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），是全球主要的健康问题，目前的药物治疗和生活方式的改变并不能阻止疾病的进展或降低死亡率。减肥手术干预，特别是Roux-en-Y胃旁路手术（RYGB）和袖式胃切除术，已被证明在持续减少肥胖和改善代谢方面有效，尽管其潜在机制尚未完全了解。鉴于其侵入性和不可逆性，减肥手术对于许多患有肥胖相关疾病的患者来说仍然是一个没有吸引力的治疗选择，并且如果其他侵入性较小的治疗方法失败，它只能作为最后的治疗手段用于病态肥胖患者。因此，确定手术引起体重减轻和T2D缓解的分子机制在科学和临床上都是必要的，以便以更小的侵入性方式靶向潜在途径。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，肠道微生物群在人类肥胖和代谢紊乱中的因果作用尚不确定，其作为减肥手术治疗成功的中介的可能作用也几乎没有被研究过。我们自己的临床前工作有力地证实了RYGB手术后改变肠道微生物组成和改善能量稳态和代谢控制的潜在因果关系。值得注意的是，我们的数据还表明，在饮食诱导肥胖（DIO）啮齿动物模型的临床反应中，rygb手术供体的粪便微生物群移植（FMT）的效果明显优于瘦健康供体，这种效果似乎明显受到供体代谢特征的驱动。为了为可能的基于微生物群的创新疗法铺平道路，迫切需要更精确地描述肠道微生物群在人类肥胖和相关疾病中的生物学影响。本研究项目的第一个目的是评估临床前数据对人类肥胖的可转移性，并在24周的随机双盲随访设计中直接比较瘦供体与rygb手术供体的FMT对肥胖受体能量和代谢控制的效应大小。其次，本研究项目旨在通过多组学方法和适当的体外和临床前体内模型的实施，识别和功能表征宿主代谢中微生物来源的信号通路。总之，这项工作将为肠道微生物群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.