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Guo Z, He L, Wang W, Tian S, Lin R. FUT2-dependent fucosylation of LAMP1 promotes the apoptosis of colorectal cancer cells by regulating the autophagy-lysosomal pathway. Cancer Lett 2025; 619:217643. [PMID: 40112906 DOI: 10.1016/j.canlet.2025.217643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/06/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
Fucosyltransferase 2 (FUT2) is an enzyme that adds fucose to proteins or lipids via α-1,2-fucosylation in the intestinal mucosa. While FUT2 deficiency is linked to increased susceptibility to inflammatory bowel disease (IBD), its role in colorectal cancer (CRC) is unclear, and the molecular mechanisms involved remain largely unknown. We established an azoxymethane (AOM) and dextran sulfate sodium (DSS) model to induce CRC. FUT2 expression was assessed in human CRC tissues, AOM/DSS-induced mouse models, and CRC cell lines using qRT-PCR, western blotting, and UEA-I staining. FUT2 knockout (FUT2△IEC) mice were treated with AOM/DSS, and FUT2-overexpressing CRC cells were created to evaluate the effects of FUT2 on apoptosis in both in vitro and in vivo settings through Western blot analyses and functional assays. N-glycoproteomics, UEA-I chromatography, and co-immunoprecipitation were utilized to identify regulatory mechanisms and target fucosylated proteins. FUT2 expression and α-1,2-fucosylation were significantly decreased in CRC. FUT2 deficiency worsened AOM/DSS-induced CRC and reduced tumor apoptosis, while FUT2 overexpression induced apoptosis and inhibited proliferation in CRC cells and xenografts. Mechanistically, FUT2 appears to suppress autophagy by impairing lysosomal function and directly targeting and fucosylating LAMP1, contributing to lysosomal dysfunction. Our study reveals a fucosylation-dependent antitumor mechanism of FUT2 in CRC, suggesting potential therapeutic strategies for CRC treatment.
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Affiliation(s)
- Zijun Guo
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lingnan He
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, Shanghai, China
| | - Weijun Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuxin Tian
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Lin
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Shi J, Peng B, Xu R, Chang X, Wang C, Zhou X, Zhang L. Exploration oxidative stress underlying gastroesophageal reflux disease and therapeutic targets identification: a multi-omics Mendelian randomization study. Postgrad Med J 2025; 101:517-525. [PMID: 39671389 DOI: 10.1093/postmj/qgae182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 10/12/2024] [Accepted: 12/06/2024] [Indexed: 12/15/2024]
Abstract
INTRODUCTION Gastroesophageal reflux disease (GERD) is a chronic inflammatory gastrointestinal disease, which has no thoroughly effective or safe treatment. Elevated oxidative stress is a common consequence of chronic inflammatory conditions. METHODS We employed Summary-data based MR (SMR) analysis to assess the associations between gene molecular characteristics and GERD. Exposure data were the summary-level data on the levels of DNA methylation, gene expression, and protein expression, which obtained from related methylation, expression, and protein quantitative trait loci investigations (mQTL, eQTL, and pQTL). Outcome data, Genome-wide association study (GWAS) summary statistics of GERD, were extracted from the Ong's study (discovery), the Dönertaş's study (replication), and the FinnGen study (replication). Colocalization analysis was performed to determine if the detected signal pairs shared a causative genetic mutation. Oxidative stress related genes and druggable genes were imported to explore oxidative stress mechanism underlying GERD and therapeutic targets of GERD. The Drugbank database was utilized to conduct druggability evaluation. RESULTS After multi-omics SMR analysis and colocalization analysis, we identified seven key genes for GERD, which were SUOX and SERPING1, DUSP13, SULT1A1, LMOD1, UBE2L6, and PSCA. SUOX was screened out to be the mediator, which suggest that GERD is related to oxidative stress. SERPING1, SULT1A1, and PSCA were selected to be the druggable genes. CONCLUSIONS These findings offered strong support for the identification of GERD treatment targets in the future as well as for the study of the oxidative stress mechanism underlying GERD.
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Affiliation(s)
- Jiaxin Shi
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
| | - Bo Peng
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
| | - Ran Xu
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
| | - Xiaoyan Chang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
| | - Chenghao Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
| | - Xiang Zhou
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
| | - Linyou Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin 150081, China
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Zhou S, Zi J, Hu Y, Wang X, Cheng G, Xiong J. Genetic correlation, pleiotropic loci and shared risk genes between major depressive disorder and gastrointestinal tract disorders. J Affect Disord 2025; 374:84-90. [PMID: 39800072 DOI: 10.1016/j.jad.2025.01.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 01/07/2025] [Accepted: 01/09/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Major depressive disorder (MDD) is associated with gastrointestinal tract (GIT) disorders, while genetic correlation, pleiotropic loci and shared risk genes remain to be explored. METHODS Leveraging genome-wide association study statistics for MDD (n = 170,756), peptic ulcer disease (PUD; n = 16,666), gastroesophageal reflux disease (GORD; n = 54,854), PUD and/or GORD and/or medications (PGM; n = 90,175), irritable bowel syndrome (IBS; n = 28,518), and inflammatory bowel disease (IBD; n = 7045), we determined global and local genetic correlations, identified pleiotropic loci, performed gene-level evaluations, and inferred causal associations using bidirectional Mendelian randomization. RESULTS We found global correlation of MDD with PUD (rg = 0.444, P = 3.135 × 10-24), GORD (rg = 0.459, P = 2.568 × 10-65), PGM (rg = 0.498, P = 6.094 × 10-114), IBS (rg = 0.621, P = 2.483 × 10-63), and IBD (rg = 0.171, P = 1.824 × 10-5). We identified 12 locally correlated regions between MDD and GIT disorders except for IBD, and one shared region (chr11:111985737-113,103,996) for PGM, GORD, and IBS. We found one pleiotropic locus for PUD, 12 for GORD, 30 for PGM, eight for IBS, and seven for IBD, and five shared loci (rs138786869, rs2284189, rs3130063, rs35789010, rs7568369) for GORD and PGM. We respectively observed 14 and 20 overlapping genes for MDD-GORD and MDD-PGM. We showed genetic liabilities to GORD, PGM, and IBS causally increase MDD risk, while all reverse causalities are significant. CONCLUSIONS Our work identifies genetic architectures shared between MDD and GIT disorders, contributes genetic insights to understand depression in the context of gut-brain interactions, and provides potential targets to treat gastrointestinal symptoms in depressive patients.
