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Article(id=1240972418529939601, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240972413354176744, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202312158, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1702310400000, receivedDateStr=2023-12-12, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773800480730, onlineDateStr=2026-03-18, pubDate=1715270400000, pubDateStr=2024-05-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773800480730, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773800480730, creator=13701087609, updateTime=1773800480730, updator=13701087609, issue=Issue{id=1240972413354176744, tenantId=1146029695717560320, journalId=1227665162245664772, year='2024', volume='51', issue='9', pageStart='1537', pageEnd='1728', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773800479495, creator=13701087609, updateTime=1773800596829, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1240972905568334240, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240972413354176744, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1240972905568334241, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1240972413354176744, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1537, endPage=1543, ext={EN=ArticleExt(id=1240972418882261138, articleId=1240972418529939601, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=A two-sample Mendelian randomized study on the relationship between intestinal microorganisms and anxiety, columnId=1240413921954295836, journalTitle=Modern Preventive Medicine, columnName=Epidemiology and Statistical Methods, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the causal relationship between 211 intestinal microorganisms and anxiety by Mendelian randomization analysis.

Methods

Based on the genome-wide association study data of MiBioGen Alliance and Finnish database, the qualified instrumental variables were extracted, and the inverse variance weighting method was used as the main Mendelian randomized analysis method, combined with MR-Egger and Weighted median methods. Finally, the results were verified by Cochran’s Q statistics, intercept terms of MR-Egger regression, MR-PRESSO, and leave-one-out methods.

Results

Cyanobacteria (OR=1.103, 95%CI: 1.001-1.215, P=0.048), Shigella (OR=1.159, 95%CI: 1.027-1.309, P=0.017), and Slackia (OR=1.170, 95%CI: 1.047-1.307, P=0.017) were positively correlated with the risk of anxiety. Firmicutes (OR=0.857, 95%CI:0.754-0.974, P=0.018), Clostridium (OR=0.817, 95%CI: 0.701-0.951, P=0.009), Clostridium (OR=0.849, 95%CI: 0.736-0.980, P=0.025), Eubacterium_rectale_group (OR=0.861, 95%CI: 0.748-0.993, P=0.039), Ruminococcaceae_UCG004(OR=0.886, 95%CI: 0.789-0.994, P=0.039), and Ruminococcaceae_UCG011(OR=0.919, 95%CI: 0.854-0.989, P=0.025) were negatively correlated with anxiety risk. The results were verified and no heterogeneity and horizontal pleiotropy were found.

Conclusion

This study evaluates the potential causal relationship between intestinal microorganisms and anxiety, providing reference for the diagnosis, prevention and treatment of anxiety in the future.

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目的

利用孟德尔随机化探究211种肠道微生物与焦虑的因果关系。

方法

基于MiBioGen联盟和芬兰数据库中的全基因组关联研究数据集，提取符合条件的工具变量，以逆方差加权法为主要的孟德尔随机化分析方法，配合MR-Egger、Weighted median方法进行研究。最后通过Cochran Q统计量、MR-Egger回归的截距项、MR-PRESSO以及leave-one-out法对结果进行验证。

结果

蓝藻细菌门（OR=1.103，95%CI：1.001～1.215，P=0.048）、埃希-志贺菌属（OR=1.159，95%CI：1.027～1.309，P=0.017）、史雷克菌属（OR=1.170，95%CI：1.047～1.307，P=0.005）与焦虑风险呈正相关；厚壁菌门（OR=0.857，95%CI：0.754～0.974，P=0.018）、梭菌纲（OR=0.817，95%CI：0.701～0.951，P=0.009）、梭菌目（OR=0.849，95%CI：0.736～0.980，P=0.025）、真杆菌属（OR=0.861，95%CI：0.748～0.993，P=0.039）、瘤胃球菌_UCG004属（OR=0.886，95%CI：0.789～0.994，P=0.039）、瘤胃球菌_UCG011属（OR=0.919，95%CI：0.854～0.989，P=0.025）与焦虑风险呈负相关。所得结果通过验证，未发现异质性与水平多效性。

结论

本研究评估了肠道微生物与焦虑潜在的因果关系，为今后焦虑的诊断、预防与治疗等方面的相关研究提供参考。

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戴晓矞，E-mail:
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付进杰（2000—），男，硕士在读，研究方向：中医临床基础

