益生菌调节镉暴露引起的肠道功能异常的作用机制

Heavy metal cadmium (Cd) is a common pollutant in the food chain. Dietary Cd exposure induces intestinal dysfunction such as atony and peristalsis inhibition, which amplifies Cd absorption in the gut and exacerbates tissue Cd accumulation. Our preliminary work showed that a probiotic, Lactobacillus plantarum CCFM8610, is able to decrease Cd burden and alleviate Cd toxicity in the host. We also observed that this strain is effective in regulating intestinal dysfunction, but the involved mechanism is still unclear. Based on the results in the prophase, this study aims to investigate the molecular mechanism of the regulation of cadmium-induced intestinal dysfunction by L. plantarum CCFM8610 in Cd exposed cell and animal models. The regulatory effects of the strain on intestinal cells of Cajal, myoelectric activity and neurotransmitters are evaluated firstly to analyze the protection against Cd-induced gut atony. The regulation of the transcellular and paracellular Cd-enterocytes transporting pathways by the strain is also investigated to understand the inhibition on Cd-induced abnormal increase of intestinal permeability. Moreover, the molecular regulatory mechanisms of intestinal immune systems by the strains are analyzed with proteomic methods. With a consideration on intestinal function regulation, the results of present study may provide further understanding on the dietary strategy against Cd exposure.

镉是食物链污染中最常见的重金属之一。膳食镉暴露可引起肠道动力缺失等功能异常，进一步加剧镉在肠道中的吸收，引起机体镉蓄积的恶化。本课题前期研究表明益生菌（植物乳杆菌CCFM8610）可在宿主体内实现对镉的生物减除，同时可有效调节镉暴露导致的肠道功能异常，但相关作用机制尚不清楚。基于此，本课题拟利用镉暴露动物和细胞模型，从细胞和蛋白分子水平上系统阐明植物乳杆菌CCFM8610调节镉暴露引起肠道功能异常的作用机制。首先解析益生菌对肠道Cajal间质细胞、肌电活动及神经递质的调节作用，揭示菌株缓解镉暴露导致肠道动力缺失的生理机制；并阐明益生菌对镉穿越肠道跨细胞/细胞旁路途径的调节作用，明确菌株抑制镉暴露导致肠道通透性升高的作用机制；同时利用蛋白质组学手段研究菌株调控镉暴露导致肠道免疫异常的蛋白质分子机制。本研究有望从肠道功能调控的角度深入解析镉暴露的膳食防治机制，为相关研究和应用提供理论基础。

本课题对植物乳杆菌CCFM8610缓解镉暴露诱导肠道损伤的效果评价及机制进行相关探究。通过构建慢性镉暴露小鼠模型，测定小鼠粪便含水量、排便时间、结肠张力、肠道内神经递质及结肠内Cajal细胞，对植物乳杆菌CCFM8610缓解镉暴露诱导肠道损伤的效果进行评价。进一步对小鼠肠道紧密连接蛋白、肠道炎症及肠道菌的测定，探寻植物乳杆菌CCFM8610缓解肠道镉暴露诱导损伤的可能途径。基于细胞蛋白组学数据分析，寻找镉毒性肠道毒性相关的靶向蛋白位点。最后通过植物乳杆菌CCFM8610细胞干预实验，探究植物乳杆菌CCFM8610缓解镉暴露诱导肠道损伤的蛋白质分子机制。