炎症性肠病与消化道功能障碍性疾病的双向孟德尔随机化研究
Investigating Causal Relations between Inflammatory Bowel Disease and Digestive Tract Dysfunction Diseases: Bidirectional Mendelian Randomization Study
摘要: 目的:采用孟德尔随机化(MR)方法研究炎症性肠病和消化道功能障碍性疾病(胃食管反流病、功能性消化不良、贲门失弛缓症)的双向因果关系。方法:通过IEU数据库、芬兰数据库以及国际炎症性肠病遗传学联盟获得研究疾病的全基因组关联研究的汇总数据。本研究采用逆方差加权法(IVW)作为主要分析方法,MR-Egger、Weighted Median和Weighted Mode方法作为补充方法,以炎症性肠病为暴露因素,以三种消化道功能障碍性疾病为结局变量进行正向MR分析;以三种消化道功能障碍性疾病为暴露因素,以炎症性肠病为结局变量进行反向MR分析。使用Cochran’s Q检验评估异质性,MR-PRESSO和MR-Egger 截距评估水平多效性。结果:IVW法预测克罗恩病与功能性消化不良呈正向因果效应(OR = 1.04, 95%CI: 1.01~1.06, P = 0.003),其余疾病的正反向分析均不存在因果效应。Cochran’s Q检验显示结果均不存在异质性(P > 0.05)。MR-PRESSO和MR-Egger截距显示结果均不存在水平多效性(P > 0.05)。结论:克罗恩病可能会增加功能性消化不良的风险。
Abstract: Objective: To study the bidirectional causality between inflammatory bowel disease and digestive tract dysfunction diseases (gastroesophageal reflux disease, functional dyspepsia, achalasia) using Mendelian randomization (MR) method. Methods: Aggregated data from Genome-Wide Association Studies were obtained from the IEU database, the FinnGen database, and the inflammatory bowel disease Genetics Consortium. This study used the inverse variance weighted (IVW) as the main analysis method, and the MR-Egger, Weighted Median and Weighted Mode methods as supplementary methods. Forward MR analysis was performed using inflammatory bowel disease as the exposure factor and three digestive tract dysfunction diseases as the outcome variables. Reverse MR analysis was performed using three digestive tract dysfunction diseases as exposure factors and inflammatory bowel disease as outcome variables. Heterogeneity was assessed using Cochran’s Q test, and horizontal pleiotropy was assessed using MR-PRESSO and MR-Egger intercept methods. Results: The IVW method predicted a positive causal effect between Crohn’s disease and functional dyspepsia (OR = 1.04, 95%CI: 1.01~1.06, P = 0.003). There was no causal effect in the forward and reverse analyses of other diseases. Cochran’s Q test showed that there was no heterogeneity in the results (P > 0.05). MR-PRESSO and MR-Egger intercept showed that there was no horizontal pleiotropy in the results (P > 0.05). Conclusion: Crohn’s disease may increase the risk of functional dyspepsia.
文章引用:马彦妮, 陈敏. 炎症性肠病与消化道功能障碍性疾病的双向孟德尔随机化研究[J]. 临床医学进展, 2024, 14(11): 1486-1494. https://doi.org/10.12677/acm.2024.14113036

