CN113122646A - 炎性肠病特异性肠道微生物检测靶标及其应用 - Google Patents
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Abstract
本发明涉及生物信息技术及医疗健康领域，公开了一类炎性肠病(IBD)特异性微生物检测靶标及其应用，其特征在于这类靶标涉及Clostridium tertium，Odoribacter splanchnicus，Ruminococcus gnavus和Flavonifractor plautii四种细菌中的任意一种或数种。本发明基于微生物物种组成及物种间复杂网络结构等分析，通过比较IBD患者和健康对照肠道黏膜菌群间存在的差异，从众多候选微生物中筛选出上述四种细菌。这四种细菌与IBD的发病及病情恶化间存在显著的相关性。通过检测粪便或肠道黏膜内这四种细菌的变化，可辅助IBD的诊断和相关治疗效果的评估。这四种细菌也可作为治疗靶标，用于包括药物、益生菌及粪便移植等在内的任何IBD治疗当中，同时也为IBD相关治疗制剂和治疗策略的研发提供了思路和基础。
Description
技术领域
本发明涉及生物信息技术和医疗健康领域，特别涉及可用于炎性肠病诊断和治疗的特异性微生物靶标及其应用，其中该类靶标主要由Clostridium tertium，Odoribactersplanchnicus，Ruminococcus gnavus和Flavonifractor plautii四个细菌物种中的任意一种或数种构成。
背景技术
炎症性肠病(IBD)是一种慢行非特异性肠道炎症性疾病，包括溃疡性结肠炎(UC)、克罗恩病(CD)和未定型结肠炎。IBD的发病率在全球范围内呈上升趋势，其病因和发病机制却仍不明确，但初步认为是环境、感染等理化因素作用于具有遗传易感性的个体，引发免疫系统异常反应，导致肠道非特异性炎症。IBD不仅会引起腹痛、腹泻、血便等消化道症状，甚至会引发高热、贫血、肛周病变、肠病性关节炎、原发性硬化性胆管炎等肠外表现。
人体肠道菌群在营养代谢、防止病原体入侵和免疫系统发育等方面起着关键作用。现有研究已发现肠道菌群失调与IBD发生发展间存在密切的联系。与健康人相比，IBD患者肠道微生物菌群结构发生了明显改变，并且肠道菌群失调导致条件致病菌增多，从而还会引发与IBD相关的一系列免疫损伤。传统的IBD治疗包括类皮质激素、氨基水杨酸、免疫抑制剂等，但因缺乏明确的治疗靶标，导致副作用较强，临床治疗效果欠佳。近年来，伴随肠道菌群研究的深入，许多基于微生物的疗法逐渐发展起来，例如益生菌和粪便微生物移植。这些疗法可以通过抑制肠道致病菌、改善肠黏膜屏障功能及免疫调节等恢复肠道菌群的稳态，从而一定程度上有效缓解了IBD的临床症状。但同样因缺乏针对性和相对较高的成本，一些菌群相关的疗法只是作为辅助治疗，或只适用于个别临床病例，未大规模普及。
针对上述提到诊治缺乏针对性的问题，本发明提供了一类特异性针对IBD的微生物检测靶标，其中主要包括Clostridium tertium，Odoribacter splanchnicus，Ruminococcus gnavus和Flavonifractor plautii四个细菌物种。这四个物种是在肠道菌群中发现与IBD疾病发生、发展密切相关的潜在病原体。该类检测靶标可用于IBD的特异性诊断、治疗和愈后评估，具有很好的临床应用价值。
发明内容
本发明的目的在于：
缺乏炎性肠病(IBD)诊断和治疗针对性的问题，提供IBD特异性肠道微生物检测靶标，及其在IBD诊断、治疗和愈后效果评估中的应用。
为实现上述发明目的，本发明的技术方案为：
采集IBD患者的肠道菌群及等样本量的健康人肠道菌群，通过16S rRNA测序及分析技术获得菌群内的物种信息。首先，获取IBD患者和健康人肠道菌群中每个微生物物种的组成，例如物种丰度。其次，通过复杂网络分析技术分别构建IBD患者和健康人的肠道菌群网络，并应用发明人2016年发明的(专利受理号：201611127036.1)方法，计算每个网络中各物种的正负关系比值(P/N Ratio)。基于IBD患者与健康人肠道菌群的比较结果，从肠道菌群中筛选出物种组成、正负相互作用关系数量和正负关系比值均存在显著统计学差异的微生物物种，这些微生物物种便为IBD的检测靶标。通过上述技术方案，共找出四个符合要求的微生物物种，分别为Clostridium tertium，Odoribacter splanchnicus，Ruminococcusgnavus和Flavonifractor plautii。
本发明的有益效果在于：
