远端小肠“胆汁酸-FXR-神经酰胺”通路在十二指肠空肠旁路术后胰岛素敏感性改善中的作用和机制研究

Duodenal-jejunal bypass (DJB) can induce rapid and durable amelioration of type 2 diabetes mellitus. However, the underlying mechanisms remain unknown. Our preliminary study indicates that the composition of total bile acids (BA) within the distal small intestine after DJB has changed, with significant increase of taurine-conjugated-β-muricholic acids and taurine-conjugated ursodeoxycholic acids, both of which are FXR-inhibited bile acids. The latest reports find that FXR inhibition leads to decrease of regional and circulating ceramides, increasing hepatic and peripheral insulin sensitivity as well as subsequent T2DM amelioration. Therefore, we hypothesize that DJB changes intraluminal bile acid composition in the distal small intestine, with increase of FXR-inhibited bile acid species, inhibiting “FXR-ceramide” pathway, reducing hepatic lipid synthesis and leading to T2DM amelioration by increasing hepatic and peripheral insulin sensitivity. In the present study, we first perform DJB in a T2DM rat model, confirming the effects of intraluminal bile acids on intestinal FXR by tissue and cell experiments, and then investigate the effect and mechanism of “BA-FXR-ceramide” pathway within the distal small intestine in improvement of T2DM after DJB by regional inhibition of the pathway together with basal insulin-euglycemic glucose clamp.

十二指肠空肠旁路术（DJB）可以迅速、持久地缓解T2DM，但具体机制不明。我们前期研究发现，DJB术后远端小肠内胆汁酸谱出现变化，FXR受体抑制性胆汁酸T-β-MCA（牛磺酸结合β鼠胆酸）和TUDCA（牛磺酸结合熊去氧胆酸）的比例升高。最新研究发现，抑制肠道FXR受体可以减少局部及血清中神经酰胺的含量，增加肝脏及外周胰岛素敏感性，进而改善T2DM。因此我们推测：DJB术后远端小肠内胆汁酸谱出现改变，以FXR受体抑制性胆汁酸的比例升高为主，通过抑制肠道“FXR-神经酰胺”通路，减轻肝脏及外周胰岛素抵抗，进而缓解T2DM。本研究首先在T2DM大鼠中建立DJB手术模型，通过组织学和细胞学实验，明确DJB术后远端小肠内胆汁酸对FXR受体的影响；进而通过阻断远端小肠内“胆汁酸-FXR-神经酰胺”通路，结合基础胰岛素-正葡萄糖钳夹等技术，探究该通路在DJB术后肝脏和外周胰岛素敏感性改善中的作用和机制。

十二指肠空肠旁路术(DJB)可以迅速、持久地缓解2型糖尿病（T2DMM），但具体机制不明。我们前期研究发现，DJB术后远端小肠内胆汁酸谱出现变化，FXR受体抑制性胆汁酸T-β-MCA(牛磺酸结合β鼠胆酸)和TUDCA(牛磺酸结合熊去氧胆酸)的比例升高。最新研究发现，抑制肠道FXR受体可以减少局部及血清中神经酰胺的含量，增加肝脏及外周胰岛素敏感性，进而改善T2DM。因此我们推测:DJB术后远端小肠内胆汁酸谱出现改变，以FXR受体抑制性胆汁酸的比例升高为主，通过抑制肠道“FXR-神经酰胺”通路，减轻肝脏及外周胰岛素抵抗，进而缓解T2DM。.本研究首先在T2DM大鼠中建立了DJB手术模型，应用HPLC-MS/MS技术对远端肠道内胆汁酸谱进行了检测，验证了远端肠道内总胆汁酸水平升高，且以FXR受体抑制性胆汁酸升高为主。肠腔内胆汁酸谱的变化抑制了FXR受体，下调了其下游神经酰胺合成关键酶SMPD3及SPTLC2的表达水平，并最终降低了门静脉内神经酰胺的浓度。在体水平补充肠道FXR受体激动剂CDCA后，空腹血糖水平出现升高，但OGTT试验显示糖耐量并无明显受损，提示“胆汁酸-FXR-神经酰胺”通路可能主要影响肝脏胰岛素敏感性，对外周胰岛素敏感性影响较小。本研究揭示了代谢手术改善胰岛素敏感性的其中一个机制，对该机制的深入研究有助于为今后的非手术治疗T2DM提供潜在的药物治疗靶点，具有一定临床应用前景。