Data_Sheet_3_Deciphering the brain-gut axis: elucidating the link between cerebral cortex structures and functional gastrointestinal disorders via integrated Mendelian randomization.xlsx

BackgroundObservational studies have suggested associations between functional gastrointestinal disorders (FGIDs) and variations in the cerebral cortex. However, the causality of these relationships remains unclear, confounded by anxiety and depression. To clarify these causal relationships and explore the mediating roles of anxiety and depression, we applied univariate, multivariable, and mediation Mendelian randomization (MR) analyses.
MethodWe utilized genome-wide association study (GWAS) summary data from the FinnGen database and the ENIGMA consortium, identifying genetic variants associated with irritable bowel syndrome (IBS), functional dyspepsia (FD), and cerebral cortex structures. Data on anxiety and depression came from FinnGen and a large meta-analysis. Utilizing a bidirectional univariate MR approach, we explored correlations between FD, IBS, and cortex variations. Then, independent effects were assessed through multivariable MR. A meta-analysis of these results, incorporating data from two cohorts, aimed to increase precision. We also explored the potential mediating roles of anxiety and depression.
ResultsOur findings indicate a negative causal correlation between FD and the thickness of the rostral anterior cingulate cortex (rACC) across both global and regional adjustments (β = −0.142, 95% confidence interval (CI): −0.209 to-0.074, P.FDR = 0.004; β = −0.112, 95%CI: −0.163 to-0.006, P.FDR = 0.003) and a positive causal correlation with the globally adjusted thickness of the superior frontal gyrus (SFG) (β = 0.107, 95%CI: 0.062 to 0.153, P.FDR = 0.001). The causal correlation with the rACC persisted after multiple variable adjustments (β = −0.137, 95% CI: −0.187 to-0.087, P.FDR = 1.81 × 10−5; β = −0.109, 95%CI: −0.158 to-0.06, P.FDR = 0.002). A significant causal association was found between globally adjusted surface area of the caudal anterior cingulate cortex (cACC) and IBS (odds ratio = 1.267, 95%CI: 1.128 to 1.424, P.FDR = 0.02). The analysis showed that neither anxiety nor depression mediated the relationship between FGIDs and cerebral cortex structures.
ConclusionOur research provides significant MR evidence of a bidirectional causal relationship between FGIDs and the cerebral cortex structures. This evidence not only confirms the two-way communication along the brain-gut axis but also illuminates the underlying pathophysiology, paving the way for identifying potential therapeutic approaches.

研究背景
观察性研究已提示功能性胃肠病（functional gastrointestinal disorders, FGIDs）与大脑皮层结构变异存在关联。然而，此类关联的因果关系尚不明确，且受焦虑与抑郁因素的混杂影响。为阐明此类因果关系并探究焦虑与抑郁的中介作用，本研究采用了单变量、多变量及中介孟德尔随机化（Mendelian randomization, MR）分析方法。

研究方法
本研究使用了来自FinnGen数据库与ENIGMA联盟的全基因组关联研究（Genome-Wide Association Study, GWAS）汇总数据，筛选出与肠易激综合征（Irritable Bowel Syndrome, IBS）、功能性消化不良（Functional Dyspepsia, FD）及大脑皮层结构相关的遗传变异。焦虑与抑郁的相关数据来源于FinnGen数据库及一项大型荟萃分析。本研究采用双向单变量孟德尔随机化方法，探究了FD、IBS与大脑皮层结构变异之间的关联；随后通过多变量孟德尔随机化分析评估其独立效应。本研究对两项队列的相关结果进行荟萃分析以提升统计效力，并额外探究了焦虑与抑郁的潜在中介作用。

研究结果
本研究结果显示，在全局与区域校正分析中，FD与喙侧前扣带回皮层（rostral anterior cingulate cortex, rACC）厚度呈负向因果关联（β = -0.142，95%置信区间（Confidence Interval, CI）：-0.209 ~ -0.074，校正后P值（P.FDR）= 0.004；β = -0.112，95%CI：-0.163 ~ -0.006，P.FDR=0.003），而与全局校正后的额上回（superior frontal gyrus, SFG）厚度呈正向因果关联（β=0.107，95%CI：0.062 ~ 0.153，P.FDR=0.001）。经多变量校正后，与rACC的因果关联仍显著存在（β=-0.137，95%CI：-0.187 ~ -0.087，P.FDR=1.81×10^-5；β=-0.109，95%CI：-0.158 ~ -0.06，P.FDR=0.002）。全局校正后的尾侧前扣带回皮层（caudal anterior cingulate cortex, cACC）表面积与IBS之间存在显著因果关联（比值比（Odds Ratio, OR）=1.267，95%CI：1.128 ~ 1.424，P.FDR=0.02）。分析结果显示，焦虑与抑郁均未在FGIDs与大脑皮层结构的关联中发挥中介作用。

研究结论
本研究提供了强有力的孟德尔随机化证据，证明FGIDs与大脑皮层结构之间存在双向因果关联。该结果不仅证实了脑-肠轴的双向信号传导，还阐明了其潜在的病理生理机制，为潜在治疗策略的开发提供了理论依据。