1. 引言

炎症性肠病(Inflammatory bowel disease, IBD)包括克罗恩病(Crohn’s disease, CD)和溃疡性结肠炎(ulcerative colitis, UC),是一种慢性、非特异性炎症性疾病,受遗传易感性等多种因素调节[1],研究显示吸烟、感染、抗生素使用可增加IBD风险[2]。炎症性肠病常反复发作,当前在亚洲的发病率正在迅速增加,一项对中国大陆发病率数据的荟萃分析显示,1950年至2002年间,全国范围内CD的年发病率为0.28/100,000人,1950年至2007年间上升至0.85/100,000人,这为全球带来了巨大的社会和经济负担[3]。然而,即使经过了充分的治疗,仍有高达三分之一的IBD患者会出现因消化道功能障碍导致的各种胃肠道症状,严重影响了患者的生活质量[4]。消化道功能障碍性疾病包括胃食管反流病(Gastroesophageal reflux disease, GERD)、功能性消化不良(functional dyspepsia, FD)、贲门失弛缓症(achalasia, AC)等,近年来,随着生活水平的提高以及生活方式和饮食习惯的改变,这类消化道功能障碍性疾病的发病率也在逐年上升[5] [6]。研究表明,腹部肥胖和吸烟可能会增加GERD的发生风险[7],睡眠障碍[8]及抑郁[9]是FD的危险因素,相关家族史可能与AC发病有关[10]

然而,IBD与消化道功能障碍性疾病的因果关系目前却仍不清楚。由于观察性研究容易受到潜在混杂因素、样本量和群体异质性的影响,并且在探究疾病关联中随机对照试验(RCT)在伦理和实践中不具有可行性,因此本文采用孟德尔随机化(mendelian randomization, MR)方法评估IBD与消化道功能障碍性疾病之间的因果关联以避免混杂因素和反向因果关系的干扰。

2. 资料与方法

2.1. 资料来源

暴露变量GERD的数据来自IEU GWAS数据库,可从https://gwas.mcieu.ac.uk/datasets/获取。FD与AC的数据来自芬兰生物银行(https://www.finngen.fi/fi)。结局变量IBD、UC、CD的数据来源于国际炎症性肠病遗传学联盟(IBD Genetics Consortium),数据可从IEU GWAS数据库获取。该研究限制在欧洲人群且涉及男女的队列中,GWAS具体信息见表1。GWAS数据公开的,因此我们没有向上述GWAS的任何参与者申请任何特定的伦理审查。

Table 1. Summary of the GWAS

1. GWAS数据汇总信息

变量

数据来源

种族人群

样本量

SNP个数

发布时间

GERD

IEU

欧洲人群

467,253

24,173,002

2021

FD

FinnGen

欧洲人群

359,744

19,344,766

2023

AC

FinnGen

欧洲人群

350,604

19,344,576

2023

IBD

IIBDGC

欧洲人群

34,652

12,716,084

2015

UC

IIBDGC

欧洲人群

27,432

12,255,197

2015

CD

IIBDGC

欧洲人群

20,883

12,276,506

2015

2.2. 方法

2.2.1. 研究设计

本研究采用双向两样本MR分析以评估IBD与消化道功能障碍性疾病的因果关系。评估IBD、UC、CD与GERD、FD、AC之间的双向影响。MR分析遵循以下三大假设:① 工具变量与暴露因素具有强相关性;② 工具变量不与混杂因素相关;③ 工具变量不与结局变量直接相关[11]。双向MR分析流程图见图1

Figure 1. Design of mendelian randomization

1. MR分析示意图

2.2.2. 工具变量的选择

基于上述三大假设,本研究根据以下条件筛选暴露因素相关的工具变量:① 工具变量与暴露因素应达到显著性阈值(P < 5 × 108)且相互独立(连锁不平衡R2 < 0.001,距离在10,000 kb以内)。其中R2的计算公式为R2 = 2 × (1 − eaf) × eaf × β2,eaf为次要等位基因频率,β为等位基因效应值。在反向MR中,以消化道功能障碍性疾病为暴露因素,由于以P < 5 × 108为统计相关性得到的工具变量较少,因此将统计相关性扩大到P < 5 × 106;② 排除无法协调及回文序列中无法匹配的工具变量;③ 进行Steiger Test过滤掉相较于暴露因素与结局因素相关性更大的SNP,以避免反向因果关系;④ 通常F统计量 < 10表明工具变量为目标表型的弱工具变量,其计算公式为F = R2 (n − 2)/1 − R2,n代表样本量,因此本研究剔除F值小于10的SNP以解决弱工具变量带来的潜在偏差;⑤ 使用LDlink数据库剔除与潜在混杂因素和结局相关的工具变量。

