姜黄素通过肠道菌群及其代谢产物抑制肥胖的机制研究

Obesity is an important risk factor for multiple chronic diseases, causing serious damages to human health. Curcumin reduces obesity. At present, some studies have been conducted to explore the mechanisms of curcumin to inhibit obesity based on adipocyte differentiation and fatty acid oxidation. Some researches approved that curcumin has poor systemic bioavailability. Thus, we inferred that the gut microbiota might mediate the effect of curcumin on obesity. Nowadays, there are no studies on investigating the mechanisms that curcumin decreases obesity by modulating the composition of gut microbiota. So the underlying mechanisms remain to be elucidated. Our preliminary research found that curcumin determined the gut microbiota composition and protected against obesity by enhancing thermogenesis in brown adipose tissue and inducing browning of subcutaneous white adipose tissue. Moreover, the protective effects of curcumin on enhancing thermogenesis were eliminated after microbiota depletion by antibiotic treatment. Then, we proposed a scientific hypothesis that curcumin’s altering gut microbiota may reduce obesity through inducing thermogenesis in brown adipose tissue and browning of white adipose tissue. Our current project is designed to testify that the gut microbiota orchestrates the preventive effects of curcumin on obesity in vivo and explore the molecular mechanisms that curcumin enhances thermogenesis in brown adipose tissue and promotes browning of white adipose tissue through shaping the gut microbiota and its metabolites in vivo and vitro approaches. The significance of the project is composed of providing a new theoretical basis for the clinical application of curcumin and uncovering novel ideas for treating obesity and related metabolic diseases.

肥胖是诱发多种慢性病的重要危险因素，严重危害人类健康。姜黄素能够有效抑制肥胖。目前，有研究基于脂肪细胞分化和脂肪酸氧化角度探索姜黄素抑制肥胖的机制。考虑到姜黄素的生物利用度极低，因此我们推断，肠道菌群可能介导姜黄素抑制肥胖的作用。目前尚未有研究从肠道菌群角度探索姜黄素抑制肥胖的机制，因此其具体作用机制仍有待探讨。我们的前期研究发现姜黄素可以改善肠道菌群，促进小鼠棕色脂肪产热和白色脂肪棕色化；利用广谱抗生素清除小鼠内源性肠道菌群后，姜黄素促进产热的作用消失，于是我们提出“姜黄素通过改善肠道菌群促进棕色脂肪产热和白色脂肪棕色化，进而抑制肥胖”的科学假设。本项目拟通过动物实验揭示肠道菌群介导姜黄素对肥胖的抑制作用，并通过体内和体外实验阐明姜黄素通过调控肠道菌群及其代谢产物促进棕色脂肪产热和白色脂肪棕色化的分子机制。以期为姜黄素的临床应用提供新的理论基础，为肥胖和相关代谢性疾病的治疗提供新思路。

肥胖是诱发多种慢性疾病的危险因素，严重危害人类健康，但是针对肥胖的防治手段仍非常有限。虽然有研究发现姜黄素具有抗肥胖效应，考虑到口服姜黄素的生物利用度极低且优先在肠道中分布及积累的特性，姜黄素增加能量消耗的机制仍有待诠释。越来越多的研究表明肠道菌群与宿主的能量代谢密切相关。基于此，本项目致力于探索肠道菌群是否介导姜黄素对高脂饮食导致能量代谢异常的改善作用及其机制。高脂饮食时，C57BL/6J、Ucp1-/-和Gpbar1-/-小鼠作为研究对象用于探讨姜黄素对高脂饮食诱导肥胖的抑制作用及其机制。通过肠道菌群清除以及粪菌移植实验验证姜黄素对高脂饮食导致能量代谢异常的改善作用是否依赖于其对肠道菌群的调控。综合体重变化、H&E染色实验、代谢笼实验、冷刺激实验和红外成像实验评价姜黄素对能量代谢的调控作用。实时定量PCR以及Western blotting探索特定基因在转录和翻译水平的表达情况。16SrDNA高通量测序技术分析姜黄素对肠道菌群组成的影响。UPLC-MS/MS用于检测血清胆汁酸谱的组成。ELISA用于检测相关的生化指标。研究发现，姜黄素对高脂饮食诱导肥胖的改善作用依赖于Ucp1依赖产热的增强。高脂饮食时，姜黄素改变小鼠肠道菌群的组成并调控肝脏的胆汁酸合成，使血清胆汁酸谱的组成发生显著变化，作为TGR5激动剂的DCA和LCA的占比显著增多。肠道菌群清除以及粪菌移植实验表明，肠道菌群介导姜黄素对高脂饮食导致能量代谢异常的改善作用，定植姜黄素组高脂饮食小鼠的粪便微生物具有与口服姜黄素相似的调控能量代谢的作用，即通过激活产热脂肪中的cAMP/ PKA信号通路增强Ucp1依赖产热。并且，姜黄素对产热脂肪中cAMP/PKA信号通路的激活作用依赖于TGR5。总的来说，本研究表明姜黄素通过改变肠道菌群组成以及胆汁酸代谢使血清胆汁酸谱组成发生显著变化，由于血清DCA和LCA占比的增多激活TGR5，进而激活产热脂肪细胞中cAMP/PKA信号通路，最终使Ucp1依赖产热增强，通过增加能量消耗改善高脂饮食导致的肥胖，揭示肠-肝轴具有通过增强Ucp1依赖产热实现治疗和预防肥胖及相关代谢性疾病。