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付进杰（2000—），男，硕士在读，研究方向：中医临床基础

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注：A蓝藻细菌门; B厚壁菌门; C梭菌纲; D梭菌目; E真杆菌属; F埃希-志贺菌属; G瘤胃球菌_UCG004属; H瘤胃球菌_UCG011属; I史雷克菌属。

, figureFileSmall=xof2EjFQrjWBpaq7Tl9P3g==, figureFileBig=tjgyt5DV//1uTMFTOQhRVg==, tableContent=null), ArticleFig(id=1240986261951935014, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240972418529939601, language=EN, label=Figure 4, caption=Results of the leave-one-out sensitivity analysis of gut microorganisms and anxiety disorders, figureFileSmall=ZH0C+KOmCKRYUVMuNVjRHg==, figureFileBig=bMgtpbu74WuPKDCBB/LjuQ==, tableContent=null), ArticleFig(id=1240986262107124278, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240972418529939601, language=CN, label=图4, caption=GM与焦虑的“leave-one-out”敏感性分析结果

注：A蓝藻细菌门; B厚壁菌门; C梭菌纲; D梭菌目; E真杆菌属; F埃希-志贺菌属; G瘤胃球菌_UCG004属; H瘤胃球菌_UCG011属; I史雷克氏菌属。

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Main results of MR analysis

, figureFileSmall=null, figureFileBig=null, tableContent=
ExposureMethodSNPsBeta P值OR值（95%CI）
CyanobacteriaMR-Egger80.1770.1760.3551.193 (0.845～1.686)
WME80.1460.0640.0241.157 (1.020～1.312)
IVW80.0980.0490.0481.103 (1.001～1.215)
FirmicutesMR-Egger14-0.2260.1780.2280.798 (0.563～1.130)
WME14-0.1420.0870.1020.867 (0.731～1.029)
IVW14-0.1540.0650.0180.857 (0.754～0.974)
ClostridiaMR-Egger11-0.7630.3080.0350.466 (0.255～0.853)
WME11-0.1030.0990.3020.902 (0.742～1.097)
IVW11-0.2020.0780.0090.817 (0.701～0.951)
ClostridialesMR-Egger12-0.7890.2760.0170.454 (0.264～0.780)
WME12-0.0680.0920.4580.934 (0.781～1.118)
IVW12-0.1630.0730.0250.849 (0.736～0.980)
Eubacterium _ rectale _ groupMR-Egger9-0.1070.2730.7060.898 (0.526～1.534)
WME9-0.1250.0930.1820.883 (0.735～1.060)
IVW9-0.1490.0720.0390.861 (0.748～0.993)
Escherichia. ShigellaMR-Egger100.1160.1930.5661.123 (0.769～1.639)
WME100.1500.0800.0591.162 (0.994～1.358)
IVW100.1480.0620.0171.159 (1.027～1.309)
Ruminococcaceae_UCG004MR-Egger11-0.2190.3430.5390.803 (0.410～1.573)
WME11-0.1470.0740.0470.863 (0.747～0.998)
IVW11-0.1220.0590.0390.886 (0.789～0.994)
Ruminococcaceae_UCG011MR-Egger8-0.2520.1890.2310.777 (0.536～1.126)
WME8-0.0410.0480.3920.960 (0.873～1.055)
IVW8-0.0840.0370.0250.919 (0.854～0.989)
SlackiaMR-Egger60.0120.3680.9751.012 (0.492～2.083)
WME60.1520.0730.0381.164 (1.008～1.343)
IVW60.1570.0570.0051.170 (1.047～1.307)
), ArticleFig(id=1240986263008899689, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240972418529939601, language=CN, label=表1, caption=

