从改善胃肠动力障碍和肠道菌群紊乱研究糖肾方治疗糖尿病性非酒精性脂肪肝的机制

Non-alcoholic fatty liver disease (NAFLD) is a serious hazard to human health. Gut flora disorder is an important factor for causing NAFLD. The disorder of gastrointestinal (GI) motility can aggravate gut flora disorder. NAFLD also can aggravate GI motility disorder and bacteriological disorder. Our previous studies have found that Tangshen formula could effectively inhibit the inflammation of the gut and liver, attenuate GI motility disorder and liver steatosis. Therefore, we hypothesize that Tangshen formula could attenuate NAFLD by inhibiting liver inflammation through attenuating the gut dysbiosis, maintaining GI motility. The db/db mice, which have been established successfully in our lab, will be applied in this study. We will investigate the relationship among GI motility disorder, intestinal flora disorder and NAFLD; observe the effects of Tangshen formula on the gut flora, gastrointestinal motility and NAFLD, and clarify the therapeutical effect of Tangshen formula on NAFLD by improving GI motility and reducing the intestinal flora disorder. Meanwhile, lipopolysaccharide will be used to stimulate intestinal cells of Cajal and Kupffer cells in order to explore the molecular mechanism of endotoxemia in inducing gastrointestinal motility disorder and NAFLD, and to clarify the drug targets of Tangshen formula on improving intestinal motility and reducing NAFLD. This study will provide the scientific evidence of Chinese traditional medicine to treat complicated and refractory diseases.

糖尿病合并症非酒精性脂肪肝（NAFLD）严重危害人类健康。肠道菌群紊乱是引发脂肪肝的重要因素，胃肠动力障碍加重菌群紊乱，NAFLD发展到一定程度又可加重胃肠动力障碍和菌群紊乱。课题组前期发现，糖肾方可减轻糖尿病胃肠动力障碍及肝脂肪变性、有效抑制肠道及肝脏炎症。因此，我们提出科学假说：糖肾方通过改善糖尿病胃肠动力、减轻肠道菌群紊乱，从而抑制肝脏炎症，起到治疗NAFLD的作用。本研究拟利用已建立的糖尿病db/db小鼠模型，进一步研究胃肠动力障碍、肠道菌群失调和NAFLD三者的相互关系，阐明糖肾方通过保护胃肠动力、改善肠道菌群结构治疗NAFLD的药效学基础；进而，利用脂多糖刺激肠道Cajal间质细胞、肝脏Kupffer细胞，研究内毒素引发胃肠动力障碍、NAFLD的分子机制，阐明糖肾方改善肠道动力、治疗NAFLD的作用靶点；为中医药治疗复杂难治性疾病提供科学依据。

背景：糖尿病合并症非酒精性脂肪肝（NAFLD）严重危害人类健康。肠道菌群紊乱是引发脂肪肝的重要因素，胃肠动力障碍加重菌群紊乱，NAFLD发展到一定程度又可加重胃肠动力障碍和菌群紊乱。课题组前期发现，糖肾方可减轻糖尿病胃肠动力障碍及肝脂肪变性、有效抑制肠道及肝脏炎症。因此，我们提出科学假说：糖肾方通过改善糖尿病胃肠动力、减轻肠道菌群紊乱，从而抑制肝脏炎症，起到治疗NAFLD的作用。.主要研究内容：利用自发性2 型糖尿病Zucker大鼠模型及高脂外加小剂量STZ腹腔注射诱导的2型糖尿病大鼠模型，通过组织学（包括光镜、电镜、免疫组织化学、免疫荧光等）、生物力学、分子生物学、肠道菌群分析、血清学等观察糖肾方对胃肠动力障碍、肠道菌群紊乱和NAFLD 的药效学作用，探讨相关作用机制，以及胃肠动力障碍、肠道菌群紊乱、NAFLD 三者之间的相互关系。.结果：1、糖肾方可优化糖尿病大鼠肠道菌群，改善肠道上皮细胞超微结构，降低促炎细胞及其细胞因子含量，减轻肠壁结构重塑及生物力学特性的改变；2、糖肾方可明显降低糖尿病大鼠被抬高的血脂水平、减轻脂肪肝；3、糖肾方大鼠粪便移植及改善胃肠动力的西药亦可明显降低血脂水平、减少肝脏脂肪含量，对肠道菌群、肠壁结构重塑及生物力学特性有一定的改善作用。.结论：1、糖肾方通过优化肠道菌群，降低炎症，减轻肠壁重塑，从而改善机体代谢，减轻糖尿病脂肪肝及胃肠症状；2、胃肠动力障碍、肠道菌群紊乱、NAFLD三者互为因果，相互促进。.科学意义：阐明了糖肾方减轻胃肠症状的机制，明确了肠道菌群紊乱、胃肠动力障碍、NAFLD 三者之间的相互关系，对制定预防和治疗糖尿病胃肠动力障碍、脂肪肝具有重要的临床意义。