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Intestinal Microbiota Polymorphism of Epilepsy Patients in Middle and High Altitude Areas: A Case-control Study
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摘要:目的 探究中高海拔地区癫痫患者肠道菌群组成与分布特征，以期为癫痫病因学研究提供理论依据。方法 2021年9月至2022年8月，连续招募世居于中高海拔地区(海拔2200~4500 m)癫痫患者(middle-high altitude epilepsy, MHE)和中高海拔地区健康人群(middle-high altitude normal, MHN)。其中MHE来自于青海省人民医院神经内科癫痫患者，MHN来自于青海省人民医院体检中心体检的健康人群，并按照年龄、性别与MHE进行1∶1匹配。收集两组粪便组织标本，对肠道菌群16S rDNA V3~V4区进行DNA测序并进行生物信息学分析。结果 共入选符合纳入与排除标准的MHE 32例、MHN 33名。α多样性分析显示，MHE组ACE指数、Shannon指数、Chao指数均低于MHN组(P均＜0.05)；β多样性分析显示，二者的肠道菌群分布存在显著差异。在对肠道菌群组成成分的分析中，MHE组在门水平、属水平亦显示出不同于MHN组的特征，其疣微菌门(Verrucomicrobiota)、柯林斯氏菌属(Collinsella)、梭杆菌属(Fusobacteriota)、双歧杆菌属(Bifidobacterium)等菌种的相对丰度增高，拟杆菌门(Bacteroidota)、拟杆菌属(Bacteroides)、普氏菌属(Prevotella)、粪杆菌属(Faecalibacterium)等菌种的相对丰度降低。结论 中高海拔地区癫痫患者肠道菌群呈现出不同于同海拔健康人群的多态性，可能与癫痫发生具有一定关联性。Abstract:Objective To investigate the composition and distribution characteristics of intestinal flora in patients with epilepsy at middle-high altitude, in order to provide theoretical reference for the etiological study of epilepsy.Methods From September 2021 to August 2022, we continuously recruited middle-high altitude epilepsy (MHE) patients (altitude 2200-4500 m) and healthy people at the same altitude as middle- high altitude normal (MHN). MHE were epileptic patients in neurology department of Qinghai Provincial People's Hospital, and MHN were healthy people in physical examination center of Qinghai Provincial People's Hospital which matched 1∶1 with MHE by age and gender. Stool tissue specimens from both groups were collected, and the 16S rDNA V3 to V4 regions of the intestinal flora were sequenced for DNA and analyzed bioinformatically.Results A total of 32 cases of MHE and 33 cases of MHN who met the inclusion and exclusion criteria. Alfa diversity analysis showed that ACE index, Shannon index and Chao index in MHE group were lower than those in MHN group (all P < 0.05). Beta diversity analysis showed that there were significant differences in the distribution of intestinal flora between the two groups. In the analysis of intestinal flora composition, MHE group also showed different characteristics from MHN group at phylum level and genus level. The relative abundance of Verrucomicrobiota, Collinsella, Fusobacteriota, Bifidobacterium and other bacteria increased, whereas the relative abundance of Bacteroidota, Bacteroides, Prevotella, Faecalibacterium and other bacteria decreased.Conclusion The intestinal flora of epilepsy patients at middle and high altitude has different polymorphisms from that of healthy people at the same altitude, which may be associated with epilepsy.
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Keywords:
- epilepsy /
- intestinal flora /
