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Investigating the Causal Association Between Crohn’s Disease and Atrial Fibrillation Based on the Theory of "Heart and Small Intestine are Interior-Exteriorly Related" and Prediction of Interventing Traditional Chinese Medicine
Received date: 2025-06-25
Revised date: 2025-08-04
Accepted date: 2025-12-24
Online published: 2026-01-26
Objective： Based on the traditional Chinese medicine theory of "the heart and small intestine are interior-exteriorly related"， the Mendelian randomization （MR） method was used to explore the causal association between Crohn's disease （CD） and atrial fibrillation （AF） in the East Asian population， and to predict the potential traditional Chinese medicines that can intervene in AF by regulating CD.Methods： The genetic summary data of CD and AF were obtained from the IEU database. The TwoSampleMR software package in R language was used to perform MR analysis， and the inverse variance weighted method was mainly used to evaluate the genetic causal effect. Through the functional enrichment analysis of the neighboring genes of instrumental variables， the potential signaling pathways of CD in AF were explored. The Coremine database was used to predict the traditional Chinese medicines that have potential regulatory effects on these neighboring genes of instrumental variables， and their properties， flavors， meridian tropism and efficacy were statistically analyzed. Finally， by comparing with the most commonly used traditional Chinese medicines for the treatment of CD and AF in clinical practice， the intersection was identified to determine the final predicted traditional Chinese medicines.Results： The study found that CD was a risk factor for AF. The neighboring genes of instrumental variables were mainly enriched in regulating signaling pathways such as Th1， Th2， Th17 cells， MHC class Ⅱ molecules， endoplasmic reticulum， tumor necrosis factor receptor binding and cytokine receptors. The potential regulatory traditional Chinese medicines were mainly cold in the four natures， followed by warm and mild； in the five flavors， they were mainly bitter， followed by sweet and pungent； in terms of meridian tropism， they mainly involved the lung， followed by the spleen， liver and stomach； in terms of efficacy， they were mainly for tonifying deficiency， followed by clearing heat， resolving phlegm and stopping cough， promoting blood circulation to remove blood stasis and promoting diuresis and eliminating dampness. Through comparison with commonly used traditional Chinese medicines in clinical practice， Atractylodes macrocephala， Poria cocos， Glycyrrhiza uralensis， Coptis chinensis， Panax notoginseng， Citri reticulatae pericarpium and Astragalus membranaceus were finally determined as the final predicted traditional Chinese medicines.Conclusion： According to the classic traditional Chinese medicine theory of "the heart and small intestine are interior-exteriorly related"， the MR method confirmed that CD is a risk factor for AF in the East Asian population. This study revealed that CD affects the occurrence of AF by regulating Th1， Th2， Th17 cells， MHC class Ⅱ molecules， endoplasmic reticulum， tumor necrosis factor receptor binding and cytokine receptors. The study also found a variety of traditional Chinese medicines with potential regulatory effects， such as medicines for clearing heat， resolving phlegm and stopping cough， promoting blood circulation to remove blood stasis and promoting diuresis and eliminating dampness， which provides a new strategy for the prevention and treatment of CD-related AF with traditional Chinese medicine.
司南 肖
.
Investigating the Causal Association Between Crohn’s Disease and Atrial Fibrillation Based on the Theory of "Heart
and Small Intestine are Interior-Exteriorly Related" and Prediction of
Interventing Traditional Chinese Medicine
［1］ Veauthier B， Hornecker JR. Crohn’s disease： diagnosis and management［J］.Am Fam Physician， 2018， 98（11）：661-669.
［2］ 曾耀明，汪洋鹏，柯晓.基于藏象学说论治炎症性肠病的理论探讨［J］.中华中医药学刊，2018，36（10）：2375-2377.
［3］ Xu L， He B， Sun Y， et al. Incidence of inflammatory bowel disease in urban China： a nationwide population-based study［J］.Clin Gastroenterol Hepatol， 2023， 21（13）：3379-3386..