MR分析的主要结果

, figureFileSmall=null, figureFileBig=null, tableContent=
ExposureMethodSNPsBeta P值OR值（95%CI）
CyanobacteriaMR-Egger80.1770.1760.3551.193 (0.845～1.686)
WME80.1460.0640.0241.157 (1.020～1.312)
IVW80.0980.0490.0481.103 (1.001～1.215)
FirmicutesMR-Egger14-0.2260.1780.2280.798 (0.563～1.130)
WME14-0.1420.0870.1020.867 (0.731～1.029)
IVW14-0.1540.0650.0180.857 (0.754～0.974)
ClostridiaMR-Egger11-0.7630.3080.0350.466 (0.255～0.853)
WME11-0.1030.0990.3020.902 (0.742～1.097)
IVW11-0.2020.0780.0090.817 (0.701～0.951)
ClostridialesMR-Egger12-0.7890.2760.0170.454 (0.264～0.780)
WME12-0.0680.0920.4580.934 (0.781～1.118)
IVW12-0.1630.0730.0250.849 (0.736～0.980)
Eubacterium _ rectale _ groupMR-Egger9-0.1070.2730.7060.898 (0.526～1.534)
WME9-0.1250.0930.1820.883 (0.735～1.060)
IVW9-0.1490.0720.0390.861 (0.748～0.993)
Escherichia. ShigellaMR-Egger100.1160.1930.5661.123 (0.769～1.639)
WME100.1500.0800.0591.162 (0.994～1.358)
IVW100.1480.0620.0171.159 (1.027～1.309)
Ruminococcaceae_UCG004MR-Egger11-0.2190.3430.5390.803 (0.410～1.573)
WME11-0.1470.0740.0470.863 (0.747～0.998)
IVW11-0.1220.0590.0390.886 (0.789～0.994)
Ruminococcaceae_UCG011MR-Egger8-0.2520.1890.2310.777 (0.536～1.126)
WME8-0.0410.0480.3920.960 (0.873～1.055)
IVW8-0.0840.0370.0250.919 (0.854～0.989)
SlackiaMR-Egger60.0120.3680.9751.012 (0.492～2.083)
WME60.1520.0730.0381.164 (1.008～1.343)
IVW60.1570.0570.0051.170 (1.047～1.307)
), ArticleFig(id=1240986263172477558, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240972418529939601, language=EN, label=Table 2, caption=

Quality control results of 9 gut microorganisms and anxiety disorders

, figureFileSmall=null, figureFileBig=null, tableContent=
ExposureMethodQQP值Egger_interceptP值MR-PRESSO
P值
CyanobacteriaIVW5.5590.592-0.0100.6570.621
FirmicutesIVW17.8610.1630.0060.6710.168
ClostridiaIVW14.0040.1730.0370.0940.182
ClostridialesIVW16.5370.2210.0280.1390.207
Eubacterium _ rectale _ groupIVW3.5040.899-0.0030.8780.904
Escherichia. ShigellaIVW3.8600.9200.0030.8640.936
Ruminococcaceae_UCG004IVW14.1720.1650.0080.7790.197
Ruminococcaceae_UCG011IVW8.1400.3200.0230.3990.332
SlackiaIVW2.7660.7360.0150.7110.770
), ArticleFig(id=1240986263411552897, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1240972418529939601, language=CN, label=表2, caption=

9种GM与焦虑的质量控制结果

, figureFileSmall=null, figureFileBig=null, tableContent=
ExposureMethodQQP值Egger_interceptP值MR-PRESSO
P值
CyanobacteriaIVW5.5590.592-0.0100.6570.621
FirmicutesIVW17.8610.1630.0060.6710.168
ClostridiaIVW14.0040.1730.0370.0940.182
ClostridialesIVW16.5370.2210.0280.1390.207
Eubacterium _ rectale _ groupIVW3.5040.899-0.0030.8780.904
Escherichia. ShigellaIVW3.8600.9200.0030.8640.936
Ruminococcaceae_UCG004IVW14.1720.1650.0080.7790.197
Ruminococcaceae_UCG011IVW8.1400.3200.0230.3990.332
SlackiaIVW2.7660.7360.0150.7110.770
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肠道微生物与焦虑关系的两样本孟德尔随机化研究
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付进杰 1, 2 , 秦元 3, 4 , 肖凌勇 3, 4 , 戴晓矞 3, 4
现代预防医学 | 流行病与统计方法 2024,51(9): 1537-1543
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现代预防医学 | 流行病与统计方法 2024, 51(9): 1537-1543
肠道微生物与焦虑关系的两样本孟德尔随机化研究
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付进杰1, 2, 秦元3, 4, 肖凌勇3, 4, 戴晓矞3, 4
作者信息
  • 1.天津中医药大学研究生院，天津 301617
  • 2.天津中医药大学中医学院，天津 301617
  • 3.天津中医药大学第一附属医院，天津 300380
  • 4.国家中医针灸临床医学研究中心，天津 300380