提供了一类基于Clostridium tertium，Odoribacter splanchnicus，Ruminococcusgnavus和Flavonifractor plautii四个细菌物种中任意一种或数种的检测靶标，该类靶标可辅助IBD的诊断，用于任何形式的治疗当中，并评估治疗的效果。此外还可为IBD的相关诊治制剂和策略的研发奠定了基础。
附图说明
图1是本发明技术方案流程图
图2是IBD患者肠道菌群互作网络
图3是健康对照肠道菌群互作网络
具体实施方式
下面结合具体实施例对本发明做进一步的说明，但并不局限于此。
数据来源
肠道微生物数据采自28位IBD患者及其健康伴侣的肠道粘膜，他们的年龄在18岁到60岁之间。健康志愿者没有肠胃疾病，没有在内窥镜检查期间使用任何药物，也没有在采样前一年服用过抗生素。从样本中提取出DNA后扩增出16S rRNA片段，利用Illumina焦磷酸测序平台进行测序。测序得到的16S rRNA测序片段，通过后续的生物信息学分析得到97％相似性的微生物分类操作单元(Operational Taxonomic Unit，OTU)。其中每个OTU代表一个微生物物种，每个OTU对应的reads数量即为每个微生物物种的物种丰度(Abundance)。
肠道菌群物种间互作网络构建：
为尽可能提高准确率，删除了每组中28个样本物种总丰度小于25的OTU。剩余的OTU以物种丰度为基础，分别计算IBD患者组和健康对照组肠道菌群内OTU间的Spearman相关系数R，通过错误发现率(False Discovery Rate，FDR)矫正后，选取p≤0.05相互作用关系用于下一步构建网络。其中相关系数R＜0表示物种间为负相互作用关系，R＞0表示物种间为正相互作用关系。利用Cytoscape 2.8.3可视化两组肠道菌群的相互作用关系网络，如专利附图2和3所示，附图2为IBD患者的肠道菌群网络，附图3为健康对照的肠道菌群网络。图中每个点代表一个OTU(或微生物物种)，黑色虚线代表负相互作用关系，灰色实线代表正相互作用关系。
肠道菌群互作网络中正负关系比值计算：
以上述网络分析的结果为基础，应用发明人于2016年发明的正负关系比值(专利受理号：201611127036.1)，根据如下公式计算IBD患者组和健康对照组菌群互作网络中每个OTU的正负关系比值：
其中，P/N表示正负边比值，p为互作网络中正相互作用关系的数量，n为互作网络中负相互作用关系数量。
筛选IBD微生物检测靶标：
根据比较IBD患者与健康对照肠道菌群，设置了如下筛选标准：(1)物种丰度在两组间存在显著差异(Wilcoxon检验p值≤0.05)；(2)在健康对照菌群网络中，拥有至少5条负相互作用关系，且P/N比值＜0.5；(3)在IBD患者肠道菌群中，负相互作用关系数量显著下降，且P/N比值显著升高(P/N比值≥1.5)。在菌群中只有4个细菌符合上述筛选条件，分别是Clostridium tertium，Odoribacter splanchnicus，Ruminococcus gnavus和Flavonifractor plautii，表1中列出了这四个细菌对应的参数指标。
表1.四个IBD微生物检测靶标的相关筛选信息
Claims (5)
1.一类炎性肠病(IBD)特异性肠道微生物检测靶标及其应用，其特征在于：该类检测靶标主要由Clostridium tertium，Odoribacter splanchnicus，Ruminococcus gnavus和Flavonifractor plautii四个细菌物种中的一种或数种组成。
2.按照权利要求1所述的微生物检测靶标及应用，其特征在于：通过检测粪便和/或肠道黏膜内该类微生物靶标，辅助IBD的诊断和治疗效果评估。
3.按照权利要求1所述的微生物检测靶标及应用，其特征在于：该类微生物为包括药物、益生菌及粪便移植等在内的任何IBD治疗提供靶标。
4.按照权利要求1所述的微生物检测靶标及应用，其特征在于：该类微生物为IBD相关诊断和治疗的制剂及策略的研发提供靶标。
5.按照权利要求1-4任意一条或多条所述的对象，其特征在于：以任何软件、固件和(或)硬件(包括各种医疗仪器、观测仪器等)形式应用其概念和功能从而提供服务的产品。
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| CN114517228A (zh) * | 2021-12-31 | 2022-05-20 | 青岛锐翌精准医学检验有限公司 | 炎症性肠病标志基因及其应用 |
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| CN114517228A (zh) * | 2021-12-31 | 2022-05-20 | 青岛锐翌精准医学检验有限公司 | 炎症性肠病标志基因及其应用 |
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