2.2.3. MR分析

本研究中使用了4种MR方法来评估暴露因素是对目标结果的因果影响。逆方差加权(inverse variance weighted, IVW)方法是将每个SNP对结果的Wald估计值进行荟萃分析,是最有效、统计能力最强的分析方法,因此将其作为主要分析。MR-Egger可以在即使所有工具变量无效的情况下正确估计因果关联,Weighted Median可以在高达50%的工具变量无效的情况下做出可靠的因果估计[12],Weighted Mode的可靠性取决于具有相似因果关系的最大工具变量子集是否有效[13]。将MR-Egger、Weighted Median和Weighted Mode方法作为补充方法,可以在更广泛的情况下提供更可靠的估计。

2.2.4. 敏感性分析

敏感性分析包括异质性检测和多效性检测。异质性的存在会导致MR分析对因果效应的估计产生偏差,因此我们采用了Cochran’Q检验(P < 0.05则存在异质性)和漏斗图识别异质性。当与暴露因素相关的工具变量通过除假设暴露之外的途径直接影响结果时,就会出现水平多效性。因此,我们进一步进行了MR-PRESSO (多效性残差和和异常值检验)和MR-Egger截距、Leave-one-out来检测多效性并评估结果的稳健性。如果MR-PRESSO和MR-Egger截距检验的P值小于0.05,则可以检测到水平多效性。应用MR-PRESSO和Radial MR [14]剔除离群值。本文进行Leave-one-out方法的步骤为依次丢弃每个与暴露相关的SNP,重复IVW分析,以评估因果估计是否由任何单个SNP驱动。

2.3. 统计分析

本研究应用FDR法校正MR结果的P值,以调整假阳性率的出现。以上分析使用R软件(版本4.3.3)的“TwoSampleMR”及“MR-PRESSO”软件包进行。

3. 结果

3.1. IBD对消化道功能障碍性疾病的MR分析

3.1.1. 工具变量的确定

在满足上述工具变量选择标准1后,剔除不协调及回文序列中的SNP,余下SNP全部通过Steiger Test和F统计值选择标准,其中F统计量范围是从142.5到2457.0。随后使用LDlink数据库未筛选出与混杂因素和结局具有相关意义的SNP,根据MR-PRESSO和Radial MR结果剔除离群值,最终IBD与GERD、FD、AC纳入的SNP个数分别为51、56、54;UC与GERD、FD、AC纳入的SNP个数分别为31、34、30;CD与GERD、FD、AC纳入的SNP个数分别为44、46、47。

3.1.2. MR分析结果

本研究MR结果提示了CD可增加FD发生风险,IVW法提供了主要的因果依据(OR = 1.04, 95%CI: 1.01~1.06, P = 0.003)。IBD与FD具有提示性因果相关性(IVW法:OR = 1.04,95%CI:1.01~1.07,P = 0.011),但P值经FDR校正后不具有显著相关性(P = 0.051),而UC与FD未提示因果关系,因此IBD中仅CD和FD的发生具有因果关联。在CD与FD的MR分析中,MR Egger、Weighted Median、Weighted mode方法中,与IVW方法方向一致,提示其余MR方法支持IVW法的因果效应判断(图2)。此外,IBD、UC、CD分别与GERD、AC的MR分析均未提示具有因果关系,具体信息见表2

在敏感性分析中,采用Cochran’Q检验评估异质性,IBD、UC、CD分别与FD、GERD、AC的分析中均未发现异质性的存在(P > 0.05)。漏斗图进一步证明了无异质性的结果。MR-Egger截距显示均不存在水平多效性(P > 0.05)。另外,Leave-one-out方法的结果显示去除任意SNP不影响因果效应判断。

Legend: The horizontal axis represents the impact of instrumental variables (IV) on CD, and the vertical axis represents the impact of instrumental variables (IV) on FD.

