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

• Applicant: Professorin Dr. Wiebke Kristin Fenske
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451967823

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.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Co-Investigator: Professor Dr. Martin von Bergen
• Cooperation Partners: Privatdozentin Dr. Patrizia Kump; Professorin Dr. Julia Mader