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Affiliation(s)
- Siquan Zhou
- Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jing Zi
- Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yifan Hu
- Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Xiaoyu Wang
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Guo Cheng
- Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital, Sichuan University, Chengdu, China.
| | - Jingyuan Xiong
- Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu 610041, China.
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Wang Y, Zhao Z, Wang R, Hu X. Genetic Links between Gastrointestinal Disorders and Kidney Stone Disease: Insights from a Genome-Wide Cross-Trait Analysis. KIDNEY360 2025; 6:616-626. [PMID: 39752564 PMCID: PMC12045493 DOI: 10.34067/kid.0000000689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/19/2024] [Indexed: 04/25/2025]
Abstract
Key Points Positive genetic links and shared genetic architecture exist between gastrointestinal disorders and kidney stone disease. Ion homeostasis and response to vitamin D bridge two types of disorders. Genetically predicted irritable bowel syndrome, gastroesophageal reflux, and Crohn's disease were associated with higher risk of kidney stone disease. Background Epidemiological associations between kidney stone disease (KSD) and gastrointestinal disorders have been reported, and intestinal homeostasis plays a critical role in stone formation. However, the underlying intrinsic link is not adequately understood. This study aims to investigate the genetic associations between these two types of diseases. Methods We obtained summary statistics from large-scale genome-wide association studies of KSD and gastrointestinal diseases, including gastroesophageal reflux disease, peptic ulcer disease, inflammatory bowel disease and its subtypes, irritable bowel syndrome, and diverticular disease (N =311,254–720,199). Their overall genetic correlations were first estimated. We then detected the shared genetic architecture, including pleiotropic single nucleotide polymorphisms, loci, genes, and biological processes, through cross-trait analyses. In addition, bidirectional Mendelian randomization analysis was performed to look for their causal relationships. Results We found significantly positive genetic correlations between KSD and all five gastrointestinal diseases. The cross-trait analysis identified 3184 potential pleiotropic single nucleotide polymorphisms, and 33 of which were pleiotropic loci shared by the two disorders. Gene-level analyses revealed eight pleiotropic causal genes, primarily enriched in biological pathways involving ion homeostasis and response to vitamin D. In the Mendelian randomization analysis, we detected causal effects from gastroesophageal reflux disease, irritable bowel syndrome, and Crohn's disease to KSD, while no reverse causality was observed. Conclusions Our study demonstrated the positive genetic links between KSD and gastrointestinal diseases and reported pleiotropic variants, loci, and genes, implicating potential biological mechanisms in the pathogenesis of stone disease. These findings further support the role of the gut-kidney axis and provide a genetic basis for the prevention, coregulation, and treatment of these diseases.
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Affiliation(s)
- Yicun Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China and Institute of Urology, Capital Medical University, Beijing, China
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You D, Wu Y, Lu M, Shao F, Tang Y, Liu S, Liu L, Zhou Z, Zhang R, Shen S, Lange T, Xu H, Ma H, Yin Y, Shen H, Chen F, Christiani DC, Jin G, Zhao Y. A genome-wide cross-trait analysis characterizes the shared genetic architecture between lung and gastrointestinal diseases. Nat Commun 2025; 16:3032. [PMID: 40155373 PMCID: PMC11953465 DOI: 10.1038/s41467-025-58248-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 03/11/2025] [Indexed: 04/01/2025] Open
Abstract
Lung and gastrointestinal diseases often occur together, leading to more adverse health outcomes than when a disease of one of these systems occurs alone. However, the potential genetic mechanisms underlying lung-gastrointestinal comorbidities remain unclear. Here, we leverage lung and gastrointestinal trait data from individuals of European, East Asian and African ancestries, to perform a large-scale genetic cross trait analysis, followed by functional annotation and Mendelian randomization analysis to explore the genetic mechanisms involved in the development of lung-gastrointestinal comorbidities. Notably, we find significant genetic correlations between 27 trait pairs among the European population. The highest correlation is between chronic bronchitis and peptic ulcer disease. At the variant level, we identify 42 candidate pleiotropic genetic variants (3 of them previously uncharacterized) in 14 trait pairs by integrating cross-trait meta-analysis, fine-mapping and colocalization analyses. We also find 66 candidate pleiotropic genes, most of which were enriched in immune or inflammatory response-related activities. Causal inference approaches result in 4 potential lung-gastrointestinal associations. Introducing the gut microbiota as a variable establishes a relationship between the genus Parasutterella, gastro-oesophageal reflux disease and asthma. In summary, our findings highlight the genetic relationship between lung and gastrointestinal diseases, providing insights into the genetic mechanisms underlying the development of lung gastrointestinal comorbidities.
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Affiliation(s)
- Dongfang You
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yaqian Wu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Mengyi Lu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fang Shao
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yingdan Tang
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sisi Liu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Liya Liu
- Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Zewei Zhou
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ruyang Zhang
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sipeng Shen
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Theis Lange
- Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hongyang Xu
- Department of Critical Care Medicine, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China
| | - Hongxia Ma
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yongmei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hongbing Shen
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Feng Chen
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
- China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu, China
- Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - David C Christiani
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Guangfu Jin
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Yang Zhao
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
- China International Cooperation Center for Environment and Human Health, Nanjing Medical University, Nanjing, Jiangsu, China.
- Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
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Sun H, Carr H, Garcia-Argibay M, Cortese S, Solmi M, Golm D, Brandt V. Large-scale evidence of a general disease (' d') factor accounting for both mental and physical health disorders in different age groups. Psychol Med 2025; 55:e78. [PMID: 40066566 PMCID: PMC12080664 DOI: 10.1017/s0033291725000522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/19/2024] [Accepted: 02/18/2025] [Indexed: 05/13/2025]
Abstract
BACKGROUND It is unknown whether there is a general factor that accounts for the propensity for both physical and mental conditions in different age groups and how it is associated with lifestyle and well-being. METHODS We analyzed health conditions data from the Millennium Cohort Study (MCS) (age = 17; N = 19,239), the National Child Development Study (NCDS) (age = 44; N = 9293), and the English Longitudinal Study of Ageing (ELSA) (age ≥ 50; N = 7585). The fit of three Confirmatory Factor models was used to select the optimal solution by Comparative Fit Index, Tucker-Lewis Index, and Root Mean Square Error of Approximation. The relationship among d factor, lifestyles, and well-being was further explored. RESULTS Supporting the existence of the d factor, the bi-factor model showed the best model fit in 17-year-olds (MCS:CFI = 0.97, TFI = 0.96, RMSEA = 0.01), 44-year-olds (NCDS:CFI = 0.96, TFI = 0.95, RMSEA = 0.02), and 50+ year-olds (ELSA:CFI = 0.97, TFI = 0.96, RMSEA = 0.02). The d factor scores significantly correlated with lifestyle and well-being, suggesting healthier lifestyles were associated with a reduced likelihood of physical and mental health comorbidities, which in turn improved well-being. CONCLUSIONS Contrary to the traditional dichotomy between mental and physical conditions, our study showed a general factor underlying the comorbidity across mental and physical diseases, related to lifestyle and well-being. Our results inform the conceptualization of mental and physical illness as well as future research assessing risk and pathways of disease transmission, intervention, and prevention. Our results also provide a strong rationale for a systematic screening for mental disorders in individuals with physical conditions and vice versa, and for integrated services addressing multimorbidity.
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Affiliation(s)
- Hongyi Sun
- Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK
| | - Hannah Carr
- Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK
| | - Miguel Garcia-Argibay
- Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Samuele Cortese
- Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK
- Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK
- Solent NHS Trust, Southampton, UK
- Hassenfeld Children’s Hospital at NYU Langone, New York University Child Study Center, New York City, NY, USA
- DiMePRe-J-Department of Precision and Rigenerative Medicine-Jonic Area, University of Bari ‘Aldo Moro’, Bari, Italy
| | - Marco Solmi
- SCIENCES Lab, Department of Psychiatry, University of Ottawa, Ontario, Canada
- Regional Centre for the Treatment of Eating Disorders and On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa Hospital, Ontario, Canada
- Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ontario, Canada
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
| | - Dennis Golm
- Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK
| | - Valerie Brandt
- Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, UK
- Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hanover, Germany
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Li JR, Kao YC, Tsai SJ, Bai YM, Su TP, Chen TJ, Liang CS, Chen MH. Comparative analysis of the risk of severe bacterial infection and septicemia in adolescents and young adults with treatment-resistant depression and treatment-responsive depression - a nationwide cohort study in Taiwan. Eur Child Adolesc Psychiatry 2025:10.1007/s00787-025-02684-y. [PMID: 40056170 DOI: 10.1007/s00787-025-02684-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 02/20/2025] [Indexed: 03/10/2025]
Abstract
Previous studies have shown an association between depression and increased susceptibility to infection in the general population. However, there has been no prior research specifically examining the relationship between treatment-resistant depression (TRD) and severe bacterial infections (SBI) in adolescents and young adults. This retrospective observational cohort study utilized the Taiwan National Health Insurance Research Database (NHIRD) from 2001 to 2010. It included adolescents (12-19 years of age) and young adults (20-29 years of age) diagnosed with major depressive disorder (MDD), comprising 6958 cases of TRD and 27,832 cases of antidepressant-responsive depression (ARPD). The TRD and ARPD groups were further matched (4:1) by chronological age, age at diagnosis of depression, sex, residence, and family income. The primary outcomes were severe bacterial infections (SBI) and septicemia. Cox regression analysis was conducted to identify the risk of hospitalization due to SBI or septicemia during the follow-up period. Compared with controls, the ARPD group had increased risks of SBI (hazard ratio [HR] with 95% confidence interval [CI]: 3.90, 2.73-5.57) and septicemia (HR, 95% CI: 2.56, 1.34-4.91). Notably, the risks of SBI and septicemia appeared to be further elevated in the TRD group. The TRD group exhibited higher incidences of SBI (HR, 95% CI: 6.99, 4.73-10.34) and septicemia (HR, 95% CI: 2.85, 1.28-6.36) than the control group. Adolescents and young adults with TRD had 6.99-fold and 3.90-fold increased risks of SBI and septicemia compared to individuals without MDD, respectively. Therefore, healthcare providers need to be vigilant when monitoring and implementing preventive measures in this population.