    • 付进杰（2000—），男，硕士在读，研究方向：中医临床基础

通讯作者:

戴晓矞，E-mail:
A two-sample Mendelian randomized study on the relationship between intestinal microorganisms and anxiety
Jin-jie FU1, 2, Yuan QIN3, 4, Ling-yong XIAO3, 4, Xiao-yu DAI3, 4
Affiliations
  • Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
出版时间: 2024-05-10 doi: 10.20043/j.cnki.MPM.202312158
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摘要
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目的

利用孟德尔随机化探究211种肠道微生物与焦虑的因果关系。

方法

基于MiBioGen联盟和芬兰数据库中的全基因组关联研究数据集，提取符合条件的工具变量，以逆方差加权法为主要的孟德尔随机化分析方法，配合MR-Egger、Weighted median方法进行研究。最后通过Cochran Q统计量、MR-Egger回归的截距项、MR-PRESSO以及leave-one-out法对结果进行验证。

结果

蓝藻细菌门（OR=1.103，95%CI：1.001～1.215，P=0.048）、埃希-志贺菌属（OR=1.159，95%CI：1.027～1.309，P=0.017）、史雷克菌属（OR=1.170，95%CI：1.047～1.307，P=0.005）与焦虑风险呈正相关；厚壁菌门（OR=0.857，95%CI：0.754～0.974，P=0.018）、梭菌纲（OR=0.817，95%CI：0.701～0.951，P=0.009）、梭菌目（OR=0.849，95%CI：0.736～0.980，P=0.025）、真杆菌属（OR=0.861，95%CI：0.748～0.993，P=0.039）、瘤胃球菌_UCG004属（OR=0.886，95%CI：0.789～0.994，P=0.039）、瘤胃球菌_UCG011属（OR=0.919，95%CI：0.854～0.989，P=0.025）与焦虑风险呈负相关。所得结果通过验证，未发现异质性与水平多效性。

结论

本研究评估了肠道微生物与焦虑潜在的因果关系，为今后焦虑的诊断、预防与治疗等方面的相关研究提供参考。

焦虑  /  肠道微生物  /  因果关联  /  孟德尔随机化
Objective

To investigate the causal relationship between 211 intestinal microorganisms and anxiety by Mendelian randomization analysis.

Methods

Based on the genome-wide association study data of MiBioGen Alliance and Finnish database, the qualified instrumental variables were extracted, and the inverse variance weighting method was used as the main Mendelian randomized analysis method, combined with MR-Egger and Weighted median methods. Finally, the results were verified by Cochran’s Q statistics, intercept terms of MR-Egger regression, MR-PRESSO, and leave-one-out methods.

Results

Cyanobacteria (OR=1.103, 95%CI: 1.001-1.215, P=0.048), Shigella (OR=1.159, 95%CI: 1.027-1.309, P=0.017), and Slackia (OR=1.170, 95%CI: 1.047-1.307, P=0.017) were positively correlated with the risk of anxiety. Firmicutes (OR=0.857, 95%CI:0.754-0.974, P=0.018), Clostridium (OR=0.817, 95%CI: 0.701-0.951, P=0.009), Clostridium (OR=0.849, 95%CI: 0.736-0.980, P=0.025), Eubacterium_rectale_group (OR=0.861, 95%CI: 0.748-0.993, P=0.039), Ruminococcaceae_UCG004(OR=0.886, 95%CI: 0.789-0.994, P=0.039), and Ruminococcaceae_UCG011(OR=0.919, 95%CI: 0.854-0.989, P=0.025) were negatively correlated with anxiety risk. The results were verified and no heterogeneity and horizontal pleiotropy were found.

Conclusion

This study evaluates the potential causal relationship between intestinal microorganisms and anxiety, providing reference for the diagnosis, prevention and treatment of anxiety in the future.

