基于宏基因组学和代谢组学的原发性胆总管结石复发风险预测模型的建立

Primary common bile duct stones have a high incidence and a high recurrence rate in China. They have seriously endangered the patients’ health. The recurrent common bile duct stones have perplexed the patients and doctors for a long time due to the lack of a clinically effective diagnosis approach. The biliary microbiota and metabolites might play an important role in choledocholithiasis recurrence, however, the biliary metagenome and metabolome related to the recurrence still need further investigation. Moreover, the combination of metagenome and metabolome has a potential to assist clinical diagnosis and treatment. Previous metagenomic studies have not assessed the recurrence risk, thus we will perform metagenomic and metabolomic analysis on the bile samples collected from the common bile duct of choledocholithiasis patients with a high or low recurrence chance. Taking the multi-dimension clinical metadata into consideration, we would investigate the correlationship among the biliary metagenome, the biliary metabolome and these metadata. We aim to identify the recurrence-related microbes and metabolites, thus to provide insights into the gallstone recurrence mechanism. Furthermore, we will build a prediction model to assess the recurrence risk of the primary common bile duct stone patients based on these microbes and metabolites, which will assist to guide clinical diagnosis and treatment, improve prognosis of the patients, reduce the financial burden for patients and save medical resources.

原发性胆总管结石在我国发病率高且易复发，严重威胁患者身体健康。由于当前还缺乏有效的临床判断手段，胆总管结石复发长期困扰着患者和临床医生。胆道菌群和代谢物可能与胆石复发密切相关，但是复发相关的胆汁微生物组和代谢组仍有待进一步研究。并且宏基因组学和代谢组学结合具有辅助临床诊疗的潜力。当前已有宏基因组学研究并未涉及患者复发风险评估，因此本项目拟对易复发/不易复发原发性胆总管结石患者胆总管胆汁样本进行宏基因组和代谢组分析，并结合详尽的临床资料，基于相关性研究，鉴别胆石复发相关微生物和代谢物，对胆石复发机制进行初步探讨；并进一步依此建立患者复发预测模型，评估患者复发风险，以达到指导临床诊疗、改善患者预后、减轻患者医疗负担、节约医疗资源的目的。

胆道菌群与人胆总管结石发病密切相关。然而，内窥镜括约肌切开术对胆道菌群及胆石复发的影响仍然未知。我们收集了100个胆总管结石患者的胆汁样本，并基于16S扩增子测序比较不同患者的菌群构成。未进行抗生素治疗的患者的胆道菌群可以聚成3类，其中具有内窥镜括约肌切开术历史的患者(也即复发患者)在1个聚类中明显富集，该聚类主要由肠道菌群构成。而另外2个聚类主要由口腔细菌和环境细菌组成。并且行括约肌切开术和未行括约肌切开术(也即初诊患者)的患者胆道菌群的β多样性明显不同，然而α多样性差别却不大。与内窥镜括约肌切开术(也即胆石复发)有关的丰度上调的唯一细菌为Pyramidobacter，另有8种细菌丰度下降。对患者进行抗生素治疗后，仍有7种细菌与括约肌切开术相关，包括Pyramidobacter。并且在经过抗生素治疗后，不同患者之间β多样性差别不再具有统计学意义。总之，内窥镜括约肌切开术导致患者胆道菌群发生显著改变，Pyramidobacter丰度与该手术相关，进而与患者胆石复发有关。