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Affiliation(s)
- Jia-Ru Li
- Department of Psychiatry, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Yu-Chen Kao
- Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, No. 60, Xinmin Road, Beitou District, Taipei City, 112, Taiwan
| | - Shih-Jen Tsai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Mei Bai
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tung-Ping Su
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Psychiatry, General Cheng Hsin Hospital, Taipei, Taiwan
| | - Tzeng-Ji Chen
- Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Family Medicine, Hsinchu Branch, Taipei Veterans General Hospital, Hsinchu, Taiwan
| | - Chih-Sung Liang
- Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, No. 60, Xinmin Road, Beitou District, Taipei City, 112, Taiwan.
| | - Mu-Hong Chen
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan.
- Department of Psychiatry, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- Department of Medical Research, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, 112, Taiwan.
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Bai Y, Zhang M, Chen L, Zhou P, Zhou B, Wang R, Li R, Si J, Zhou S, Jiang Y. Gastrointestinal traits, common inflammatory disorders, gallstones, and biliary tract cancer: A network Mendelian randomization study. J Adv Res 2025:S2090-1232(25)00151-1. [PMID: 40064441 DOI: 10.1016/j.jare.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/17/2025] Open
Abstract
INTRODUCTION Observational studies have shown that gallstone disease (GSD), cholecystitis, cholangitis, polyp of gallbladder, viral hepatitis, pancreatitis and gastrointestinal (GI) traits such as H. pylori infection, inflammatory bowel disease, and digestive ulcer are associated with the risk of biliary tract cancer (BTC). However, no study has explored their causal associations. OBJECTIVES To gain a more comprehensive understanding of the causal relationships between GI traits, inflammatory diseases of the digestive system, gallstones, and the development of BTC, further investigation into a comprehensive causal network is warranted. METHODS Based on findings of our Meta-analysis, the present study proposed to investigate the causal role of GSD (26,122 recorded cases) together with 15 GIs and common digestive system inflammatory diseases (sample size from 14,890 to 602,604) in the risk of incident BTC (832 cases and 475,259 controls), using a network Mendelian randomization. Independent associations were further discovered. RESULTS We found significant positive associations between GSD (OR = 1.26, 95 %CI: 1.05-1.51), cholecystitis (OR = 1.43, 95 %CI: 1.20-1.69), gallbladder polyps (OR = 1.11, 95 %CI: 1.00-1.24), primary sclerosing cholangitis (PSC, OR = 1.07, 95 %CI: 1.00-1.13), ulcerative colitis (UC, OR = 1.07, 95 %CI: 1.00-1.14) and the risk of BTC. The association of GSD with BTC was attenuated after adjusting for cholecystitis and gallbladder polyps (OR = 1.45, 95 %CI: 0.60-3.52), while the association of UC remained significant, without the mediation of biliary tract diseases (OR = 1.12, 95 %CI: 1.03-1.22). Beyond that, we verified that the causal associations between primary biliary cholangitis, viral hepatitis, chronic pancreatitis, gastritis, gastric ulcer, Crohn's disease, irritable bowel syndrome, peptic ulcer disease, gastroesophageal reflux disease, appendicitis, and an increased risk of BTC were not significant. CONCLUSIONS Our results implicate the effect of GSD on incident BTC to interact with cholecystitis and polyp of gallbladder, while UC as an independent risk factor for BTC. Clinical studies are needed to determine our findings.
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Affiliation(s)
- Ye Bai
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Min Zhang
- Clinical and Public Health Research Center, Women and Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Peiwen Zhou
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Bai Zhou
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ruobing Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rixin Li
- Biobank, Jilin Cancer Hospital, Changchun, Jilin, China
| | - Junzhuo Si
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shuai Zhou
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanfang Jiang
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, Jilin, China.
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9
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Zhao M, Zhang Y, Liu S, Wang F, Zhang P. Eradication of Helicobacter pylori reshapes gut microbiota and facilitates the evolution of antimicrobial resistance through gene transfer and genomic mutations in the gut. BMC Microbiol 2025; 25:90. [PMID: 40000989 PMCID: PMC11853306 DOI: 10.1186/s12866-025-03823-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 02/12/2025] [Indexed: 02/27/2025] Open
Abstract
Treating Helicobacter pylori (H. pylori) infection requires large quantities of antibiotics, thus dramatically promoting the enrichment and dissemination of antimicrobial resistance (AMR) in feces. However, the influence of H. pylori eradication on the AMR mobility and the gut microbiota evolution has yet to be thoroughly investigated. Here, a study involving 12 H. pylori-positive participants was conducted, and the pre- and post- eradication fecal samples were sequenced. Metagenomic analysis revealed that the eradication treatment drastically altered the gut microbiome, with the Escherichia and Klebsiella genera emerging as the predominant bacteria. Interestingly, the eradication treatment significantly increased the relative abundance and diversity of resistome and mobilome in gut microbiota. Eradication of H. pylori also enriched AMR genes (ARGs) conferring resistance to antibiotics not administered because of the co-location with other ARGs or mobile genetic elements (MGEs). Additionally, the Escherichia and Klebsiella genera were identified as the primary bacterial hosts of these highly transferable ARGs. Furthermore, the genomic variations associated with ARGs in Escherichia coli (E. coli) caused by the eradication treatment were profiled, including the parC, parE, and gyrA genes. These findings revealed that H. pylori eradication promoted the enrichment of ARGs and MGEs in the Escherichia and Klebsiella genera, and further facilitated bacterial evolution through the horizontal transfer of ARGs and genomic variations.
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Affiliation(s)
- Meiqi Zhao
- Life and Health Intelligent Research Institute, Tianjin University of Technology, Tianjin, 300384, China
- The Third Central Hospital of Tianjin, Nankai University, Tianjin, 300170, China
| | - Yunlong Zhang
- Hospital of Stomatology, Tianjin Medical University, Tianjin, 300070, China
| | - Shuangqing Liu
- Department of Clinical Laboratory, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Fengmei Wang
- The Third Central Hospital of Tianjin, Nankai University, Tianjin, 300170, China
- Department of Organ Transplantation, Tianjin Key Laboratory of Organ Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, 300192, China
| | - Peng Zhang
- Life and Health Intelligent Research Institute, Tianjin University of Technology, Tianjin, 300384, China.