Anxiety  /  Intestinal microorganisms  /  Causal correlation  /  Mendelian randomization
付进杰, 秦元, 肖凌勇, 戴晓矞. 肠道微生物与焦虑关系的两样本孟德尔随机化研究. 现代预防医学, 2024 , 51 (9) : 1537 -1543 . DOI: 10.20043/j.cnki.MPM.202312158
Jin-jie FU, Yuan QIN, Ling-yong XIAO, Xiao-yu DAI. A two-sample Mendelian randomized study on the relationship between intestinal microorganisms and anxiety[J]. Modern Preventive Medicine, 2024 , 51 (9) : 1537 -1543 . DOI: 10.20043/j.cnki.MPM.202312158
正文
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焦虑是最常见的精神障碍类疾病之一，全球范围内焦虑的终生患病率在5%～25%之间，特别是2020年，受COVID-19影响，全球焦虑患者比预估增加了26%[1]。焦虑在严重影响患者生活质量的同时，为人类社会带来巨大经济负担，据全球疾病负担研究显示，焦虑在精神类疾病负担中排名第二，占全球疾病负担的3.3%[2]。而且由于药物治疗逐渐产生的耐药性，大约20%的患者在减轻焦虑或抑郁症状方面没有改善[3]，可见该疾病临床治疗的需求也尚未得到解决，因此，十分需要一种新的方向思路，对焦虑进行有效预防、正确诊断及治疗干预，从而减低全球患病率和疾病负担。
肠道微生物（gut microbiota，GM）是寄居在人体肠道中的各种细菌，是人类第二大基因组，与机体健康密切相关，并且通过肠-脑轴（gut-brain axis，GBA）实现中枢神经系统和胃肠道之间作用的双向通信[4]。有研究发现，与健康人相比，广泛性焦虑患者拟杆菌和志贺菌的丰度较高，厚壁菌丰度较低，提示GM可能对焦虑的发病机制或治疗具有意义[5]；也有基础研究表明GM会通过产生的代谢物改变大脑少突胶质细胞分化和髓鞘动力学，从而影响小鼠表现出焦虑行为[6]。所以GM组群特征可能是焦虑患者新的诊断生物标志物及治疗靶点。然而，目前尚未有研究尝试评估GM在该疾病当中的特异性。因此我们可以通过GM谱系，分析不同GM对于焦虑的影响，判断其因果关系，明确危险因素与保护因素，为日后相关研究提供参考。
孟德尔随机化（Mendelian randomization，MR）作为一种研究方法，可有效运用已有的全基因组关联研究（genome-wide association studies，GWAS）数据结果，以单核苷酸多态性/遗传变异(single nucleotide polymorphisms，SNPs )为工具变量(instrumental variables，IVs )，探索暴露因素与结局之间因果关系，可以减少混杂因素或反向因果关系造成的偏差[7]。
在本研究利用GWAS汇总统计GM各类群与焦虑的MR分析，以探究两者之间的潜在因果关系，确定具体菌群对疾病产生的危险与保护作用，以期使用不同分析方法为现有的研究结果提供证据支撑，为尚未明确的发病机制提供新的研究思路，也为日后对与焦虑的预防、早期诊断及治疗提供新的方向。
1　数据与方法
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1.1　研究设计
基于GM与焦虑的GWAS，选取满足条件的SNPs作为工具变量，通过双样本MR探究肠道微生物与焦虑之间的因果关系。该项MR研究满足以下三个假设：（1）选择与GM显著相关的SNPs作为IVs；（2）所选的IVs与其他混杂因素无关；（3）IVs只能通过GM来影响焦虑。见图1。
1.2　数据来源
MiBioGen联盟贡献了GM的GWAS数据，共涉及211种GM，有来自24各队列的18 340个样本，从中获得了16Sr RNA基因的V3、V4-V3和V1-V2片段的测序图谱和基因分型数据[8]。焦虑的GWAS数据源于FinnGen（https://r5.finngen.fi/），该研究使用的表型为“焦虑”定义为一类精神疾病，其特征是焦虑感或恐惧，通常伴有与焦虑相关的身体症状，会受到吸烟、饮酒、职业、家庭环境等因素影响[9]，其诊断标准参考ICD-10：F40-F48，ICD-9：300[0～3|6～9]|3 078A|309，ICD-8：300[0～2]|30 030| 300[5～9]|305|30 680|30 799，包含20 992名焦虑患者与197 800名对照者，均来源于欧洲。本研究暴露和结局的数据均为公开数据库数据，无需伦理批准。