图注:横轴代表工具变量(IV)对CD的影响,纵轴代表工具变量(IV)对FD的影响。

Figure 2. Scatterplot of MR analysis of Crohn’s disease (CD) versus functional dyspepsia (FD)

2. 克罗恩病(CD)对功能性消化不良(FD)MR分析的散点图

Table 2. Forward MR analysis results

2. 正向MR分析结果

暴露

结局

方法

SNP个数

OR (95%CI)

P值

FDR值

IBD

GERD

IVW

51

1.00 (0.98~1.01)

0.806

0.806

MR Egger

51

0.98 (0.94~1.02)

0.371

0.477

Weighted median

51

1.00 (0.97~1.03)

0.997

0.997

Weighted mode

51

1.00 (0.96~1.04)

0.990

0.990

AC

IVW

54

0.96 (0.85~1.09)

0.521

0.586

MR Egger

54

0.73 (0.51~1.03)

0.080

0.477

Weighted median

54

0.95 (0.80~1.13)

0.589

0.888

Weighted mode

54

0.81 (0.59~1.12)

0.206

0.733

FD

IVW

56

1.04 (1.01~1.07)

0.011

0.051

MR Egger

56

1.05 (0.97~1.14)

0.219

0.477

Weighted median

56

1.04 (0.99~1.08)

0.137

0.517

Weighted mode

56

1.03 (0.97~1.10)

0.330

0.733

CD

GERD

IVW

44

0.99 (0.98~1.01)

0.223

0.584

MR Egger

44

0.99 (0.96~1.02)

0.458

0.515

Weighted median

44

1.00 (0.97~1.02)

0.665

0.888

Weighted mode

44

1.00 (0.97~1.02)

0.845

0.951

AC

IVW

47

0.96 (0.86~1.06)

0.389

0.584

MR Egger

47

0.97 (0.75~1.26)

0.842

0.842

Weighted median

47

0.89 (0.76~1.03)

0.123

0.517

Weighted mode

47

0.83 (0.65~1.05)

0.132

0.733

FD

IVW

46

1.04 (1.01~1.06)

0.003

0.031

MR Egger

46

1.03 (0.97~1.10)

0.307

0.477

Weighted median

46

1.03 (0.99~1.07)

0.172

0.517

Weighted mode

46

1.02 (0.97~1.07)

0.407

0.733

UC

GERD

IVW

31

1.01 (0.99~1.03)

0.307

0.584

MR Egger

31

1.04 (0.98~1.11)

0.226

0.477

Weighted median

31

1.00 (0.98~1.03)

0.789

0.888

Weighted mode

31

1.01 (0.96~1.05)

0.825

0.951

AC

IVW

30

0.95 (0.83~1.09)

0.471

0.586

MR Egger

30

0.79 (0.50~1.25)

0.314

0.477

Weighted median

30

0.97 (0.81~1.17)

0.775

0.888

Weighted mode

30

1.06 (0.75~1.49)

0.746

0.951

FD

IVW

34

1.02 (0.98~1.06)

0.368

0.584

MR Egger

34

1.06 (0.94~1.20)

0.361

0.477

Weighted median

34

1.03 (0.98~1.08)

0.247

0.555

Weighted mode

34

1.04 (0.97~1.12)

0.314

0.733

3.2. 消化道功能障碍性疾病对IBD的MR分析

3.2.1. 工具变量的确定

在反向分析中,由于AC与CD关联所得到的工具变量较少,因此不进行后续分析。根据上述工具变量选择方法,剔除回文序列和Steiger Test中相应的SNP,工具变量F值均大于10,未发现与混杂危险因素及结局直接相关的工具变量,另外,MR-PRESSO和Radial MR均未发现离群值,最终GERD与IBD、UC、CD纳入的SNP个数分别为27、24、23;FD与IBD、UC、CD纳入的SNP个数分别为9、6、7;AC与IBD、UC纳入的SNP个数分别为2、3。

