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摘要: 肠道菌群通过其代谢物、分泌物或细胞成分参与调节宿主代谢和免疫，并保护宿主抵抗病原微生物入侵。环境、营养、生活习惯改变以及抗生素滥用等原因均可导致肠道微生态结构和功能失调，进而导致多种疾病。与此同时，肠道菌群亦成为极具潜力的疾病治疗手段。本文将对胃肠道疾病(包括胃肠道感染性疾病、炎症性肠病、肠易激综合征等)与菌群的关系以及基于肠道菌群治疗该类疾病的最新研究成果进行总结，并对肠道菌群在未来疾病预防和干预中的前景作出展望。Abstract: Gut microbiome regulates host metabolism and immunity via their metabolites, secretions, and cellular components, and protects the host from pathogen invasion. Low diversity and dysfunction of the gut microbiome caused by environmental changes, unhealthy dietary habits and lifestyles, and antibiotics abuse are closely related to disease pathogenesis. Gut microbiome can serve as diagnostic and therapeutic tools for diseases related to gut microbiome dysbiosis. In this article, we aim to review the latest study advances on gut microbiome in the pathogenesis and therapeutics of gastrointestinal diseases, such as Clostridium difficile infection, Helicobacter pylori infection, inflammatory bowel disease, and irritable bowel syndrome, so as to shed light on the prospect of gut microbiome modulations in disease therapies.
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结节性硬化症(tuberous sclerosis complex，TSC)是一种累及多系统、以错构瘤病变为临床特征的罕见常染色体显性遗传病，眼部主要表现为视网膜星形细胞错构瘤(retinal astrocytic hamartomas，RAH)，其中超过50%的TSC相关RAH呈单眼多发[1-2]。作为一种眼内良性肿瘤，绝大多数RAH可长期维持稳定，但少数病灶可进行性生长，引起视网膜脱离，乃至新生血管性青光眼[3]。因此，完整检出RAH病灶并对其进行长期随访具有重要临床价值。
目前，临床主要采用传统彩色眼底照相(color fundus photography，CFP)对RAH病灶进行记录和随访，但CFP单次拍摄仅能获取后极部45°范围内的成像，9点固视虽可覆盖85°范围内的中周部视网膜，但需多次拍摄和拼图[4]。超广角扫描激光检眼镜(ultra-wide-field scanning laser ophthalmoscopy，UWF-SLO)是新一代视网膜成像技术，可在非接触情况下单次拍摄完成200°范围内的视网膜成像，已被广泛用于糖尿病视网膜病变、视网膜静脉阻塞、视网膜脱离等疾病的检查[5-8]，可为周边视网膜RAH病灶的评估提供帮助。但需要注意，UWF-SLO为红、绿合成“伪彩”双激光通道成像，RAH在UWF-SLO中的成像特征可能与常规可见光下的表现不同，从而对RAH病灶的识别造成影响[9]。