1.3　工具变量的选择
我们按照以下标准对IVs进行筛选：（1）本研究经过全基因组显著性阈值P<5×10-8对SNPs进行筛选，然而筛到的SNPs数量有限，可研究样本极少，因此我们选择以P<1.0×10-5为阈值筛选与GM显著相关的SNPs作为IVs以获得更为全面的研究结果[10]。（2）计算SNPs之间的连锁不平衡，相关系数设置clumping-distance=10 000 kb以及clumping-r2< 0.001。（3）为了排除存在潜在多效性，应用PhenoScannerV2（http://www.phenoscanner.medschl.cam.ac.uk/phenoscanner）搜索，进一步筛查与结局表型相关的SNPs，去除混杂因素。（4）当存在回文SNP时，回文SNP被剔除，以防止等位基因对因果关系的影响。（5）计算IVs与GM的F统计量，保留F数值大于10的SNPs[11]。
1.4　统计分析
该研究使用逆方差加权法（inverse variance weighted，IVW）、MR-Egger、加权中位数法（weighted median，WME）和MR-PRESSO方法探究GM与焦虑之间的因果关系，以IVW为主要分析方法[12]，它能在有效的IVs当中检测出具有较强因果关系的SNP；使用MR-Egger回归来对多效性进行检验，尽管与IVW相比它的统计效率较低，但IVs间存在多效性时，使用MR-Egge更为合适；若有50%的IVs无效时，使用WME来得到较为稳健的估计值。同时为了保证所得结果的稳定性，我们进行了敏感性分析。Cochran Q统计量用来检查SNPs之间是否存在异质性，P<0.05表明存在异质性[10]；通过MR-Egger回归的截距项检测是否存在水平多效性，P<0.05表明存在水平多效性[13]，其中截距项是指当暴露为0时，结局发生的情况，如果截距项和0非常接近，那么IVW与MR-Egger结果就非常接近，若截距项和0相差较大，则说明IV间存在水平多效性；如果存在水平多效性，利用MR-PRESSO删除显著差异的SNPs来校正水平多效性，以获得更加接近真实的估计值。Leave-one-out法检查是否存在影响力较强的SNPs[14]。本研究基于R软件（版本4.3.0）进行，“TwoSampleMR”R包（https://mrcieu.github.io/TwoSampleMR/）和“MRPRESSO”R包（https://github.com/rondolab/MR-PRESSO）用于MR研究。
1.5　反向MR分析
为了排除焦虑对GM的反向因果影响，我们以焦虑为暴露，以GM为结局，进行反向MR分析，其方法与正向MR分析相同。
2　结果
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2.1　获取工具变量
排除15种无名称的GM，通过对196种GM所含2 699个SNPs的筛选，最终获得91个SNPs，包含蓝藻细菌门（Cyanobacteria）、埃希-志贺菌属（Escherichia. Shigella）、史雷克菌属（Slackia）、厚壁菌门（Firmicutes）、梭菌纲（Clostridia）、梭菌目（Clostridiales）、真杆菌属（Eubacterium_rectale_group）、瘤胃球菌_UCG004属（Ruminococcaceae_UCG004）、瘤胃球菌_UCG011属（Ruminococcaceae_UCG011）9种GM。
2.2　正向MR结果
三种MR方法结果显示，IVW结果表明9种GM与焦虑有因果关系，其中蓝藻细菌门（OR=1.103，95%CI：1.001～1.215，P=0.048）、埃希-志贺菌属（OR=1.159，95%CI：1.027～1.309，P= 0.017）、史雷克菌属（OR=1.170，95%CI：1.047～1.307，P=0.005）与焦虑风险呈正相关；厚壁菌门（OR=0.857，95%CI：0.754～0.974，P=0.018）、梭菌纲（OR=0.817，95%CI：0.701～0.951，P=0.009）、梭菌目（OR= 0.849，95%CI：0.736～0.980，P=0.025）、真杆菌属（OR=0.861，95%CI：0.748～0.993，P=0.039）、瘤胃球菌_UCG004属（OR=0.886，95%CI：0.789～0.994，P=0.039）、瘤胃球菌_UCG011属（OR=0.919，95%CI：0.854～0.989，P=0.025）与焦虑风险呈负相关。见表1、图2。