3.2.2. MR分析结果

使用IVW法作为消化道功能障碍性疾病对IBD的因果关联的主要分析,未发现存在因果效应,具体信息见表3。在敏感性分析中,MR-PRESSO和MR-Egger截距均未发现水平多效性(P > 0.05)。Cochran’s Q检验未发现异质性(P > 0.05),漏斗图支持Cochran’s Q检验结果。Leave-one-out分析结果表明,消化道功能障碍性疾病对IBD的因果效应不是由任意SNP所驱动。

Table 3. Reverse MR analysis results

3. 反向MR分析结果

暴露

结局

方法

SNP个数

OR (95%CI)

P值

FDR值

GERD

IBD

IVW

27

1.05 (0.90~1.22)

0.546

0.967

MR Egger

27

1.14 (0.78~1.67)

0.514

0.922

Weighted median

27

1.08 (0.87~1.33)

0.498

0.904

Weighted mode

27

1.19 (0.88~1.60)

0.264

0.735

UC

IVW

24

1.00 (0.82~1.23)

0.967

0.967

MR Egger

24

1.32 (0.80~2.19)

0.286

0.922

Weighted median

24

1.02 (0.77~1.36)

0.884

0.904

Weighted mode

24

1.14 (0.77~1.68)

0.525

0.735

CD

IVW

23

1.10 (0.88~1.38)

0.405

0.967

MR Egger

23

1.17 (0.66~2.07)

0.590

0.922

Weighted median

23

1.19 (0.87~1.64)

0.284

0.904

Weighted mode

23

1.16 (0.76~1.77)

0.491

0.735

FD

IBD

IVW

9

1.00 (0.84~1.18)

0.956

0.967

MR Egger

9

1.11 (0.71~1.73)

0.659

0.922

Weighted median

9

1.13 (0.89~1.43)

0.313

0.904

Weighted mode

9

1.19 (0.85~1.66)

0.341

0.735

UC

IVW

6

0.96 (0.72~1.27)

0.765

0.967

MR Egger

6

0.80 (0.34~1.89)

0.635

0.922

Weighted median

6

1.02 (0.72~1.46)

0.904

0.904

Weighted mode

6

1.03 (0.69~1.54)

0.887

0.887

CD

IVW

7

0.94 (0.72~1.22)

0.630

0.967

MR Egger

7

1.01 (0.54~1.87)

0.981

0.981

Weighted median

7

0.90 (0.64~1.25)

0.525

0.904

Weighted mode

7

0.85 (0.55~1.33)

0.516

0.735

AC

IBD

IVW

2

0.98 (0.86~1.12)

0.801

0.967

UC

IVW

3

1.02 (0.93~1.13)

0.630

0.967

MR Egger

3

1.01 (0.69~1.47)

0.980

0.981

Weighted median

3

1.02 (0.90~1.15)

0.796

0.904

Weighted mode

3

1.01 (0.90~1.14)

0.839

0.887

4. 讨论

本研究旨在通过两样本双向MR分析探索IBD (包括UC与CD)与消化道功能障碍性疾病(功能性消化不良、贲门失弛缓症、胃食管反流病)的因果关系。本研究发现CD是FD的危险因素,而UC与FD并无因果关系。此外IBD (包括UC与CD)与GERD、AC无因果关联。

既往研究已经发现一些IBD与消化不良的关系。一项对FD个体和健康对照组免疫细胞计数和细胞因子水平数据的Meta分析结果显示,FD患者十二指肠局部炎症细胞浸润明显,特别是嗜酸性粒细胞和肥大细胞显著增加[15],另外已有一些学者认为十二指肠炎症可能是消化不良的潜在诱发因素[16]-[18],这说明消化不良可能与肠道炎症有关,但是否与炎症性肠病有关联需要进一步探究。一项观察性研究指出,CD患者与健康人群相比更容易出现消化不良的症状,且胃排空时间明显延长[19],这说明CD可能与消化不良相关,但两者因果关联尚不清楚。还有研究发现,临床缓解期溃疡性结肠炎患者功能性消化不良样症状的患病率与健康人群相比并无明显差别[20],这与我们MR分析结果基本一致。