目前，临床上尚缺乏传统CFP与UWF-SLO对TSC相关RAH检出效果的比较研究，关于激光扫描成像对RAH识别的影响尚不清楚。因此，本研究拟对两种眼底成像技术下TSC相关RAH的检出率进行比较，评估不同激光通道下RAH的检出情况，同时结合光学相干断层扫描(optical coherence tomography，OCT)分析影响病灶检出的相关因素，以明确UWF-SLO在TSC相关RAH识别及随访中的应用价值。
1. 资料与方法
1.1 研究对象
本研究为回顾性研究。以2018年10月至2021年3月就诊于北京协和医院内科和眼科，且明确诊断为TSC合并RAH的患者为研究对象。收集患者相关临床资料，包括性别、年龄、诊断以及眼科随访时的视力、眼压、裂隙灯显微镜、散瞳前置镜、CFP、OCT及UWF-SLO等检查资料。
纳入标准：(1)散瞳眼底检查确诊为TSC合并RAH；(2)患者在随访时，同期进行了9点固视CFP及UWF-SLO检查；(3) 上述检查结果经由散瞳前置镜检查确认并记录。排除标准：(1)屈光间质混浊(如玻璃体积血)影响眼底观察；(2)CFP或UWF-SLO图像质量较差影响RAH病灶识别；(3)9点固视CFP合成范围或UWF-SLO成像范围等小于正常拍摄范围的75%(因眼睑遮挡、患者配合等)。
本研究已通过北京协和医院伦理审查委员会审批(审批号：JS-2639)，并豁免患者知情同意。
1.2 研究方法
1.2.1 9点固视CFP及UWF-SLO检查方法
两项检查均在患者散瞳后由同1名医师实施完成。9点固视CFP以彩色眼底照相机(TRC NW6S，日本拓普康公司)内置的9个以黄斑为中心分布的固视点方位进行拍照，拼图后可覆盖后极部85°范围。UWF-SLO(Daytona，英国欧宝公司) 以后极部为中心，应用532 nm绿激光和633 nm红激光同时扫描200°范围内的视网膜，获得合成“伪彩”双激光通道成像及单红、单绿激光通道成像。
1.2.2 RAH分型及定位标准
根据眼底表现对RAH病灶进行分型。(1)1型：相对扁平、光滑、无明显钙化的灰白透明病灶；(2)2型：隆起、多结节、钙化、不透明的桑葚样病灶；(3)3型：兼具前两种形态特征的过渡型病灶[10]。RAH病灶定位以后极部、中周部及远周部进行划分。后极部以黄斑中心凹为中心，中心凹至赤道1/2距离为半径画线的近圆形区域，中周部为赤道前后各2个视盘直径(papillary diameter，PD)的环形带状区域，远周部即赤道前2个PD至锯齿缘间的环形区域[11]。对于后极部RAH病灶，本研究应用3D OCT 1000 Mark Ⅱ (日本拓普康公司)或Spectralis HRA OCT(德国海德堡公司)进行光栅扫描，同时确定视网膜受累深度，测量RAH病灶最大厚度(maximal thickness，MT)，即RAH病灶前表面最高点至视网膜色素上皮层的距离。将RAH病灶分型、定位、视网膜受累深度、MT作为检出率的可能影响因素纳入分析。
1.2.3 检出率分析
以同一次随访时眼底病专科医师散瞳前置镜检查记录结果为参照标准。前置镜检查时将结合9点固视CFP及UWF-SLO检查结果，对所有可疑的RAH病灶进行确认。RAH病灶检出率=特定检查中的RAH病灶检出数/散瞳前置镜检查记录的病灶数。
1.3 统计学处理
采用SPSS 23.0软件进行统计分析。应用配对样本卡方检验(McNemar检验)比较9点固视CFP与UWF-SLO的RAH检出率；应用独立样本卡方检验分析UWF-SLO中病灶定位、OCT视网膜累及深度与病灶检出间的关系；应用独立样本t检验分析MT对RAH病灶检出的影响。以P＜0.05为差异具有统计学意义。
2. 结果
2.1 患者一般资料