- middle and high altitude /
- microbiota polymorphism
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经过一天烈日的炙烤，住院部外面的地表温度已经高达40 ℃，进进出出需要加强监护的患者还在不断增加，面对监护室内堆积如山的病患，大家的心情已经烦躁不安。高速周转的病房似乎又经历了一波“大洗牌”，病床上躺着不同的面孔，交班正仔细且有序地进行着。“号外……又有新病人要从急诊科转入，目前鼻导管10 L/min吸氧中，呼吸困难，需要重新评估插管指征......”值班护士小罗一边接听着电话，一边冲大家喊道。此刻空气仿佛凝住了一般，最尴尬的事情莫过如此——在交班时要来病人。“大家先交班，速战速决，准备收病人......”作为今天当值的高年资主治医师，我立刻说道。
伴随着转运车的声音，病人送来了，大家立刻围了上去，按照平时标准动作过床、吸氧、完成心电监护连接。我走到病床边，那是一位白发苍苍、胸前皮下还隐约有一枚“勋章”的爷爷，一看心电监护，我本能地反应那枚东西应该是心脏永久起搏器。为了判断病人意识及症状，我拍了拍老人肩膀，问道：“爷爷，您知道这是在哪儿吗？”老人没有回答，但是眼睛在不停地转动，嘴巴似乎要表达什么，带着一点儿北方口音，但听得不太清楚。我瞬时像明白了什么，于是俯下身去对着他的耳朵大声喊道：“爷爷，您知道这是在哪儿吗？您是不是听得不太清楚？”老人摇了摇头，又点了点头。
此时，我身旁一位经验丰富的“老医生”冲我扬了扬手中的听诊器听筒，我第一反应是她要听诊，于是连忙说道：“我来吧。”但她却直接把听头给爷爷戴上了，并对着听筒大声说道：“老爷子，这样能听清吗？”老人喃喃地回答：“听清了，听清了……”慢慢地，他紧崩的神情似乎也逐渐舒展开来。经过一系列问诊和针对性的处理后，爷爷慢慢睡着了。
病人急性呼吸窘迫的病因尚未完全明确，依然有病情随时加重的危险，依照惯例，我们立即联系家属了解老人的病史并进行谈话签字。通过与家属充分沟通，我们了解到了爷爷的慢性病史以及本次发病的诱因，还得知爷爷听力不好，这几天辗转各大医院，一直没休息好，病情也越来越重了。好在经过我们悉心的治疗和照顾，两周后爷爷终于出院了！
门诊复诊时，我看到爷爷耳朵上多了一副助听器，便打趣道：“爷爷，现在声音清楚多了吧？”爷爷笑着回答：“这玩意儿还是没有你们给我戴的东西听得清楚。”我和家属听完都哈哈大笑起来……
后记
听诊器的发明已有近200年的历史，其除了可以帮助医生完成重要的听诊检查外，在某些情况下还可以成为与病人沟通的桥梁。从法国医生雷奈克为了诊治患者，第一次提出“听诊器”的概念，到吴孟超院士在冬天查房时先用双手捂热听诊器再为患者听诊，再到为了能让患者听清楚，发现听诊器的新用途……不同听诊器的故事中，有不同的主人公以及不同的场景，但伴随的都是那份来自医生的爱，那份给予患者温暖的爱。病人与医生之间的第一步，是沟通，是了解，但病人在任何时候和任何状态下，都一定是需要帮助的那个人。任何人在面对身体的病痛时，或是因为没有足够专业的知识，或是因为疾病带来的切肤之痛，无论是酸胀、麻木、疼痛、无力，还是其他任何一种异样的感觉，都会让其内心产生对于异常表现的无限猜测以及随之而来的焦虑、恐慌。初入医学院时的我，心里想的只是如何掌握高精尖的各种医学技术，如何把病看好。进入医院工作多年以后，特别是在经历新型冠状病毒感染疫情后，我深切地体会到，不管医生的技术有多精湛，医疗水平有多高超，医生的关怀和援助永远都是病人最坚实的情感堡垒。治病一定是依靠科学，但让病人感觉到舒服却更需要医生对于患者那颗帮助的心。从医和患这层关系构建起来的那一刻起，他们就不该是对立的，而是共生的，更是共情的，感同身受、同气连枝才是医治疾病的起点，更是每一个合格医生毕生追求的终点。
临床医生正如其名字一样，需要站在床边仔细观察病人。观察的目的除正确诊断病情外，更重要的是察觉病人最需要的帮助是什么。故事中的老人一直处于听不清周围声音的状态，这时候病人可能会感到恐惧与烦躁，甚至会导致病情恶化，而一次仔细的观察就能够使问题迎刃而解。一个小小的听诊器，以及听诊器带来的这份“逆向思维”，彰显的不仅是一种临床采集病史的技巧，更是医生把心打开，试图去侧耳倾听病人诉说的耐心，以及尽其所能去关爱病人的慈悲。
因此，听诊器的故事，讲述的不是一种疾病的诊断，更不是一个病例的转归，听诊器联通的亦非症状与诊断，心跳与鼓膜，而是受伤的心和呵护的手，告诉我你哪里不舒服，我一定会想办法听到你的诉说，也一定会陪着你直到疾病消散。把痛苦告诉我，把希望传给你，这才是听诊器的真正意义所在，才是医生和病人最正确的相处方式。一如美国医生特鲁多对医生这个职业的经典描述——有时是治愈，常常是帮助，总是去安慰！
作者贡献：郑美玲负责标本收集、文献查阅、数据分析及论文撰写；樊青俐负责研究设计与论文修订；钟莲梅负责论文审核。利益冲突：所有作者均声明不存在利益冲突 -
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图 1 MHE组和MHN组肠道菌群多样性比较
A.稀疏曲线(Shannon指数)；B.β多样性(主坐标分析)；C.基于加权UniFrac距离矩阵样本树树状图
MHE、MHN：同表 1![]()
图 2 MHE组与MHN组肠道菌群分布特征
A.门水平物种组成柱状图；B.属水平物种组成柱状图；C.门水平物种丰度聚类热图；D.属水平物种丰度聚类热图
MHE、MHN：同表 1表 1 两组基线资料比较
组别 年龄(x±s，岁) 男性[n(%)] BMI (x±s，kg/m2) ALT (x±s，U/L) AST (x±s，U/L) Cr (x±s，μmol/L) TC (x±s，mmol/L) TG (x±s，mmol/L) MHE组(n=32) 38.7±16.81 17(53.1) 22.6±3.27 25.68±12.8 24.59±8.36 78.6±13.02 4.11±0.68 1.35±0.56 MHN组(n=33) 42.3±16.81 20(60.6) 22.7±2.52 29.93±11.6 27.56±8.58 79.5±15.26 4.39±0.76 1.45±0.62 P值 0.383 0.335 0.842 0.455 0.286 0.861 0.482 0.396 MHE：中高海拔地区癫痫患者；MHN：中高海拔地区健康人群；BMI：体质量指数；ALT：谷丙转氨酶；AST：谷草转氨酶；Cr：肌酐；TC：总胆固醇；TG：甘油三酯 
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