CD与FD之间的因果关系可能受多种机制调节。一项通过内镜检查和离体粘膜分析的研究结果表明,功能性消化不良患者十二指肠上皮屏障受损和焦亡增多[21],另外有研究发现FD患者跨上皮电阻较低,细胞旁通透性增加,肠道屏障完整性受损,细胞间粘附蛋白的表达水平、通透性增加的程度与低度炎症的严重程度显著相关,肠道屏障功能受损可能是通过诱导低度炎症参与了FD的发生发展[22]。而肠上皮屏障破坏是IBD的病理基础[23],因此FD与CD的关联可能与肠上皮屏障受损有关。一项观察性研究发现,胃肠炎发作后的FD患者中的活化肥大细胞、内皮细胞、肠嗜铬细胞数量,以及胃黏膜组胺和5-羟色胺的释放量明显多于非特异性功能性消化不良和健康对照者,电镜检查还发现肥大细胞和内皮细胞的胞浆中均有分泌颗粒,这些物质包括组胺、类胰蛋白酶和5-羟色胺[24]。CD作为一种免疫介导的炎症性疾病,免疫细胞及其相关活性物质在疾病的发生发展过程中起到了核心作用[25],因此CD与FD的关联也可能是由免疫物质所介导。此外,还有研究表明,下调TLR/NF-κB信号通路可下调FD大鼠模型肠黏膜炎症[26],花生四烯基乙醇酰胺(anandamide, AEA)可能调节FD中的十二指肠低度炎症[27]。综上,CD与FD的因果效应可能由肠道屏障受损、免疫细胞浸润和相关物质分泌以及炎症介质和通路有关,但具体的相关机制有待进一步研究和证实。

本研究是首次确定IBD (包括UC、CD)与FD、GERD、AC之间因果关联的孟德尔随机化研究,通过MR方法阐明了CD可能是FD是危险因素。然而,这项研究有几个局限性。首先,本研究的研究对象是欧洲人群,因此本研究的结论可能不能直接适用于其他种族。其次,MR分析是依赖于随机分配的遗传变异而得出的因果假设,因此,使用两样本MR方法很难区分中介作用和多效性。第三,本研究采用全基因组关联性数据进行分析,对年龄、性别、疾病严重程度无法进行分层分析。因此,这项研究只是一项初步探索,需要进一步的研究来证实研究结果,并需要更多的研究探寻CD与FD关系之间的相关机制。但依然值得注意的是,临床医生在指导CD患者饮食或药物服用时应当更加谨慎,重视对胃功能的影响,一旦出现消化不良症状,应及时进行干预治疗。