［4］ Tse HF， Wang YJ， Ahmed Ai-Abdullah M， et al. Stroke prevention in atrial fibrillation—an Asian stroke perspective［J］.Heart Rhythm， 2013， 10（7）：1082-1088.
［5］ Brundel BJJM， Ai X， Hills MT， et al. Atrial fibrillation［J］.Nat Rev Dis Primer， 2022， 8（1）：1-23.
［6］ Choi YJ， Choi EK， Han KD， et al. Increased risk of atrial fibrillation in patients with inflammatory bowel disease： a nationwide population-based study［J］.World J Gastroenterol， 2019， 25（22）：2788-2798.
［7］ Pattanshetty DJ， Anna K， Gajulapalli RD， et al. Inflammatory bowel “cardiac” disease： point prevalence of atrial fibrillation in inflammatory bowel disease population［J］.Saudi J Gastroenterol， 2015， 21（5）：325-329.
［8］ Kristensen SL， Lindhardsen J， Ahlehoff O， et al. Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease： a nationwide study［J］.EP Eur， 2014， 16（4）：477-484.
［9］ Mubasher M， Syed T， Hanafi A， et al. An investigation into the association between inflammatory bowel disease and cardiac arrhythmias： an examination of the United States National Inpatient Sample Database［J］.Clin Med Insights Cardiol， 2020， 14：117954682095517.
［10］ Zuin M， Zuliani G， Rigatelli G， et al. Atrial fibrillation in patients with inflammatory bowel disease： a systematic review and meta-analysis［J］.Eur J Intern Med， 2020， 76：120-122.
［11］ Glass TA， Goodman SN， Hernán MA， et al. Causal inference in public health［J］.Annu Rev Public Health， 2013， 34：61-75.
［12］ Fang Z， Zang Q， Chen J， et al. Whole-body mass spectrometry imaging reveals the systemic metabolic disorder and catecholamines biosynthesis alteration on heart-gut axis in heart failure rat［J］.J Adv Res， 2025，73：411-426.
［13］ Lip GYH， Nieuwlaat R， Pisters R， et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach： the euro heart survey on atrial fibrillation［J］.Chest， 2010， 137（2）：263-272.
［14］ Du Z， Wang J， Lu Y， et al. The cardiac protection of Baoyuan decoction via gut-heart axis metabolic pathway［J］.Phytomedicine， 2020， 79：153322.
［15］ Burgess S， Small DS， Thompson SG. A review of instrumental variable estimators for Mendelian randomization［J］.Stat Methods Med Res， 2017， 26（5）：2333-2355.
［16］ Jairath V， Feagan BG. Global burden of inflammatory bowel disease［J］.Lancet Gastroenterol Hepatol， 2020， 5（1）：2-3.
［17］ 屈岚.三种不同肤色人种冠心病中医证型临床流行病学调查［D］.长沙：湖南中医药大学，2011.
［18］ 王晓艳.人种间体质差异对方剂疗法的影响——附验案3则［J］.江苏中医药，2009，41（5）：12-13.
［19］ 王晓艳.人种间体质差异与内服中成药之治疗方法［J］.中医研究，2009，22（3）：51-53.
［20］ Low SK， Takahashi A， Ebana Y， et al. Identification of six new genetic loci associated with atrial fibrillation in the Japanese population［J］.Nat Genet， 2017， 49（6）：953-958.
［21］ Hartwig FP， Davies NM， Hemani G， et al. Two-sample mendelian randomization： avoiding the downsides of a powerful， widely applicable but potentially fallible technique［J］.Int J Epidemiol， 2016， 45（6）：1717-1726.
［22］ Bowden J， Del Greco MF， Minelli C， et al. A framework for the investigation of pleiotropy in two‐sample summary data mendelian randomization［J］.Stat Med， 2017， 36（11）：1783-1802.