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Julián-Flores A, Aguilar-Zárate P, Michel MR, Sepúlveda-Torre L, Torres-León C, Aguilar CN, Chávez-González ML. Exploring the Therapeutic Potential of Medicinal Plants in the Context of Gastrointestinal Health: A Review. PLANTS (BASEL, SWITZERLAND) 2025; 14:642. [PMID: 40094542 PMCID: PMC11901797 DOI: 10.3390/plants14050642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/03/2025] [Accepted: 02/17/2025] [Indexed: 03/19/2025]
Abstract
Medicinal plants represent promising sources for the treatment of gastrointestinal disorders because of their abundance in bioactive compounds with therapeutic properties. Throughout history, various plant species have been used to alleviate digestive ailments, and studies have revealed the presence of metabolites with anti-inflammatory, antibacterial, antiviral, antiparasitic, antidiarrheal, antioxidant, and anticancer activities. The secondary metabolites responsible for these properties include alkaloids, terpenoids, and phenolic compounds, with the latter, particularly flavonoids, being the most associated with their bioactivities. Gastrointestinal diseases, such as gastritis, peptic ulcers, gastroesophageal reflux disease, inflammatory bowel disease, irritable bowel syndrome, and gastrointestinal cancer, are caused primarily by bacteria, parasites, viruses, and the consumption of raw or undercooked foods. These conditions significantly impact human health, necessitating the development of safer and more effective therapeutic alternatives. After an extensive literature review, several plant species with widespread use in the treatment of these disorders were identified, including Matricaria chamomilla, Mentha spicata, Melissa officinalis, Artemisia ludoviciana, Flourensia cernua, Phoradendron californicum, and Turnera difusa. This study revealed that the analyzed plants are rich in bioactive compounds, which confer their medicinal properties. However, many other plants commonly used to treat digestive disorders have been scarcely studied, highlighting the need for further research.
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Affiliation(s)
- Antonio Julián-Flores
- Bioprocesses & Bioproducts Group, Food Research Department, School of Chemistry, Autonomous University of Coahuila, Saltillo 25280, Coahuila, Mexico; (A.J.-F.); (L.S.-T.); (C.N.A.)
| | - Pedro Aguilar-Zárate
- Laboratorio Nacional CONAHCYT de Apoyo a la Evaluación de Productos Bióticos (LaNAEPBi), Unidad de Servicio, Tecnológico Nacional de México/I.T. de Ciudad Valles, Ciudad Valles 79010, San Luis Potosí, Mexico;
| | - Mariela R. Michel
- Laboratorio Nacional CONAHCYT de Apoyo a la Evaluación de Productos Bióticos (LaNAEPBi), Unidad de Servicio, Tecnológico Nacional de México/I.T. de Ciudad Valles, Ciudad Valles 79010, San Luis Potosí, Mexico;
| | - Leonardo Sepúlveda-Torre
- Bioprocesses & Bioproducts Group, Food Research Department, School of Chemistry, Autonomous University of Coahuila, Saltillo 25280, Coahuila, Mexico; (A.J.-F.); (L.S.-T.); (C.N.A.)
| | - Cristian Torres-León
- Research Center and Ethnobiological Garden, Autonomous University of Coahuila, Viesca 27480, Coahuila, Mexico;
| | - Cristóbal N. Aguilar
- Bioprocesses & Bioproducts Group, Food Research Department, School of Chemistry, Autonomous University of Coahuila, Saltillo 25280, Coahuila, Mexico; (A.J.-F.); (L.S.-T.); (C.N.A.)
| | - Mónica L. Chávez-González
- Bioprocesses & Bioproducts Group, Food Research Department, School of Chemistry, Autonomous University of Coahuila, Saltillo 25280, Coahuila, Mexico; (A.J.-F.); (L.S.-T.); (C.N.A.)
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11
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Ding H, Jiang Y, Sun Q, Song Y, Dong S, Xu Q, Li L, Liu C, Li B, Jiang H, Peng B, Peng S, Zhang C, Zhu J, Zhong M, Zhang G, Chang X. Integrating genetics and transcriptomics to characterize shared mechanisms in digestive diseases and psychiatric disorders. Commun Biol 2025; 8:47. [PMID: 39809838 PMCID: PMC11733146 DOI: 10.1038/s42003-025-07481-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/07/2025] [Indexed: 01/16/2025] Open
Abstract
Digestive and psychiatric disorders tend to co-occur, yet mechanisms remain unclear. Leveraging genetic and transcriptomic data integration, we conduct multi-trait analysis of GWAS (MTAG) and weighted gene co-expression network analysis (WGCNA) to explore shared mechanism between psychiatric and gastrointestinal disorders. Significant genetic correlations were found between these disorders, especially in irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), depression (DEP), and neuroticism (NE). MTAG identify 60 novel pleiotropic loci for IBS and 14 for GERD, predominantly located near genes associated with neurological pathways. Further WGCNA identifies multiple co-expression modules enriched with genes involved in neurological pathways in digestive tissues, with some modules strongly preserved across brain and digestive tissues. Moreover, our network analysis suggests BSN, CELF4, and NRXN1 as central players in the regulation of the gut-brain axis (GBA). This study enhances our understanding of the GBA and underscores BSN, CELF4, and NRXN1 as crucial targets for future research.