基金项目

成都中医药大学附属医院科研能力提升“百人计划”(20-B05)。

NOTES

*第一作者。

#通讯作者。

参考文献

[1] Khor, B., Gardet, A. and Xavier, R.J. (2011) Genetics and Pathogenesis of Inflammatory Bowel Disease. Nature, 474, 307-317.
https://doi.org/10.1038/nature10209
[2] Agrawal, M., Sabino, J., Frias-Gomes, C., Hillenbrand, C.M., Soudant, C., Axelrad, J.E., et al. (2021) Early Life Exposures and the Risk of Inflammatory Bowel Disease: Systematic Review and Meta-Analyses. EClinicalMedicine, 36, Article 100884.
https://doi.org/10.1016/j.eclinm.2021.100884
[3] Aniwan, S., Santiago, P., Loftus, E.V. and Park, S.H. (2022) The Epidemiology of Inflammatory Bowel Disease in Asia and Asian Immigrants to Western Countries. United European Gastroenterology Journal, 10, 1063-1076.
https://doi.org/10.1002/ueg2.12350
[4] Barros, L.L., Farias, A.Q. and Rezaie, A. (2019) Gastrointestinal Motility and Absorptive Disorders in Patients with Inflammatory Bowel Diseases: Prevalence, Diagnosis and Treatment. World Journal of Gastroenterology, 25, 4414-4426.
https://doi.org/10.3748/wjg.v25.i31.4414
[5] Duboc, H., Latrache, S., Nebunu, N. and Coffin, B. (2020) The Role of Diet in Functional Dyspepsia Management. Frontiers in Psychiatry, 11, Article 23.
https://doi.org/10.3389/fpsyt.2020.00023
[6] Ried, K., Travica, N., Dorairaj, R. and Sali, A. (2020) Herbal Formula Improves Upper and Lower Gastrointestinal Symptoms and Gut Health in Australian Adults with Digestive Disorders. Nutrition Research, 76, 37-51.
https://doi.org/10.1016/j.nutres.2020.02.008
[7] Richter, J.E. and Rubenstein, J.H. (2018) Presentation and Epidemiology of Gastroesophageal Reflux Disease. Gastroenterology, 154, 267-276.
https://doi.org/10.1053/j.gastro.2017.07.045
[8] Su, H., Sung, F., Kao, K., Chen, S., Lin, C., Wu, S., et al. (2021) Relative Risk of Functional Dyspepsia in Patients with Sleep Disturbance: A Population-Based Cohort Study. Scientific Reports, 11, Article No. 18605.
https://doi.org/10.1038/s41598-021-98169-4
[9] Kao, K., Sung, F., Huang, H., Lin, C., Chen, S., Lin, C., et al. (2021) Functional Dyspepsia in Depression: A Population‐based Cohort Study. European Journal of Clinical Investigation, 51, e13506.
https://doi.org/10.1111/eci.13506
[10] O’Neill, O.M. (2013) Achalasia: A Review of Clinical Diagnosis, Epidemiology, Treatment and Outcomes. World Journal of Gastroenterology, 19, 5806-5812.
https://doi.org/10.3748/wjg.v19.i35.5806
[11] Sekula, P., Del Greco M, F., Pattaro, C. and Köttgen, A. (2016) Mendelian Randomization as an Approach to Assess Causality Using Observational Data. Journal of the American Society of Nephrology, 27, 3253-3265.
https://doi.org/10.1681/asn.2016010098
[12] Xiang, M., Wang, Y., Gao, Z., Wang, J., Chen, Q., Sun, Z., et al. (2023) Exploring Causal Correlations between Inflammatory Cytokines and Systemic Lupus Erythematosus: A Mendelian Randomization. Frontiers in Immunology, 13, Article 985729.
https://doi.org/10.3389/fimmu.2022.985729
[13] Zhang, D., Hu, Y., Guo, W., Song, Y., Yang, L., Yang, S., et al. (2022) Mendelian Randomization Study Reveals a Causal Relationship between Rheumatoid Arthritis and Risk for Pre-Eclampsia. Frontiers in Immunology, 13, Article 1080980.
https://doi.org/10.3389/fimmu.2022.1080980
[14] Bowden, J., Spiller, W., Del Greco M, F., Sheehan, N., Thompson, J., Minelli, C., et al. (2018) Improving the Visualization, Interpretation and Analysis of Two-Sample Summary Data Mendelian Randomization via the Radial Plot and Radial Regression. International Journal of Epidemiology, 47, 1264-1278.
