桥本甲状腺炎患者肠道菌群分布特征及其与甲状腺功能的关系研究

Study on Distribution Characteristics of Intestinal Flora and its Relationship with Thyroid Function in Patients with Hashimoto’s Thyroiditis

目的通过分析桥本甲状腺炎(Hashimoto’s thyroiditis,HT)患者肠道菌群分布特征及肠道菌群变化与HT的相关性和对HT发生的预测价值,为临床HT诊疗提供参考。方法选取秦皇岛市中医医院2022年6月~2023年6月收治的120例HT患者纳入观察组,另选择该院同期30例健康体检者纳入对照组。两组均进行肠道菌群检测及甲状腺功能检测,对比两组及不同甲状腺功能HT患者的肠道菌群α多样性和门水平肠道菌群相对丰度,用Spearman相关性分析HT患者肠道菌群α多样性及门水平肠道菌群相对丰度与血清甲状腺球蛋白抗体(anti-thyroglobulin antibodies,TgAb)、甲状腺过氧化物酶抗体(thyroid peroxidase antibodies,TPOAb)水平及甲状腺功能的相关性;用受试者工作特征(Receiver operating characteristic,ROC)曲线分析肠道菌群α多样性及门水平肠道菌群相对丰度对HT的预测效能。结果与对照组比较,观察组的肠道菌群α香农多样性指数(Shannon-wiener diversity index,shannon)(4.66±0.61vs 5.21±0.46)和辛普森多样性指数(Simpson diversity index,simpson)(0.89±0.06 vs 0.93±0.07)均较低,差异有统计学意义(t=4.617,3.156,均P<0.05);观察组的拟杆菌门的相对丰度(52.31%±2.02%vs 58.59%±2.11%)较低,厚壁菌门(37.15%±2.43%vs 33.46%±2.56%)、变形菌门(3.36%±0.26%vs 2.79%±0.19%)、梭杆菌门(1.02%±0.09%vs 0.65%±0.11%)、放线菌门(1.01%±0.12%vs 0.57%±0.13%)和疣微菌门(0.82%±0.11%vs 0.41%±0.09%)的相对丰度均较高,差异具有统计学意义(t=15.096,7.360,11.267,19.231,17.665,18.882,均P<0.001);观察组的血清TgAb水平(169.12±10.23 IU/ml vs 18.59±1.78 IU/ml)和TPOAb水平(56.43±12.11 IU/ml vs 2.51±0.57IU/ml)均较高,差异具有统计学意义(t=80.097,24.319,均P<0.001)。该研究120例HT患者甲状腺功能正常者89例、异常者31例,与正常者比较,甲状腺功能异常者的肠道菌群α多样性指数shannon(4.49±0.64 vs 4.83±0.58),simpson(0.87±0.07 vs 0.91±0.05)较低,差异有统计学意义(t=2.736,3.439,均P<0.05);拟杆菌门相对丰度(49.10%±1.99%vs 55.52%±2.05%)较低,厚壁菌门(38.87%±2.60%vs 35.43%±2.26%)、变形菌门(3.60%±0.26%vs 3.12%±0.19%)、梭杆菌门(1.15%±0.09%vs 0.89%±0.11%)和放线菌门(1.16%±0.13%vs 0.86%±0.11%)、疣微菌门(0.97%±0.13%vs 0.67%±0.09%)的相对丰度均较高,差异具有统计学意义(t=15.128,7.016,9.849,14.576,12.464,14.148,均P<0.001)。Spearman相关性分析显示,HT患者的肠道菌群α多样性指数shannon,simpson及拟杆菌门的相对丰度与血清TgAb,TPOAb水平呈负相关(r=-0.436,-0.427,-0.402;-0.419,-0.456,-0.416,均P<0.001),与甲状腺功能均呈正相关(r=0.401,0.409,0.487,均P<0.001);厚壁菌门、变形菌门、梭杆菌门、放线菌门和疣微菌门的相对丰度与血清TgAb,TPOAb水平呈正相关(r=0.411,0.441,0.447,0.421,0.447;0.425,0.415,0.438,0.402,0.469,均P<0.001),与甲状腺功能呈负相关(r=-0.412,-0.417,-0.475,-0.463,-0.471,均P<0.001)。ROC曲线分析显示,肠道菌群α多样性指数shannon预测HT的最佳截断值、曲线下面积(areaunder curve,AUC)、敏感度、特异度、95%置信区间(95%confidence interval,95%CI)和约登指数分别为4.677,0.749,49.17%,96.67%,95%CI(0.672~0.816),0.458;simpson预测HT的最佳截断值、曲线下面积、敏感度、特异度、95%置信区间和约登指数分别为0.940,0.644,80.00%,53.33%,95%CI(0.562~0.721),0.333;simpson和shannon联合检测预测HT的曲线下面积、敏感度、特异度、95%置信区间和约登指数分别为0.752,85.83%,50.00%,95%CI(0.664~0.810),0.462;门水平各肠道菌相对丰度联合检测预测HT的AUC,敏感度、特异度、95%置信区间和约登指数分别为0.743,96.67%,46.67%,95%CI(0.665~0.811),0.548。结论HT存在肠道菌群失调;肠道菌群失调与HT患者的甲状腺细胞破坏、甲状腺功能异常有关;肠道菌群检测对HT有预测效能。