2.3　质量控制
Cochran Q检验显示9种GM与焦虑的Q检验的P值均大于0.05，表明该项研究结果涉及的IVs之间不存在异质性，见表2。MR-Egger截距项检验显示egger_intercept的P值均大于0.05，绘制散点图，MR-PRESSO中P值>0.05，表明9种GM的SNPs与结局焦虑间不存在水平多效性，见图3。Leave-one-out法结果显示，9种GM与焦虑的因果关系不受某个强IVs所影响，见图4。
2.4　反向MR结果
反向MR结果显示，焦虑与5个微生物类别存在因果关系。其中焦虑与genus Defluviitaleacea_UCG011 (OR=1.172，95%CI：1.034～1.329，P=0.013)、family Defluviitaleaceae (OR=1.163，95%CI：1.027～1.317，P=0.017)、genus Intestinibacter (OR=1.118，95%CI：1.006～1.242，P=0.038)、 genus Olsenella (OR=1.247，95%CI：1.033～1.506，P=0.022)呈正相关；焦虑与genus Erysipelatoclostridium (OR=0.873 95%CI：0.771～0.989，P=0.033)呈负相关。经对比后发现，本研究中的正向MR结果不存在反向因果关联。见图5。
3　讨论
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本研究通过结合MR和敏感性分析的证据，共确定了9种GM与焦虑之间存在因果关系。其中蓝藻细菌门、埃希-志贺菌属、史雷克菌属与结局疾病风险呈正相关，显示它们可能为焦虑疾病的危险因素；厚壁菌门、梭菌纲、梭菌目、真杆菌属、瘤胃球菌_UCG004属、瘤胃球菌_UCG011属与结局疾病风险呈负相关，显示它们可能为焦虑疾病的保护因素。
GM群是一个十分复杂的生态系统，归纳了所有与宿主健康状况密切相关的GM基因组特征，也有越来越多的研究发现GM会影响到免疫系统、色氨酸代谢、迷走神经等多种途径，通过GBA对中枢神经系统发挥重要作用[15]。例如，血清素5-羟色胺（5-HT）作为神经递质可以通过GBA调节情绪，其受体功能改变可以引发焦虑等情绪障碍[16]。5-HT2c对于焦虑的调节作用已被广泛认可，Neil等人[16-17]的研究表明，蓝藻细菌门提取物作为5-HT2c拮抗剂显示出对于焦虑的治疗潜力。而另一种蓝藻细菌门提取物DUQ0002I被研究证明是能够发挥抗抑郁作用的5-HT7R拮抗剂，通过脑室内注射能够减少雄性小鼠的抑郁和焦虑样行为，但对雌性小鼠却未表现出任何行为变化，并且通过海马体CA1给予DUQ0002I也不足以诱导产生抗焦虑样作用[18]。有趣的是，这与我们的研究结果有所差异，本研究通过MR分析显示蓝藻细菌门为焦虑发病的危险因素，我们分析造成这种差异的可能有两种原因。其一，根据上述文献研究所述，由于对5-HT受体的刺激，可能会诱发或是减少焦虑[17]，因此GM中蓝藻细菌门对于焦虑的影响作用也为双向，可能是由于蓝藻细菌门的不同化合物通过GBA在对5-HT受体发挥作用，亦或是蓝藻细菌门的化合物通过GBA作用于大脑不同脑区，因此会产生不同的作用结果；其二，由于其抗焦虑作用仅在雄性动物试验中被证明[18]，但根据相关研究我们知道，女性比男性更容易患抑郁症和焦虑[19]，因此该结果也可能与我们所选择数据库焦虑样本的性别比例有所关联。
此外，本研究还发现两组对于焦虑发病可能是危险因素的GM种群。一种为埃希-志贺菌属，这与先前的其他研究结果一致，与健康受试者相比，焦虑患者被测试出有较高丰度的埃希-志贺菌属[5，20]，并且有研究人员通过食物调节小鼠的焦虑样行为，发现过多增殖的埃希-志贺菌属会被抑制[21]。本研究通过MR分析佐证了上述研究结论，确定了埃希-志贺菌属与焦虑存在较强的因果关系，这为探索对于焦虑的预防与治疗都提供了更有针对性的策略。另一种存在风险关系的GM是史雷克菌属，该菌属此前尚未有研究对它与焦虑疾病的关系进行过探索，但有试验发现史雷克菌属与菌血症等疾病有一定相关性[22]，这足以论证目前史雷克菌属对于人体的健康是具有一定不良影响的，但其与焦虑等精神障碍类疾病的关系及机制，还需要更进一步的探究。