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Affiliation(s)
- Huanxin Ding
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Yue Jiang
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
| | - Qing Sun
- Department of Gastroentero-Anorectal Surgery, Zhuji People's Hospital of Zhejiang Province, Shaoxing City, Zhejiang Province, P. R. China
| | - Yingchao Song
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
| | - Shuohui Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China
| | - Qian Xu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Linzehao Li
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
| | - Chuxuan Liu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Bingjun Li
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Hengxuan Jiang
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
| | - Bichen Peng
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
| | - Shi Peng
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Chumeng Zhang
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China
| | - Jiankang Zhu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China.
- Medical Center for Digestive Diseases, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China.
- Laboratory of Metabolism and Gastrointestinal Tumor, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, P. R. China.
- Shandong Provincial Engineering Research Center of Minimally Invasive Diagnosis and Treatment for Digestive Diseases, Jinan, Shandong, P. R. China.
| | - Xiao Chang
- College of Medical Information and Artificial Intelligence, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China.
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12
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Wang B, Bai X, Yang Y, Yang H. Possible linking and treatment between Parkinson's disease and inflammatory bowel disease: a study of Mendelian randomization based on gut-brain axis. J Transl Med 2025; 23:45. [PMID: 39799347 PMCID: PMC11725218 DOI: 10.1186/s12967-024-06045-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 12/25/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Mounting evidence suggests that Parkinson's disease (PD) and inflammatory bowel disease (IBD) are closely associated and becoming global health burdens. However, the causal relationships and common pathogeneses between them are uncertain. Furthermore, they are uncurable. Thus, we aimed to identify the causal relationships and novel therapeutic targets shared between them based on their common pathophysiological mechanisms in gut-brain-axis (GBA). METHODS A meta-analysis on bidirectional Mendelian randomization (MR) utilizing various datasets was performed to estimate their causal relationship. Then, pleiotropic analysis under the composite null hypothesis (PLACO) with functional mapping combined with annotation of genetic associations (FUMA) analysis were conducted to identify pleiotropic genes. Next, blood, brain and intestine expression quantitative trait locus (eQTL) were taken to perform drug-target MR finding common causal genes in two diseases. Colocalization analysis ensured the eQTLs of corresponding gene colocalized with disease. Enrichment analysis and protein‒protein interaction (PPI) network were done to explore common pathogenesis pathways. Genes passed all analysis were regarded as drug targets. RESULTS Our MR meta-analysis revealed the bidirectional causal relationship between diseases, with combined ORs for PD on IBD, CD, UC (1.050 [95% CI 1.014-1.086], 1.044 [95% CI 0.995-1.095], 1.063 [95% CI 1.016-1.120]); for IBD, CD, UC on PD (1.003 [95% CI 0.973-1.034], 1.035 [95% CI 1.004-1.067], 1.008 [95% CI 0.977-1.040]). Overall, 277, 216 and 201 genes were identified as pleiotropic genes between PD and IBD, CD, UC. Total of 733 genes were classified as tier 3 (found in only one tissue) druggable targets, 57 as tier 2 (found in two tissues, 51 protein-coding genes) and 9 as tier 3 (found in three tissues). Among 60 protein-coding druggable targets over tier 2, 18 overlapped with pleiotropic genes and enriched in mitochondria, antigen presentation, processing and immune cell regulation pathways. Three druggable genes (LRRK2, RAB29 and HLA-DQA2) passed colocalization analysis. LRRK2 and RAB29 were reported to be pleiotropic genes, and RAB29 and HLA-DQA2 were reported for the first time as potential drug targets. CONCLUSIONS This study established a reliable causal relationship, possible shared drug targets and common pathogenesis pathways of two diseases, which had important implications for intervention and treatment of two diseases simultaneously.
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Affiliation(s)
- Beiming Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
- 4+4 medical doctor program, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 5, DongDanSanTiao, DongCheng District, Beijing, 100730, China
| | - Xiaoyin Bai
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China
| | - Yingmai Yang
- Department of Neurology, Peking Union Medical College Hospital, Beijing, 100730, China.
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
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13
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Liu D, Cao M, Wu S, Jiang Y, Cao W, Lin T, Li F, Sha F, Yang Z, Tang J. Modifiable factors for irritable bowel syndrome: evidence from Mendelian randomisation approach. EGASTROENTEROLOGY 2025; 3:e100126. [PMID: 39944930 PMCID: PMC11770431 DOI: 10.1136/egastro-2024-100126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 12/24/2024] [Indexed: 03/23/2025]
Abstract
ABSTRACT Background The potential modifiable factors influencing irritable bowel syndrome (IBS) have not been thoroughly documented. We aimed to systematically investigate the modifiable factors associated with IBS, while accounting for the impact of unobserved confounders and coexisting disorders. Methods Genetic correlation and Mendelian randomisation (MR) analyses were integrated to identify potential modifiable factors and coexisting disorders linked to IBS. Subsequently, multiresponse MR (MR2) was employed to further examine these associations. Summary-level genome-wide association data were used. Modifiable factors and coexisting disorders (ie, gastrointestinal and psychiatric disorders) were identified based on evidence from cohort studies and meta-analysis. In all analyses, IBS was the primary outcome, while in the MR2 analysis, coexisting disorders were also treated as outcomes alongside IBS. Results Most identified modifiable factors and coexisting disorders exhibited genetic correlations with IBS. MR analyses revealed strong causation between IBS and multisite chronic pain (OR=2.20, 95% CI 1.82 to 2.66), gastro-oesophageal reflux disease (OR=1.31, 95% CI 1.23 to 1.39), well-being spectrum (OR=0.17, 95% CI 0.13 to 0.21), life satisfaction (OR=0.31, 95% CI 0.25 to 0.38), positive affect (OR=0.30, 95% CI 0.24 to 0.37), neuroticism score (OR=1.20, 95% CI 1.16 to 1.25) and depression (OR=1.50, 95% CI 1.37 to 1.66). Additionally, smoking, alcohol frequency, college or university degree, intelligence, childhood maltreatment, frailty index, diverticular disease of the intestine and schizophrenia were suggestively associated with IBS. Robust associations were found between multisite chronic pain and both IBS and coexisting disorders. Conclusions Our study identified a comprehensive array of potential modifiable factors and coexisting disorders associated with IBS, supported by genetic evidence, including genetic correlation and multiple MR analyses. The presence of multisite chronic pain may offer a promising avenue for the concurrent prevention of IBS and its coexisting disorders.
