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Relevance between Glucocorticoid Treatment and the Intestinal Microbiota of Patients with Moderately Severe Ulcerative Colitis: A Single-center Retrospective Study
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摘要:
目的 分析接受及不接受糖皮质激素治疗的中重度溃疡性结肠炎(ulcerative colitis, UC)患者肠道菌群的差异, 并探讨肠道菌群对静脉糖皮质激素疗效的预测价值。 方法 回顾性分析2016年11月1日至2018年6月30日期间, 在北京协和医院消化内科门诊就诊或住院治疗的中重度UC患者临床资料。根据采集粪便样本时患者是否正在使用糖皮质激素, 将患者分为激素组和无激素组。无激素组患者入院后接受静脉激素、口服激素或免疫抑制剂治疗, 根据3 d后的疗效, 将入院后接受足量静脉激素治疗的患者分为治疗有效组和无效组。采用16S rRNA扩增子测序方法对粪便菌群测序分析, 采用香农指数评估肠道菌群α多样性, 采用Metastats分析比较不同组患者肠道菌群的物种构成差异。 结果 共35例符合入选和排除标准的中重度UC患者入选本研究, 无激素组20例, 激素组15例。无激素组中13例患者在采集粪便样本后接受静脉足量糖皮质激素治疗, 其中有效组8例, 无效组5例。激素组和无激素组患者的肠道菌群α多样性(香农指数:无激素组3.57±0.73, 激素组3.03±1.15, P=0.123)及物种组成无统计学差异。激素治疗有效组和无效组患者的肠道菌群α多样性亦无统计学差异(香农指数:有效组3.69±0.61, 无效组3.15±1.01, P=0.248), 但无效组的乳杆菌属(无效组0.0015±0.0000, 有效组0.0141±0.0002, P=0.010)和双歧杆菌属(无效组0.0178±0.0005, 有效组0.1716±0.0382, P=0.011)相对丰度显著低于有效组, 而志贺菌属(无效组0.4161±0.0750, 有效组0.1093±0.0173, P=0.008)和普雷沃氏菌属类群9(无效组0.0176±0.0004, 有效组0.0018±0.0000, P=0.044)的相对丰度则显著高于有效组。 结论 中重度UC患者肠道菌群的α多样性及物种组成可能与是否激素暴露无关, 但治疗前肠道菌群的物种组成可能是静脉激素疗效的潜在预测指标。 Abstract:Objective The aim of this study was to analyze the difference of intestinal microbiota in patientswith moderately severe ulcerative colitis (UC) treated with or without glucocorticoid (GC), and explore the predictive value for the response to intravenous GC medication. Methods The clinical data of outpatients and inpatients with moderately severe UC treated between November 1, 2016 and June 30, 2018 in the Department of Gastroenterology, Peking Union Medical College Hospital were retrospectively collected and analyzed. Patients were divided into GC-exposed group and non GC-exposed group based on whether they were exposed to GC when the fecal sample was collected. Patients from non GC-exposed group who received a full-dose of intravenous GC treatment were divided into GC-effective group and GC-refractory group according to the response after the 3-day treatment. The intestinal microbiota from fecal samples of the UC patient was detected by 16S rRNA gene amplicon sequencing method. α diversity was estimated using the Shannon index. Metastats analysis was employed in multiple comparisons of the microbiota composition. Results Totally 35 moderately severe UC patients were enrolled in this study, among which 20 were non GC-exposed and the other 15 were GC-exposed. Thirteen patients from the non GC-exposed group received a full-dose of intravenous GC treatment after the collection of fecal samples, and 8 of them were GC-effective, while the other 5 were GC-refractory. Patients exposed to GC or not showed little difference in intestinal microbiota α divesity(Shannon index:non GC-exposed group 3.57±0.73, GC-exposed group 3.03±1.15, P=0.123) or microbiota composition. Compared with the GC-effective group (Shannon index 3.69±0.61), the microbiota α diversity of the GC-refractory group (Shannon index 3.15±1.01) was not significantly different (P=0.248). Based on the microbiota composition, the relative abundance of Genus lactobacillus (GC-refractory 0.0015±0.0000, GC-effective 0.0141±0.0002, P=0.010) and Genus bifidobacterium(GC-refractory 0.0178±0.0005, GC-effective 0.1716±0.0382, P=0.011) was significantly lower in the GC-refractory group while that of Genus escherichia-shigella(GC-refractory 0.4161±0.0750, GC-effective 0.1093±0.0173, P=0.008) and Genus prevotella 9 (GC-refractory 0.0176±0.0004, GC-effective 0.0018±0.0000, P=0.044) was significantly higher. Conclusions The α diversity or composition of intestinal microbiota of patients with moderately severe UC may not be correlated with GC treatment. It is possible that pre-treated microbiota composition is related to the response to the intravenous GC treatment. -
Key words:
- ulcerative colitis /
- intestinal microbiota /
- glucocorticoid
利益冲突 无 -
图 2 中重度溃疡性结肠炎无激素组和激素组患者肠道菌群差异分析
A.菌群α多样性比较；B.菌群主成分分析；C.菌群相似性分析；D.菌群在门水平的构成；E.菌群在属水平的构成
图 3 中重度溃疡性结肠炎患者激素治疗有效组和无效组间肠道菌群的差异
A.菌群α多样性比较；B.菌群主成分分析；C.菌群相似性分析；D.菌群在门水平的构成; E.菌群在属水平的构成
表 1 35例中重度溃疡性结肠炎患者一般临床资料及激素疗效比较
指标 所有患者(n=35) 无激素组接受足量静脉激素治疗者(n=13) 激素组 无激素组 t值或χ2值 P值 有效 无效 t值或χ2值 P值 病例数(n) 15 20 - - 8 5 - - 年龄(x±s，岁) 38.3±13.4 45.9±16.1 1.479 0.149 41.4±17.7 52.4±10.9 1.243 0.240 性别(男/女，n) 9/6 11/9 0.088 0.767 4/4 4/1 1.229 0.268 病变范围(E2/E3，n) 1/14 4/16 1.344 0.246 2/6 0/5 2.165 0.141 疾病活动度(中度/重度，n) 9/6 12/8 0.000 1.000 5/3 2/3 0.630 0.427 
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表 2 中重度溃疡性结肠炎患者激素治疗有效组和无效组间细菌相对丰度比较
菌门/属 有效组 无效组 P值 门水平 变形菌门 0.1599±0.0279 0.4982±0.0794 0.017 放线菌门 0.1971±0.0327 0.0236±0.0005 0.009 属水平 乳杆菌属 0.0141±0.0002 0.0015±0.0000 0.010 双歧杆菌属 0.1716±0.0382 0.0178±0.0005 0.011 Peptoclostridium 0.0167±0.0004 0.0013±0.0000 0.015 志贺菌属 0.1093±0.0173 0.4161±0.0750 0.008 普雷沃氏菌属类群9 0.0018±0.0000 0.0176±0.0004 0.044
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