［23］ 张辛欣，钟霞，焦华琛，等.基于数据挖掘探索房颤中医用药规律研究［J］.中国中医急症，2019，28（12）：2077-2080，2087.
［24］ 傅琳然.口服中药汤剂治疗克罗恩病的Meta分析及用药规律分析［D］.长沙：湖南中医药大学，2024.
［25］ Sun J， Roelstraete B， Svennberg E， et al. Long-term risk of arrhythmias in patients with inflammatory bowel disease： a population-based， sibling-controlled cohort study［J］.PLoS Med， 2023， 20（10）：e1004305.
［26］ Sun J， Yao J， Ludvigsson J. Familial coaggregation of inflammatory bowel disease with cardiovascular disease： a nationwide multigenerational cohort study［J］.J Crohns Colitis， 2024， 18（Supplement_1）：i2054.
［27］ Chen B， Collen LV， Mowat C， et al. Inflammatory bowel disease and cardiovascular diseases［J］.Am J Med， 2022， 135（12）：1453-1460.
［28］ El Amrousy D， El Ashry H， Maher S， et al. Risk of atrial fibrillation development in adolescent patients with inflammatory bowel disease［J］.Eur J Pediatr， 2024， 183（4）：1917-1923.
［29］ Kalin A， Usher-Smith J， Jones VJ， et al. Cardiac arrhythmia： a simple conceptual framework［J］.Trends Cardiovasc Med， 2010， 20（3）：103-107.
［30］ Haïssaguerre M， Jaïs P， Shah DC， et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins［J］.N Engl J Med， 1998， 339（10）：659-666.
［31］ Wijesurendra RS， Casadei B. Mechanisms of atrial fibrillation［J］.Heart， 2019， 105（24）：1860-1867.
［32］ Torres J， Mehandru S， Colombel JF， et al. Crohn’s disease［J］.The Lancet， 2017， 389（10080）：1741-1755.
［33］ van Haaften WT， Mortensen JH， Karsdal MA， et al. Misbalance in type Ⅲ collagen formation/degradation as a novel serological biomarker for penetrating （Montreal B3） Crohn’s disease［J］.Aliment Pharmacol Ther， 2017， 46（1）：26-39.
［34］ Bornaun HA， Yılmaz N， Kutluk G， et al. Prolonged P-wave and QT dispersion in children with inflammatory bowel disease in remission［J］.Biomed Res Int， 2017， 2017：1-7.
［35］ Dogan Y， Soylu A， Eren GA， et al. Evaluation of QT and P wave dispersion and mean platelet volume among inflammatory bowel disease patients［J］.Int J Med Sci， 2011， 8（7）：540-546.
［36］ Pelaez AF， Varma D， Pereira CH， et al. Abstract 14228： mechanism of atrial fibrillation in an animal model of inflammatory bowel disease［J］.Circulation， 2021， 144（Suppl_1）：3.
［37］ Hu YF， Chen YJ， Lin YJ， et al. Inflammation and the pathogenesis of atrial fibrillation［J］.Nat Rev Cardiol， 2015， 12（4）：230-243.
［38］ Efe TH， Cimen T， Ertem AG， et al. Atrial electromechanical properties in inflammatory bowel disease［J］.Echocardiography， 2016， 33（9）：1309-1316.
［39］ Camm AJ， Naccarelli GV， Mittal S， et al. The increasing role of rhythm control in patients with atrial fibrillation［J］.J Am Coll Cardiol， 2022， 79（19）：1932-1948.
［40］ Dobrev D， Heijman J， Hiram R， et al. Inflammatory signalling in atrial cardiomyocytes： a novel unifying principle in atrial fibrillation pathophysiology［J］.Nat Rev Cardiol， 2023， 20（3）：145-167.
［41］ Bradshaw AD， DeLeon-Pennell KY. T-cell regulation of fibroblasts and cardiac fibrosis［J］.Matrix Biol， 2020， 91-92：167-175.