正常的人类GM由两大门组成，即拟杆菌门（Bacteroidetes）和厚壁菌门（Firmicutes），本研究结果中5个与焦虑疾病呈负相关的菌属都属于厚壁菌门，即梭菌纲、梭菌目、真杆菌属、瘤胃球菌_UCG004属、瘤胃球菌_UCG011属。一项统计研究分析了GM与神经系统疾病之间的关联证据，发现一些GM会增加疾病的风险，而另一些则显示出GM有益的证据，其中被统计到最多的有益GM是厚壁菌门[23]。本研究结果也显示出厚壁菌门与所属的五种GM菌属，对焦虑均为保护因素。先前的研究发现，颞叶癫痫伴焦虑患者表现出较低丰度的梭菌纲和瘤胃球菌属[20]；瘤胃球菌_UCG014属和Eubacterium_coprostanoligenes_ group的丰度与焦虑呈明显负相关[5]。上述研究均提示GM与焦虑相关，但因果关系尚未明确，而我们的研究证明，厚壁菌门与所属的五种GM菌属可以降低患焦虑的风险，是潜在的保护因素，这能够为焦虑的发病机制与预防治疗提供新的研究思路，并从另一方面为上述相关研究结果提供证据支持。
益生菌是一种非致病性微生物，目前已有益生菌被用作其他药物的补充剂来作为焦虑的替代疗法[24]，有研究人员通过实验证明，对小鼠使用益生菌处理，可以恢复GM的组成和下丘脑-垂体-肾上腺（the hypothalamic-pituitary-adrenal axis，HPA）轴的功能[25]，而有研究证明HPA轴的失调也是重度抑郁和焦虑的重要影响因素[26]。直肠真杆菌、瘤胃球菌属等产生短链脂肪酸丁酸盐的GM也被认为是对人类健康有益的微生物，可以通过抑制炎症标志物（如IL-6、C反应蛋白、TNF-α）从而起到抗炎作用[27]，同时也有研究发现IL-6和TNF-α水平升高与会促进抑郁和焦虑的发展[28]。本研究以MR方法确定直肠真杆菌、瘤胃球菌属两类GM种群与焦虑存在因果关系，是疾病潜在的保护因素，可能会通过不同方式对疾病产生影响，未来可以进一步探索挖掘其与疾病关联的具体机制，或许能够成为预防或治疗焦虑新的益生菌研究方向。
但我们的研究还存在一些局限性：（1）由于满足严格阈值(P<5×10-8)的IVs数量极少，因此采用相对宽松的阈值(P<1×10-5)来筛选IVs；（2）本研究主要分析欧洲个体，这可能会限制我们对更广泛结果的概括能力，后续还需要在其他人群中进行因果关系分析，来进一步探究GM与焦虑之间的关系；（3）遗传工具的多效性可能导致效应估计的偏差，因此进行了敏感性分析，以尽可能减少它们的影响。
综上所述，本研究评估了GM对焦虑的潜在因果关系，发现蓝藻细菌门、埃希-志贺菌属、史雷克菌属可能为焦虑的危险因素；厚壁菌门、梭菌纲、梭菌目、真杆菌属、瘤胃球菌_UCG004属、瘤胃球菌_UCG011属可能为焦虑的保护因素。该研究结果期待为未来探究焦虑潜在的生物标志物以及治疗靶点提供参考。
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  • 国家重点研发计划(2022YFC3500501)
  • 天津市科技计划项目(18PTLCSY00050)
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2024年第51卷第9期
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doi: 10.20043/j.cnki.MPM.202312158
  • 接收时间：2023-12-12
  • 首发时间：2026-03-18
  • 出版时间：2024-05-10
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  • 收稿日期：2023-12-12
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国家重点研发计划(2022YFC3500501)
天津市科技计划项目(18PTLCSY00050)
作者信息
    1.天津中医药大学研究生院，天津 301617
    2.天津中医药大学中医学院，天津 301617
    3.天津中医药大学第一附属医院，天津 300380
    4.国家中医针灸临床医学研究中心，天津 300380

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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