基于代谢组学的溃疡性结肠炎大鼠肠道微生态变化及安肠汤干预机制研究

Ulcerative colitis (UC) is a chronic inflammatory bowel disease, and it has been researchful hotspot that to explore its pathogenesis and look for effective drugs, due to increasing incidence year by year, undefined pathogenesis and lack of effective drug treatment to UC.There is close relationship between Intestinal microflora disorders and UC during its occurrence and development,but it was still unclear that causality and key factor's target point between the two. However, further deep research is restricted by shortcomings and defects of methods. As a new branch of science, metabolomics is through detecting metabolites in the body during the process of physiology and pathology,thus to explore the mechanism of the change about activities of body.But it has not been seen relevant reports at home and abroad about exploring the intestinal microecological change of UC on adopting metabonomics. Anchang decoction is compound Chinese herbs that we have applicated and researched in clinic more than 20 years，its clinical effective is well and no obvious toxic side effect. This study would get to analysis metabonomics'characteristics and change characteristics of intestinal microflora of UC rats by establishing the UC model of rats,putting to use metabonomics and molecular biology,in order to explore the pathogenesis of UC and observe the change in intestinal microflora of UC rats intervened Anchang soup decoction,and accordingly reveal the target spot to prevent UC by anchang decoction.

溃疡性结肠炎(UC)是一种慢性炎症性肠病，由于该病发病率逐年增加，发病机制尚未完全阐明，又缺乏有效的治疗药物，故探究其发病机制及寻找有效防治药物一直是研究热点。肠道微生态失调在UC的发生发展中具有密切关联性，但两者之间的因果关系及关键因素靶点仍不明确，而研究方法的不足和缺陷限制了更深入的研究。代谢组学作为一门新兴学科，是通过检测机体在生理病理活动过程中的代谢产物，来推究机体生命活动发生变化的机制。而采用代谢组学来探索UC的肠道微生态变化，目前国内外尚未见有相关报道。安肠汤是课题组临床应用和研究20余年治疗UC的中药复方，临床疗效佳，无明显毒副作用。本课题通过建立 UC 大鼠模型，运用代谢组学、分子生物学分析UC大鼠代谢组学特征及肠道微生态变化特征，探索UC发病机制，观察安肠汤对UC大鼠肠道微生态的干预作用，揭示其防治UC的作用靶点。

研究内容：通过建立 UC 大鼠模型，运用代谢组学、分子生物学分析UC大鼠代谢组学特征及肠道微生态变化特征，探索UC发病机制，观察安肠汤对UC大鼠肠道微生态的干预作用，揭示其防治UC的作用靶点。.研究结果及意义：①UC大鼠和正常大鼠结肠组织间存在代谢组学上存在差异代谢组分，9种代谢物可作为与UC相关的潜在生物学标志物，或可考虑作为辅助手段应用于UC的诊断和治疗。②在UC模型建立中发现第二个时间点（第10天）模型最为成功，提示第10天的造模效果最好。③安肠汤对11种代谢物的调节作用可能是安肠汤防治UC的途径和机制。④安肠汤治疗组中中剂量组的11种代谢物回调幅度优于低、高剂量组，提示安肠汤中剂量治疗组从代谢角度分析更适合于推广应用。⑤UC大鼠较正常大鼠肠道菌群变化具有明显差异性和特征性。⑥美沙拉嗪与丽珠肠乐对UC大鼠肠道菌群具有具有明确的调控作用，且二者间具体调节作用存在一定差异。⑦安肠汤对UC大鼠肠道菌群的调控方向上与美沙拉嗪和丽珠肠乐总体具有一致性，可能是其治疗UC的作用机制。⑧在不同剂量的对比中发现安肠汤中剂量组在总体菌群调控上较其他两组更接近空白对照组，说明从UC肠道菌群调节作用角度考虑安肠汤中剂量更适于临床应用和推广。⑨UC大鼠肠道内毒素及乙酸含量较正常大鼠明显增高，美沙拉嗪、丽珠肠乐和安肠汤治疗组对内毒素和乙酸均有明显的抑制作用，但各组间调节不具有差异性。说明内毒素和乙酸可能是UC发生的病因或病理产物，安肠汤的抑制作用可能是其治疗UC作用机制之一。