［42］ Lu M， Qin X， Yao J， et al. Th17/Treg imbalance modulates rat myocardial fibrosis and heart failure by regulating LOX expression［J］.Acta Physiol， 2020， 230（3）：e13537.
［43］ 谢建，梁珊珊，宋波，等.半乳糖凝集素3在心房颤动中主要来源及作用机制［J］.中国老年学杂志，2022，42（1）：121-125.
［44］ Liu J， Liu F， Liang T， et al. The roles of th cells in myocardial infarction［J］.Cell Death Discov， 2024， 10：287.
［45］ Ovchinnikov A， Filatova A， Potekhina A， et al. Blood immune cell alterations in patients with hypertensive left ventricular hypertrophy and heart failure with preserved ejection fraction［J］.J Cardiovasc Dev Dis， 2023， 10（7）：310.
［46］ Meng X， Yang J， Dong M， et al. Regulatory T cells in cardiovascular diseases［J］.Nat Rev Cardiol， 2016， 13（3）：167-179.
［47］ Boixel C， Fontaine V， Rücker-Martin C， et al. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat［J］.J Am Coll Cardiol， 2003， 42（2）：336-344.
［48］ Keestra-Gounder AM， Byndloss MX， Seyffert N， et al. NOD1 and NOD2 signalling links ER stress with inflammation［J］.Nature， 2016， 532（7599）：394-397.
［49］ Nattel S， Heijman J， Zhou L， et al. Molecular basis of atrial fibrillation pathophysiology and therapy： a translational perspective［J］.Circ Res， 2020， 127（1）：51-72.
［50］ Yan J， Bare DJ， DeSantiago J， et al. JNK2， a newly-identified SERCA2 enhancer， augments an arrhythmic ［Ca2+］SR leak-load relationship［J］.Circ Res， 2021， 128（4）：455-470.
［51］ Yan J， Zhao W， Thomson JK， et al. Stress signaling JNK2 crosstalk with CaMKII underlies enhanced atrial arrhythmogenesis［J］.Circ Res， 2018， 122（6）：821-835.
［52］ Zhang YL， Cao HJ， Han X， et al. Chemokine receptor CXCR-2 initiates atrial fibrillation by triggering monocyte mobilization in mice［J］.Hypertens Dallas Tex 1979， 2020， 76（2）：381-392.
［53］ Horiuchi T， Mitoma H， Harashima S， et al. Transmembrane TNF-alpha： structure， function and interaction with anti-TNF agents［J］.Rheumatology， 2010， 49（7）：1215-1228.
［54］ Deng H， Xue YM， Zhan XZ， et al. Role of tumor necrosis factor-alpha in the pathogenesis of atrial fibrillation［J］.Chin Med J （Engl）， 2011， 124（13）：1976-1982.
［55］ Goyette P， Boucher G， Mallon D， et al. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01：03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis［J］.Nat Genet， 2015， 47（2）：172-179.
［56］ Glas J， Martin K， Brünnler G， et al. MICA， MICB and C1_4_1 polymorphism in Crohn’s disease and ulcerative colitis［J］.Tissue Antigens， 2001， 58（4）：243-249.
［57］ 黄从新，张澍，黄德嘉，等.心房颤动：目前的认识和治疗的建议-2018［J］.中国心脏起搏与心电生理杂志，2018，32（4）：315-368.
［58］ 李志雄.克罗恩病的中医古籍文献整理［D］.广州：广州中医药大学，2017.
［59］ 陈锦锋.克罗恩病中医证治探讨［J］.中医药导报，2017，23（5）：9-11.
［60］ 俞瀛.心房颤动住院患者的临床特征与中医证候要素规律分析［D］.北京：北京中医药大学，2022.
［61］ 黄丹，李建华，甘桃梅.中医治疗心房颤动的近况［J］.中国中医药现代远程教育，2024，22（17）：84-86.