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Affiliation(s)
- Di Liu
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Meiling Cao
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Shanshan Wu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- State Key Laboratory for Digestive Health, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Yiwen Jiang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Weijie Cao
- Edith Cowan University, Joondalup, Western Australia, Australia
| | - Tengfei Lin
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Fuxiao Li
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
- Department of Computational Biology and Medical Big Data, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China
| | - Feng Sha
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Zhirong Yang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
- Department of Computational Biology and Medical Big Data, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China
| | - Jinling Tang
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
- Department of Computational Biology and Medical Big Data, Shenzhen University of Advanced Technology, Shenzhen, Guangdong, China
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14
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Deng ZH, Li X, Liu L, Zeng HM, Chen BF, Peng J. Role of gut microbiota and Helicobacter pylori in inflammatory bowel disease through immune-mediated synergistic actions. World J Gastroenterol 2024; 30:5097-5103. [PMID: 39713161 PMCID: PMC11612865 DOI: 10.3748/wjg.v30.i47.5097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/19/2024] [Accepted: 11/04/2024] [Indexed: 11/26/2024] Open
Abstract
A recent study published in the World Journal of Gastroenterology, suggests that transplanting the gut microbiota from healthy donors can alleviate the pathological processes linked to inflammatory bowel disease (IBD), particularly Crohn's disease. In addition, that paper illustrates the effect of changes in the gut microbiota on IBD and points out that altered mesenteric adipose tissue caused by the gut microbiota and creeping fat lead to increased inflammation, which exacerbates IBD. Moreover, recent research has shown that the interaction between Helicobacter pylori (H. pylori) and the gut microbiota is mediated through immune mechanisms, resulting in a synergistic impact on IBD. Therefore, in this manuscript, we will focus on the role of the gut microbiota and H. pylori in the immune response to IBD, as well as the possible impact of H. pylori on the gut microbiota. We will also explore their individual and synergistic immune effects on IBD and look at future therapeutic perspectives for IBD.
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Affiliation(s)
- Zhi-Hao Deng
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xin Li
- The First Clinical Medical College, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 310006, Jiangxi Province, China
| | - Li Liu
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hai-Min Zeng
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Bo-Fan Chen
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jie Peng
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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15
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Wang Z, Ye R, Zhang S, Liu C, Chen K, Zhu K, Wang P, Wang F, Huang J. Amelioration of LPS-Induced Jejunum Injury and Mucus Barrier Damage in Mice by IgY Embedded in W/O/W Emulsion. Foods 2024; 13:4138. [PMID: 39767078 PMCID: PMC11675984 DOI: 10.3390/foods13244138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Chicken yolk immunoglobulin (IgY) is a natural immunologically active antibody extracted from egg yolk and can be used as a natural dietary supplement for the treatment of inflammation and damage to the intestines. In our study, IgY was embedded in a double emulsion (W/O/W; DE) to explore the therapeutic effect of the embedded IgY on Lipopolysaccharide (LPS)-induced jejunal injury in mice. The results showed that W/O/W-embedded IgY as a dietary supplement (IgY + DE) attenuated LPS-induced damage to mouse small intestinal structures and protected the integrity of the jejunal mucosal barrier. IgY + DE increased the amount of related transcription factors (Math1, Spdef, Elf3, and Klf4) and promoted thrush cell differentiation. IgY + DE ameliorated LPS-induced reduction in mucin quantity and markers. It promoted the expression of Muc1 and Muc2 and increased the mRNA expression levels of Muc1, Muc2, Muc3, Muc4, Muc13, and Agr2 (p < 0.05). IgY + DE increased the expression of several glycosyltransferases involved in mucin glycosylation. IgY + DE also neutralized the LPS attack on the expression of jejunal inflammatory factors IL-1β, IL-6, IL-4, and TNF-α. In conclusion, the IgY-embedded double emulsion can be used as a dietary supplement for immunotherapy to prevent LPS-induced jejunal injury in mice.
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Affiliation(s)
- Zhaohui Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Ruihua Ye
- College of Veterinary Medicine, China Agricultural University, Beijing 100083, China;
| | - Shidi Zhang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Chuanming Liu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Ke Chen
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Kongdi Zhu
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Pengjie Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
| | - Fuqing Wang
- Tibet Tianhong Science and Technology Co., Ltd., Lasha 851414, China
| | - Jiaqiang Huang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, Ministry of Education, China Agricultural University, Beijing 100083, China; (Z.W.); (S.Z.); (C.L.); (K.C.); (K.Z.); (P.W.)
