'Metabolic surgery restores nutrient sensing and gut-brain signaling pathways towards metabolic health: perspective towards a microbiome-based metabolite treatment of obesity and related diseases'

今天，肥胖和超重困扰着一半以上的德国人口，使肥胖成为一个重大的公共卫生问题，主要是因为它与限制生命的健康问题有关，包括2型糖尿病、肝脂肪变性、肺病和心血管疾病、神经退行性疾病和不同的癌症。富含饱和脂肪酸和缺乏身体活动的营养环境会促进慢性低度炎症状态，从而导致全身代谢功能障碍，从而导致肥胖的流行。最近的证据表明，饮食诱导的下丘脑胶质细胞增生和炎症状况，调节下丘脑基因表达，导致暴饮暴食，独立地作为体重增加和代谢窘迫的关键介质。尽管我们对肠脑轴在能量平衡和代谢控制中的核心作用的理解取得了重要进展，但抗肥胖药物治疗进展甚微，使代谢外科手术成为当今唯一能够持续减肥和代谢健康益处的策略。然而，考虑到这些手术的高侵入性特征，以及它们仅作为病态肥胖患者的最后治疗手段的局限性，破译它们的作用机制是一个重要的挑战，可以为可能的新型低侵入性治疗干预确定关键目标，并建立我实验室的主要科学兴趣。事实上，胃肠道是代谢外科手术的主要目标，使其成为关键的参与者。值得注意的是，胃肠道的手术重构严重改变了肠道微生物群及其代谢物的组成和多样性，而肠道微生物群已成为宿主免疫、代谢和食欲控制的重要调节因子。然而，重塑的肠道微生物组在术后代谢健康恢复中的功能作用尚未被确定，其发挥基于代谢物信号治疗肥胖策略的潜力仍有待阐明。本项目旨在描述能量饮食和肠道生态失调对下丘脑胶质细胞增生和神经元损伤的有害影响，作为肥胖和代谢疾病的驱动因素。此外，通过体内、体外和体外方法，该研究将验证RYGB手术后微生物-宿主相互作用的调节整合了免疫、代谢和环境线索，以重新编程下丘脑能量和代谢控制，从而恢复代谢健康的假设。

Obesity and excess weight concerns more than half of the Germanpopulation today, making obesity to a major public health issue,mainly due to its association with life-limiting health issues includingtype 2 diabetes, hepatic steatosis, pulmonary and cardiovasculardiseases, neurodegenerative disorders, and different cancers.Nutritional environments, with high abundance of saturated fatty acidsand lack of physical activity contribute to the obesity epidemic bypromoting a state of chronic low-grade inflammation, which leads tosystemic metabolic dysfunction. More recent evidence indicates thatdiet-induced conditions of hypothalamic gliosis and inflammation,which modulate hypothalamic gene expression towards overeating,independently serve as critical mediators of weight gain and metabolicdistress. Despite important advances in our understanding of the gutbrainaxis as a central player in energy balance and metabolic control,little progress has been made for anti-obesity pharmacotherapy,leaving metabolic surgical procedures as the only strategy enablingsustained weight loss and metabolic health benefits today. However,given the highly invasive character of these surgeries and theirlimitation as a last therapeutic resort to only morbidly obese patients,deciphering their mechanisms of action is an important challenge toidentify critical targets for possibly novel less invasive therapeuticinterventions and builds a main scientific interest of my lab. The factthat the gastrointestinal (GI) tract is the prime target of metabolicsurgery makes it a key player. Notably, surgical reconfiguration of theGI tract critically changes the composition and diversity of the gutmicrobiome and its metabolite products, which has emerged as animportant regulator of the host immunity, metabolism and appetitecontrol. However, the functional role of the reshaped gut microbiomein the reinstatement of metabolic health after surgery has not yet beencharacterized, and its potential to exert metabolite signaling-basedtreatment strategies against obesity remains to be elucidated. Thisproject aims to characterize the deleterious effects of energetic dietand gut dysbiosis on hypothalamic gliosis and neuronal injury as adriver for obesity and metabolic disease. Moreover, using in vivo, exvivo and in vitro approaches, it will test the hypothesis that modulationof the microbial-host interaction after RYGB surgery integratesimmunologic, metabolic, and environmental cues to reprogramhypothalamic energy and metabolic control towards restoredmetabolic health.