关联。尽管有大量的观察性关联研究，但肠道微生物区系在人类肥胖和代谢紊乱中的因果作用尚不清楚，而且它作为减肥手术治疗成功的中介的可能作用也很少被调查。我们自己的临床前工作有力地证实了RYGB手术后肠道微生物组成改变以及能量平衡和代谢控制改善的潜在因果关系。值得注意的是，我们的数据还显示，在饮食诱导肥胖(DIO)啮齿动物模型中，来自RYGB操作的捐赠者的粪便微生物区系移植(FMT)在临床反应方面明显优于瘦健康捐赠者-这种效果似乎显然是由捐赠者的代谢特征驱动的。为了为可能的基于微生物区系的创新疗法铺平道路，迫切需要更准确地描述肠道微生物区系在人类肥胖和相关疾病中的生物学影响。该研究项目的第一个目的是评估临床前数据在人类肥胖中的可转移性，并在24周的随机化和双盲设计中，直接比较来自瘦捐赠者和RYGB操作捐赠者的FMT对肥胖受者能量和代谢控制的影响大小。其次，本研究旨在通过多组学方法和建立合适的体外和临床前体内模型，鉴定和功能表征宿主代谢中的微生物信号通路。总之，这项工作将为肠道微生物区系的生物学影响及其在人类肥胖和相关疾病中的治疗潜力提供新的见解。

Obesity and related metabolic diseases, like type 2 diabetes (T2D), are major global health problems for which current pharmacological treatment and lifestyle modification do not halt disease progression or mortality reduction. Bariatric surgical interventions, in particular the Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, have proven effective in sustained adiposity reduction and metabolic improvements, although the underlying mechanisms are not yet fully understood. Given its invasive and irreversible character, bariatric surgery remains an unattractive therapeutic option for many patients suffering from obesity-related diseases, and it is limited as a last therapeutic resort to only morbidly obese patients if other less invasive treatment approaches have failed. Therefore, identifying the molecular mechanisms responsible for surgery-induced weight loss and T2D remission is scientifically and clinically imperative to target underlying pathways in a less invasive manner. Several preclinical and clinical studies have shown associations between obesity, impaired glucose tolerance and the intestinal microbiome. Despite a multitude of observational association studies, a causal role for the intestinal microbiota in human obesity and metabolic disorders is less established, and its possible role as a mediator for the treatment success of bariatric surgery has only scarcely been investigated. Our own preclinical work strongly confirms a potential causality of the altered gut microbial composition and improved energy homeostasis and metabolic control following RYGB surgery. Notably, our data also demonstrate a robustly superior effect of fecal microbiota transplantation (FMT) from RYGB-operated donors compared to lean healthy donors in the clinical response in diet-induced obesity (DIO) rodent models - an effect that seems clearly driven by donor metabolic characteristics. In order to pave the way for possible innovative microbiota-based therapies, more precise characterization of the biological impact of the gut microbiota in human obesity and related diseases is urgently needed. The first aim of this research project is to assess the transferability of preclinical data into human obesity and to directly compare the effect size of FMT from lean donors versus RYGB-operated donors on energy and metabolic control in obese recipients in a randomized and double-blinded design over 24-wk follow-up. Secondly, this research project aims to identify and functionally characterize the operating microbial-derived signaling pathways on host metabolism by multiomics approach and implementation of appropriate in vitro and preclinical in vivo models. Together, this work will provide novel insights into the biological impact of the gut microbiota and its therapeutic potential in human obesity and related diseases.