本研究共纳入TSC合并RAH患者24例，其中男性7例，女性17例；随访时平均年龄(28.8±7.7)岁(最小年龄14岁，最大年龄44岁)。所有患者均在同次随访时完成9点固视CFP、UWF-SLO、OCT及散瞳前置镜等检查。经散瞳眼底检查共发现RAH病灶140个，其中1型RAH占绝大多数(95.0%，133/140)，2型和3型RAH分别仅为2个和5个。以后极部、中周部及远周部定位RAH病灶，RAH由后极向周边分布依次减少，其中后极部68个、中周部58个、远周部14个。
2.2 UWF-SLO与9点固视CFP的RAH病灶检出情况
在140个RAH病灶中，UWF-SLO(合成“伪彩”双激光通道成像)共检出病灶138个，检出率为98.6%，而9点固视CFP检出病灶92个，检出率为65.7%，且CFP检出的病灶中，17个RAH病灶因位于CFP图像边缘，病灶仅部分得以记录，RAH的完整记录率仅为53.6%。在TSC相关RAH病灶检出方面，UWF-SLO的检出率显著高于9点固视CFP(P＜0.001)(表 1)，两种眼底成像技术检出RAH病灶的示例情况详见图 1。不同类型RAH在9点固视CFP和UWF-SLO中的表现及其OCT特征详见图 2。
表 1 两种眼底成像技术对TSC相关RAH病灶的检出情况比较[n(%)]RAH定位 UWF-SLO检出数(个) 9点固视CFP检出数(个) χ2值* P值 双通道 单绿激光通道 单红激光通道 后极部(n= 68) 66(97.1) 66(97.1) 39(57.4) 68(100) 0.500 0.480 中周部(n= 58) 58(100) 58(100) 27(46.6) 24(41.4) 32.029 ＜0.001 远周部(n= 14) 14(100) 14(100) 7(50) 0(0) 12.071 ＜0.001 总体情况(n= 140) 138(98.6) 138(98.6) 73(52.1) 92(65.7) 40.500 ＜0.001 TSC：结节性硬化症；RAH：视网膜星形细胞错构瘤；UWF-SLO：超广角扫描激光检眼镜；CFP：彩色眼底照相；*为双通道UWF-SLO与9点固视CFP的病灶检出率比较 ![]()
图 1 TSC相关RAH的9点固视CFP(拼图)与UWF-SLO影像学表现9点固视CFP中可见4个1型RAH病灶(白色箭头)，UWF-SLO成像范围更广，除上述病灶外，另可见周边部2个1型RAH病灶(白色虚线圆)，病灶均表现为无明显钙化的灰白病灶；TSC、RAH、CFP、UWF-SLO：同表 1![]()
图 2 不同类型RAH的9点固视CFP、UWF-SLO及OCT影像学表现A.1型RAH：位于视盘颞上方，在CFP及UWF-SLO表现为灰白、扁平半透明病灶，OCT表现为神经纤维层增厚伴内层视网膜结构紊乱，病灶处玻璃体视网膜粘连；B.2型RAH：两处病灶均位于视盘，在CFP及UWF-SLO表现为钙化隆起结节，其中较大者呈桑葚样改变，OCT表现为神经上皮层内散在高反射点及蚕食空洞，后方有声影遮挡；C.3型RAH：位于颞下视盘处，在CFP及UWF-SLO表现为灰白半透明病灶中合并钙化结节及空腔，各组成部分在UWF-SLO中显示更为清晰，OCT表现为增厚的神经纤维层中出现蚕食样空腔改变。CFP、UWF-SLO同表 1；OCT：光学相干断层扫描进一步对病灶部位进行分析，对于后极部RAH，UWF-SLO(合成“伪彩”双激光通道成像)与9点固视CFP的病灶检出率分别为97.1%(66/68)和100%；对于中周部RAH，二者的病灶检出率分别为100% 和41.4%(24/58)；对于远周部RAH，UWF-SLO的病灶检出率依然保持100%，而9点固视CFP受限于拍摄范围无法对远周部视网膜进行拍摄。两种成像技术在TSC相关RAH病灶检出方面的差异主要集中在中周部和远周部(P＜0.001)(表 1)。
2.3 UWF-SLO不同激光通道的RAH病灶检出情况