Objective To explore the intestinal flora distribution characteristics in patients with Hashimoto’s thyroiditis(HT)and analyze the correlation between intestinal flora changes and HT and the predictive value on the occurrence of HT,so as to provide reference for clinical diagnosis and treatment of HT.Methods A total of 120 patients with HT admitted to Qinhuangdao Traditional Chinese Medicine Hospital from June 2022 to June 2023 were included in observation group,and 30 healthy physical examination subjects during the same period were enrolled as control group.Both groups performed intestinal flora detection and thyroid function detection.Theαdiversity and the relative abundance of intestinal flora at phylum level were compared between the two groups and among HT patients with different thyroid functions,and the correlation betweenαdiversity of intestinal flora and relative abundance of intestinal flora at phylum level,serum levels of anti-thyroglobulin antibody(TgAb)and thyroid peroxidase antibody(TPOAb)and thyroid function was analyzed by spearman correlation analysis.Receiver operating characteristic(ROC)curve was used to analyze the predictive efficiency ofαdiversity and relative abundance of intestinal flora at phylum level on HT.Results Compared with control group,the intestinal floraαdiversity indexes of shannon-wiener diversity index(shannon)and simpson diversity index(simpson)were lower in observation group[4.66±0.61 vs 5.21±0.46,0.89±0.06 vs 0.93±0.07],and the differences were statistically significant(t=4.617,3.156,P<0.05).The relative abundance of Bacteroidetes in observation group was lower than that in control group(52.31%±2.02%vs 58.59%±2.11%),while the relative abundances of Firmicutes,Proteobacteria,Fusobacteria,Actinobacteria and Verrucomicrobia were higher than those in control group(37.15%±2.43%vs 33.46%±2.56%,3.36%±0.26%vs 2.79%±0.19%,1.02%±0.09%vs 0.65%±0.11%,1.01%±0.12%vs 0.57%±0.13%,0.82%±0.11%vs 0.41%±0.09%),and the differences were statistically significant(t=15.096,7.360,11.267,19.231,17.665,18.882,all P<0.001).The levels of serum TgAb(169.12±10.23 IU/ml vs 18.59±1.78 IU/ml)and TPOAb(56.43±12.11 IU/ml vs 2.51±0.57 IU/ml)in observation group were higher compared with those in control group,and the differences were statistically significant(t=80.097,24.319,all P<0.001).Among 120 HT patients in this study,there were 89 cases with normal thyroid function and 31 cases with abnormal thyroid function.The intestinal floraαdiversity indexes of shannon(4.49±0.64 vs 4.83±0.58),and simpson(0.87±0.07 vs 0.91±0.05)in patients with abnormal thyroid function were lower than those in normal patients,and the differences were statistically significant(t=2.736,3.439,all P<0.05).The relative abundance of Bacteroides was lower(49.10%±1.99%vs 55.52%±2.05%),while the relative abundances of Firmicutes,Proteobacteria,Fusobacteria,Actinobacteria and Verrucomicrobia were higher than those in normal people(38.87%±2.60%vs 35.43%±2.26%,3.60%±0.26%vs 3.12%±0.19%,1.15%±0.09%vs 0.89%±0.11%,1.16%±0.13%vs 0.86%±0.11%,0.97%±0.13%vs 0.67%±0.09%)],and the differences were statistically significant(t=15.128,7.016,9.849,14.576,12.464,14.148,all P<0.001).Spearman correlation analysis showed that the intestinal floraαdiversity indexes(shannon and simpson)and relative abundance of Bacteroides in patients with HT were negatively correlated with serum TgAb and TPOAb levels(r=-0.436,-0.427,-0.402;-0.419,-0.456,-0.416,all P<0.001),but were positively correlated with thyroid function(r=0.401,0.409,0.487,all P<0.001).The relative abundances of Firmicutes,Proteobacteria,Fusobacteria,Actinobacteria and Verrucomicrobia were positively correlated with serum TgAb and TPOAb levels(r=0.411,0.441,0.447,0.421,0.447;0.425,0.415,0.438,0.402,0.469,all P<0.001),but were negatively correlated with thyroid function(r=-0.412,-0.417,-0.475,-0.463,-0.471,all P<0.001).ROC curve analysis revealed that the best cut-off value,the area under curve(AUC),sensitivity,specificity,95%confidence interval(95%CI)and Youden index in shannon,simpson,combined detection of simpson and shannon,and the combined detection of relative abundance of intestinal bacteria at phylum level for predicting HT were 4.677,0.749,49.17%,96.67%,95%CI(0.672~0.816)and 0.458,0.940,0.644,80.00%,53.33%,95%CI(0.562~0.721)and 0.333,0.752,85.83%,50.00%,95%CI(0.664~0.810)and 0.462,0.743,96.67%,46.67%,95%CI(0.665~0.811)and 0.548,respectively Conclusion HT had intestinal flora imbalance which was related to thyroid cell destruction and thyroid dysfunction in patients with HT.Intestinal flora detection has predictive efficiency on HT.