https://doi.org/10.1093/ije/dyy101
[15] Du, L., Chen, B., Kim, J.J., Chen, X. and Dai, N. (2018) Micro‐Inflammation in Functional Dyspepsia: A Systematic Review and Meta‐Analysis. Neurogastroenterology & Motility, 30, e13304.
https://doi.org/10.1111/nmo.13304
[16] Lee, K.J. and Tack, J. (2010) Duodenal Implications in the Pathophysiology of Functional Dyspepsia. Journal of Neurogastroenterology and Motility, 16, 251-257.
https://doi.org/10.5056/jnm.2010.16.3.251
[17] Vanheel, H. and Farré, R. (2013) Changes in Gastrointestinal Tract Function and Structure in Functional Dyspepsia. Nature Reviews Gastroenterology & Hepatology, 10, 142-149.
https://doi.org/10.1038/nrgastro.2012.255
[18] Wauters, L., Talley, N.J., Walker, M.M., Tack, J. and Vanuytsel, T. (2019) Novel Concepts in the Pathophysiology and Treatment of Functional Dyspepsia. Gut, 69, 591-600.
https://doi.org/10.1136/gutjnl-2019-318536
[19] Nóbrega, A.C.M., Ferreira, B.R.S., Oliveira, G.J., Sales, K.M.O., Santos, A.A., Nobre e Souza, M.Â., et al. (2012) Dyspeptic Symptoms and Delayed Gastric Emptying of Solids in Patients with Inactive Crohn’s Disease. BMC Gastroenterology, 12, Article No. 175.
https://doi.org/10.1186/1471-230x-12-175
[20] Kotani, S., Fukuba, N., Kawashima, K., Mishima, Y., Sonoyama, H., Okimoto, E., et al. (2020) Prevalence of Functional Dyspepsia-Like Symptoms in Ulcerative Colitis Patients in Clinical Remission and Overlap with Irritable Bowel Syndrome-Like Symptoms. Scandinavian Journal of Gastroenterology, 55, 560-564.
https://doi.org/10.1080/00365521.2020.1761998
[21] Nojkov, B., Zhou, S., Dolan, R.D., Davis, E.M., Appelman, H.D., Guo, X., et al. (2020) Evidence of Duodenal Epithelial Barrier Impairment and Increased Pyroptosis in Patients with Functional Dyspepsia on Confocal Laser Endomicroscopy and “ex vivo” Mucosa Analysis. American Journal of Gastroenterology, 115, 1891-1901.
https://doi.org/10.14309/ajg.0000000000000827
[22] Vanheel, H., Vicario, M., Vanuytsel, T., Van Oudenhove, L., Martinez, C., Keita, Å.V., et al. (2013) Impaired Duodenal Mucosal Integrity and Low-Grade Inflammation in Functional Dyspepsia. Gut, 63, 262-271.
https://doi.org/10.1136/gutjnl-2012-303857
[23] Schoultz, I. and Keita, Å.V. (2019) Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease—Focusing on Intestinal Barrier Function. Cells, 8, Article 193.
https://doi.org/10.3390/cells8020193
[24] Li, X., Chen, H., Lu, H., Li, W., Chen, X., Peng, Y., et al. (2010) The Study on the Role of Inflammatory Cells and Mediators in Post-Infectious Functional Dyspepsia. Scandinavian Journal of Gastroenterology, 45, 573-581.
https://doi.org/10.3109/00365521003632576
[25] Segal, A.W. (2019) Studies on Patients Establish Crohn’s Disease as a Manifestation of Impaired Innate Immunity. Journal of Internal Medicine, 286, 373-388.
https://doi.org/10.1111/joim.12945
[26] Wu, Y., Zhong, Z., Ye, Z., Zhang, W., He, G., Zheng, Y., et al. (2021) D-Galacturonic Acid Ameliorates the Intestinal Mucosal Permeability and Inflammation of Functional Dyspepsia in Rats. Annals of Palliative Medicine, 10, 538-548.
https://doi.org/10.21037/apm-20-2420
[27] Ji, S., You, Y., Peng, B., Zhong, T., Kuang, Y., Li, S., et al. (2022) Multi-Omics Analysis Reveals the Metabolic Regulators of Duodenal Low-Grade Inflammation in a Functional Dyspepsia Model. Frontiers in Immunology, 13, Article 944591.
https://doi.org/10.3389/fimmu.2022.944591