在RAH病灶检出方面，UWF-SLO单绿激光(532 nm)通道成像与合成双通道成像检出情况一致，而单红激光(633 nm)通道成像仅检出病灶73个，显著低于单绿激光通道成像和合成双激光通道成像(P＜0.001)。单红激光通道成像未检出的67个病灶均为1型RAH，检出组与未检出组的病灶分布无显著统计学差异(P=0.812)。
本研究共有19例患者的42个1型RAH病灶进行了完整的OCT扫描，其RAH病灶MT均值为(481.5±134.6)μm。单红激光通道成像中检出组病灶的MT均值显著高于未检出组[(527.3±134.7)μm比(389.7±76.6)μm，P＜0.001]，而OCT中两组病灶累及深度则无显著统计学差异(P=1.000)(表 2)。
表 2 1型RAH在单红激光通道UWF-SLO中的检出情况3. 讨论
多发RAH是TSC的主要临床特征之一，完整检出并长期随访有助于发现具有进行性生长潜质的RAH病灶。UWF-SLO作为新一代视网膜成像技术，具有非接触、成像快、覆盖广的特点，其单次拍摄即可完成200°范围内的视网膜成像，在周边视网膜RAH病灶的评估方面具有潜在优势[5]。但同时，UWF-SLO的激光“伪彩”成像属性则可能对病灶的识别造成干扰[9]。本研究比较了UWF-SLO与传统CFP对TSC相关RAH病灶的检出情况，以明确前者在TSC相关RAH识别及随访中的应用价值。
在本研究中，UWF-SLO的TSC相关RAH检出率为98.6%，显著高于9点固视CFP，而后者RAH病灶的检出率仅为53.6%。检出差异主要在于对中周部及远周部RAH病灶的识别，其与两种眼底成像技术的覆盖范围相匹配。传统CFP单次拍摄仅能获得45°范围内的成像，9点固视CFP虽可将成像范围扩展至85°，但需多次拍摄和拼图，且对患者配合度要求较高，在采集便利性上亦不及UWF-SLO[4]。需注意的是，在后极部RAH病灶检出方面，虽然两种眼底成像技术未体现出差异，但就UWF-SLO而言，未检出的2个病灶均位于后极部，考虑可能与激光成像在后极部穿透性较强，以致RAH病灶表现不明显有关。
UWF-SLO以红、绿双激光同时扫描，在RAH病灶的检出中，仅有50%的病灶可由单红激光通道成像检出。未检出的病灶均为1型RAH，且OCT提示病灶厚度越小越不易检出，考虑可能与红激光穿透性强，主要显示视网膜深层及脉络膜结构相关[12]。1型RAH主要位于视网膜的神经纤维层，位置表浅，若病灶厚度小，则更易穿透，在单红激光通道成像难以检出。从检出情况看，合成“伪彩”双激光通道超广角扫描成像的结果主要依赖于单绿激光通道成像获得。绿激光波长较短，主要显示视网膜浅层至视网膜色素上皮层结构，与RAH病灶位置相匹配[12]。
本研究的不足之处在于病灶检出的标准是以散瞳眼底检查记录为准，散瞳眼底检查综合了UWF-SLO及9点固视CFP的RAH检查结果(UWF-SLO及CFP检查结果由同一名医师根据病灶形态判定)，未对实施该项检查的眼底疾病专科医师施盲，可能会提高检查医师对RAH病灶所在视网膜区域的关注度，从而提高RAH病灶的检出率。此外，UWF-SLO在周边视网膜成像上存在形变，周边视网膜放大效果约为后极部的2倍，且水平较垂直方向放大更为明显，因此UWF-SLO上的RAH病灶大小并不能直接测量或比较，未来在TSC相关RAH的随访研究中需特别注意[13]。
4. 小结
本研究显示，相较于传统CFP，UWF-SLO可能与更高的TSC相关RAH检出率相关。UWF-SLO对RAH病灶的检出可能主要依赖于单绿激光通道成像获得，单红激光通道不利于病灶厚度较小的1型RAH病灶检出。因激光成像具有较强的穿透性，在后极部RAH病灶的评估方面，建议与传统CFP及OCT相结合，以利于病灶的识别及疾病的长期随访。
作者贡献：黄子誉负责文献检索及论文撰写；兰平、左涛共同参与论文选题和设计；左涛负责论文修订。利益冲突：所有作者均声明不存在利益冲突 -
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