三氯蔗糖对鼠肠道菌群影响及其相关肠道疾病易感性提高的机制研究

In recent years, the incidence of inflammatory bowel disease (IBD) and colorectal cancer has been increasing year by year.Commonly used treatments give only temporary respite to symptoms, but soon the resistance or toxicity will appear and prognosis is poor, which makes IBD, colon cancer and other intestinal diseases become a serious threat to human health.Therefore, it is extremely urgent to find the cause of these diseases.There are increasing evidences that the use of artificial sweetener sucralose may be associated with an increase in intestinal diseases worldwide, but the mechanism of the increased incidence of intestinal disease by sucralose is not clear. Our previous study found that sucralose effected the microbial balance of intestinal microflora, and intestinal flora imbalance will lead to the development of a variety of intestinal diseases, and even the occurrence of cancer. Therefore, this study proposes the hypothesis that the widely use of artificial sweetener sucralose could influence and change the gut microflora to trigger disorder of digestive protease inactivation and damage of intestinal mucosal barrier, then cause intestinal disease reaction and increase susceptibility to intestinal diseases. This study intends to verify the hypothesis by the studies of IBD and colon cancer on model animals to illuminate relationship between the effect of sucralose on intestina flora and increased susceptibility to intestinal diseases, elucidating the mechanism by which alteration of intestinal flora induce intestinal diseases.

近年来炎症性肠病(IBD)、结肠癌发病率逐年增加。常用的治疗手段只能暂时缓解症状，但很快会出现耐药或毒副反应且预后差，这使IBD、结肠癌等肠道疾病成为严重威胁人类健康的疾病。因此寻找该疾病的发病原因迫在眉睫。越来越多证据表明，人工甜味剂三氯蔗糖的使用可能与世界范围的肠道疾病增加有关，但是关于三氯蔗糖提高肠道疾病发病率的机制却不甚清楚。我们的前期研究发现，三氯蔗糖影响肠道菌群微生态的平衡，而肠道菌群失调将会导致多种肠道疾病的发生发展，甚至癌症的发生。因此，本研究提出了“人工甜味剂三氯蔗糖的广泛使用可影响及改变肠道菌群微生态-消化蛋白酶的灭活障碍-肠道粘膜屏障破坏，进而引起肠道疾病反应，并提高肠道疾病的易感性”的假说。本课题拟通过对IBD和结肠癌模型动物的研究去验证假说，旨在揭示三氯蔗糖对肠道菌群影响与肠道疾病易感性提高的相关性，并阐明肠道菌群微生态改变影响肠道疾病易感性的作用机制。

随着人工甜味剂三氯蔗糖的广泛的使用，与其使用平行发生的是有关欧美国家肠道疾病高发病率的报导接踵而至。我们的前期研究发现，人工甜味剂三氯蔗糖可破坏肠道菌群微生态的平衡。已有文献报道，肠道菌群失调与多种肠道疾病的发生发展，甚至癌症的发生密切相关。“三氯蔗糖是否真的可以促进肠道疾病发生?三氯蔗糖又是如何提高肠道疾病易感性的呢?”本课题以肠道菌群的改变为切入点，初步探究三氯蔗糖对炎症性肠病（IBD）和结肠癌易感性的影响及其作用机制。我们的研究结果表明，三氯蔗糖通过改变肠道菌群的微生态影响肠道内β-葡萄糖醛酸酶的水平，从而引起胰蛋白酶和糜蛋白酶的灭活障碍，未完全灭活的消化蛋白酶对肠道黏液层的过度消化导致肠道屏障受损，肠道菌群突破受损的肠黏膜屏障，移位至肠黏膜上皮细胞。肠道菌群的异常移位既能激活TLR4/5-MyD88-NF-κB相关的免疫炎症通路，促进炎症因子TNF-α、IL-1β、IL-6等的表达上调和慢性炎症的形成；也可激活与肿瘤形成相关的STAT3/VEGF信号通路，并能上调肿瘤增殖标志物PCNA的表达水平，最终导致IBD甚至结肠癌的发生。这些研究结果为人们安全和合理地使用人工甜味剂提供理论依据，并为预防、治疗IBD和结肠癌等相关肠道疾病提供新思路。