肠道微生态与蒙古族抗结核药物性肝损伤的相关性研究

The specific mechanism of anti-tuberculosis drug-induced liver injury (ADLI) is still not clear. It may be a chronic complex pathological process involving multiple factors (eg, genetic and environmental factors) with multiple routes. There is rarely reported on the pathogenesis of ADLI in Mongolian. In recent years, the relationship between intestinal microecological balance and diseases has attracted much scientific interest, which provides new insights into the mechanisms of diseases. Due to the presence of "gut -liver axis", the intestinal microflora may also be involved in the pathogenesis of ADLI and further affect the treatment result. Therefore, to explore the relationship between intestinal microbial and ADLI in mongolian will help us to better understand the pathogenesis of ADLI. We took the Mongolian tuberculosis patients as the research object, collected fecal specimens from the patients who subjected to liver injury caused by anti-tuberculosis chemotherapy or no liver injury, and then explored intestinal flora structure characteristics of ADLI patients by using 16S rDNA sequencing technology and identified the ADLI-related bacteria. Eventually, we expect to reveal the relationship between ADLI and intestinal microflora. in mongolian and to provide new ideas for the pathogenesis and prevention of ADLI

抗结核药物性肝损伤（anti-tuberculosis drug-induced liver injury, ADLI)的发病机制迄今仍不明确，可能是多因素参与（如遗传、环境），通过多种途径所致的慢性复杂的病理过程。关于蒙古族ADLI发病的研究更鲜见报道。近几年，有关肠道微生态平衡与疾病之间关系的研究越来越受重视，为疾病的发生机制研究提供了新思路。由于“肠-肝轴”的存在，肠道微生物群落也可能参与ADLI的发病机制并影响治疗结果，因此，研究蒙古族肠道微生物与ADLI发生发展的关系，将有助于我们更为深入的了解蒙古族ADLI的发病机理。我们以蒙古族肺结核患者为研究对象，收集抗结核化疗出现肝损伤，未发生肝损伤患者粪便标本，运用16S rDNA技术全面深入探索ADLI患者肠道菌群结构特征，识别与ADLI相关的菌属，揭示ADLI与肠道菌群的关系，为蒙古族ADLI发病机制、防治手段研究提供新的思路和方法

直接面视下督导化疗是目前控制结核病最有效的策略，该方案要求连续每日服用4种一线药物6~9个月，抗结核药物能够有效地控制和杀死结核分枝杆菌，但也会引起各种不良反应，包括肝损伤、皮肤反应、胃肠道反应等。其中抗结核药物性肝损伤是最重要和最严重的不良反应之一，是导致患者抗结核治疗失败、复发和产生耐药性的重要原因，严重影响结核病疫情控制的总体效果。为了探究肺结核患者治疗前和治疗后肠道菌群的改变情况，并分析肠道菌群与抗结核药物性肝损伤（ADLI）的关系；收集2017年10月~2018年10月期间在内蒙古呼伦贝尔市传染病医院确诊的肺结核患者治疗前（TI）和治疗后（T2）的两份粪便标本，并按照治疗后3~4周间是否发生肝损伤将患者分为肝损伤组（ADLI组）和非肝损伤组（Non_ADLI组）。利用细菌16S rDNA高通量测序方法分析肠道菌群的差异。结果如下：1.患者治疗前和治疗后的比较结果显示，ADLI组和Non_ADLI组α多样性均下降（均P<0.05）；而β多样性比较中均未显示出任何差异（均P>0.05）；LEfse分析结果发现，ADLI组和Non_ADLI组从T1到T2时分别发现50个、59个分类群存在统计学差异（均P>0.05）。2 ADLI和Non_ADLI组比较时，在T1和T2时α多样性和β多样性均未显示出差异（均P>0.05）；LEfse数据表明，T1时，ADLI和Non_ADLI组共发现13个分类群存在差异（在属水平上为9个）；T2时，ADLI和Non_ADLI组共发现29个分类群存在差异。3 进一步分析T2时的差异改变的14个菌属与肝功能ALT、AST、TNF-α和IL-6指标的相关性，可知艾克曼菌属、梭菌属、Ruminiclostridium_5、Comamonas、未分类的脱硫弧菌属。、梭杆菌属和Morganella共7个菌属均与ALT指标存在相关性。结论 ： ADLI患者和Non_ADLI患者在接受抗结核治疗前和治疗后肠道菌群变化存在显著差异。ADLI患者相比于Non_ADLI患者，肠道菌群的α多样性下降，而菌群的结构并未发生显著变化。艾克曼菌属、梭菌属、Ruminiclostridium_5、Comamonas、未分类的脱硫弧菌属、梭杆菌属和Morganella与抗结核药性肝损伤的发生有关。