［62］ 张小琴.刘沈林教授运用寒温并用法治疗克罗恩病的经验［J］.云南中医中药杂志，2011，32（7）：3-4.
［63］ 贾思涵，连妍洁，尚菊菊，等.从“虚气留滞”论治心房颤动［J］.中医杂志，2024，65（12）：1235-1239.
［64］ 张翠萍.周立华教授辨治心房颤动临床经验研究［D］.郑州：河南中医药大学，2022.
［65］ 赵梦瑜，王凯，吕玲，等.张伯礼教授治疗克罗恩病验案一例［J］.天津中医药大学学报，2019，38（1）：6-8.
［66］ Xu C， Zhao Y， Shang X， et al. The effects of supplementing diets with Atractylodes macrocephala Koidz rhizomes on growth performance and immune function in piglets［J］.J Anim Feed Sci， 2012， 21（2）：302-312.
［67］ 邱根全，赵旭升，孙烨，等.白术挥发油治疗癌性恶病质的实验研究［J］.西安交通大学学报（医学版），2006，（5）：477-479.
［68］ 周晓敏，陶谢鑫，杨洋，等.黄芪总黄酮与丹参酮Ⅱa磺酸钠对病毒性心肌炎小鼠心肌细胞内质网伴侣蛋白及L-型钙通道表达的作用［J］.临床心血管病杂志，2015，31（3）：254-256.
［69］ Jeong JW， Lee HH， Han MH， et al. Ethanol extract of Poria cocos reduces the production of inflammatory mediators by suppressing the NF-kappaB signaling pathway in lipopolysaccharide-stimulated RAW 264.7 macrophages［J］.BMC Complement Altern Med， 2014， 14：101.
［70］ 连科迅.硒化新疆乌拉尔甘草多糖抗炎免疫调节作用研究［D］.石河子：石河子大学，2019.
［71］ Han X， Yang Y， Zhang M， et al. Liquiritin protects against cardiac fibrosis after myocardial infarction by inhibiting CCL5 expression and the NF-&kappa；B signaling pathway［J］.Drug Des Devel Ther， 2022， 16：4111-4125.
［72］ Kim ME， Kim HK， Kim DH， et al. 18β-glycyrrhetinic acid from licorice root impairs dendritic cells maturation and Th1 immune responses［J］.Immunopharmacol Immunotoxicol， 2013， 35（3）：329-335.
［73］ 姜辉，汪永忠，刘晓闯，等.三七总皂苷对肝纤维化大鼠细胞因子的影响［J］.中药材，2013，36（7）：1123-1127.
［74］ 郭钰琪，齐冬梅，郝钰，等.三七皂苷R1调节炎性T细胞亚群保护血管内皮的实验研究［J］.中国药理学通报，2012，28（2）：240-244.
［75］ 赵文娟，陈静，邢海晶，等.三七总皂苷对哮喘小鼠气道炎性反应及Th17细胞因子的影响［J］.中华中医药杂志，2015，30（4）：1310-1312.
［76］ Li H， Fan C， Lu H， et al. Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions［J］.Acta Pharm Sin B， 2020， 10（3）：447-461.
［77］ Li MH， Zhang YJ， Yu YH， et al. Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy［J］.Eur J Pharmacol， 2014， 728：67-76.
［78］ Yu XT， Xu YF， Huang YF， et al. Berberrubine attenuates mucosal lesions and inflammation in dextran sodium sulfate-induced colitis in mice［J］.PLoS One， 2018， 13（3）：e0194069.
［79］ 曹景文，任玲，王秋红，等.广陈皮总多糖对小鼠迟发型超敏反应的影响［J］.广东药科大学学报，2019，35（6）：779-782.
［80］ Cheng H， Wu X， Ni G， et al. Citri reticulatae pericarpium protects against isoproterenol-induced chronic heart failure via activation of PPARγ［J］.Ann Transl Med， 2020， 8（21）：1396.
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