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Pinakhina D, Kasyanov E, Rukavishnikov G, Larin AK, Veselovsky VA, Rakitko A, Neznanov N, Kibitov A, Mazo G, Artomov M. The effect size of rs521851 in the intron of MAGI2/S-SCAM on HADS-D scores correlates with EAT-26 scores for eating disorders risk. Front Psychiatry 2024; 15:1416009. [PMID: 39703455 PMCID: PMC11656592 DOI: 10.3389/fpsyt.2024.1416009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 10/30/2024] [Indexed: 12/21/2024] Open
Abstract
An association between the MAGI2 (S-SCAM) intron variant rs521851 and depression symptoms, as measured by the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D), has been recently reported. The role of MAGI2 in depression has been linked to disruptions in the gut-brain axis. In this study, we investigated the association between rs521851 and HADS-D scores in an independent cohort of 380 individuals, consisting of 238 patients with an ICD-10 diagnosis of depression and 142 healthy controls. The original association was replicated in the patient cohort but not in the control group. Further analysis revealed that the effect size of rs521851 on HADS-D scores was moderated by Eating Attitudes Test 26 (EAT-26) scores. In participants with an EAT-26 score of ≥20, the effect size of rs521851 on HADS-D was more than 20 times greater compared to those with an EAT-26 score of <20. These findings successfully replicate the original association signal for MAGI2 and HADS-D, and highlight the role of MAGI2 in gut-brain interactions.
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Affiliation(s)
- Daria Pinakhina
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
| | - Evgeny Kasyanov
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
| | - Grigory Rukavishnikov
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
| | - Andrey K. Larin
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia
| | - Vladimir A. Veselovsky
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Moscow, Russia
| | - Alexander Rakitko
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
- Genotek Ltd., Moscow, Russia
| | - Nikholay Neznanov
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
- Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia
| | - Alexander Kibitov
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
- Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia
| | - Galina Mazo
- V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint-Petersburg, Russia
| | - Mykyta Artomov
- Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, United States
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17
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Chasman DI, Guo Y, Chan AT, Rist PM, Staller K. Shared Genetics of Migraine and Gastrointestinal Disorders Implicates Underlying Neurologic Mechanisms Yet Heterogeneous Etiologies. Neurol Genet 2024; 10:e200201. [PMID: 39677849 PMCID: PMC11637577 DOI: 10.1212/nxg.0000000000200201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 08/28/2024] [Indexed: 12/17/2024]
Abstract
Background and Objectives Migraine is strongly comorbid with irritable bowel syndrome (IBS), one of several gastrointestinal (GI) conditions that are distinguished by symptomatic profiles that are partly overlapping. Potential shared mechanisms of migraine and the GI conditions were investigated by assessing shared genetics on a genome-wide basis. Methods Analyses leveraged genome-wide summary statistics from large-scale genetic studies for migraine, including by aura status, IBS, peptic ulcer disease (PUD), gastrointestinal reflux (GERD), functional dyspepsia (FD), diverticular disease (DD), and the immune-related inflammatory bowel disease (IBD) or its constituents, ulcerative colitis (UC) and Crohn disease (CD). Genetic correlation was evaluated on a genome-wide basis and at independent local regions, including those related to therapeutic targeting of serotonin and the calcitonin gene-related peptide. Genetic correlation was assessed for enrichment at genes according to tissue specificity of gene expression. Potential causality between migraine and the GI conditions was assessed by Mendelian randomization. Results Genetic correlation with migraine was strongly significant among the nonimmune GI disorders, maximally for IBS (rg [SE] = 0.37[0.04], p = 10-21) and minimally for DD (0.18 (0.04), 7.5 × 10-7), but null for IBD. There were distinct patterns of local genetic sharing with migraine across the GI conditions at 22 significant segments of the genome, 7 of which were novel for either migraine or GI or both. Enrichment analysis suggested involvement of the CNS in genetic overlap of GERD, IBS, and PUD with migraine. There was local genetic sharing with migraine at CALCA/CALCB (encoding calcitonin gene-related peptide [CGRP]) in an inverse sense for GERD and PUD, but with concordance and greater significance for DD, IBD, and UC. Mendelian randomization supported causal effects of PUD, GERD and particularly DD (OR[SE] = 1.90 (1.35-2.68, p = 2.2 × 10-4) on migraine, but not of migraine on any GI condition. Discussion Genetic sharing of migraine and non-immune-related GI disorders was extensive yet distinct across GI disorders that have overlapping symptoms, with enrichment signals that imply neurologic mechanisms. Causal effects of some GI conditions on migraine were supported. A concordant local correlation at CALCA/CALCB of migraine with both DD and the immune-related disorders suggests potential benefit to these conditions from repurposed migraine therapeutics targeting CGRP.
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Affiliation(s)
- Daniel I Chasman
- From the Division of Preventive Medicine (D.I.C., Y.G., P.M.R.), Brigham and Women's Hospital and Harvard Medical School; and the Clinical and Translational Epidemiology Unit (A.T.C., K.S.) and Division of Gastroenterology (A.T.C., K.S.), Massachusetts General Hospital, and Harvard Medical School, Boston, MA
| | - Yanjun Guo
- From the Division of Preventive Medicine (D.I.C., Y.G., P.M.R.), Brigham and Women's Hospital and Harvard Medical School; and the Clinical and Translational Epidemiology Unit (A.T.C., K.S.) and Division of Gastroenterology (A.T.C., K.S.), Massachusetts General Hospital, and Harvard Medical School, Boston, MA
| | - Andrew T Chan
- From the Division of Preventive Medicine (D.I.C., Y.G., P.M.R.), Brigham and Women's Hospital and Harvard Medical School; and the Clinical and Translational Epidemiology Unit (A.T.C., K.S.) and Division of Gastroenterology (A.T.C., K.S.), Massachusetts General Hospital, and Harvard Medical School, Boston, MA
| | - Pamela M Rist
- From the Division of Preventive Medicine (D.I.C., Y.G., P.M.R.), Brigham and Women's Hospital and Harvard Medical School; and the Clinical and Translational Epidemiology Unit (A.T.C., K.S.) and Division of Gastroenterology (A.T.C., K.S.), Massachusetts General Hospital, and Harvard Medical School, Boston, MA
| | - Kyle Staller
- From the Division of Preventive Medicine (D.I.C., Y.G., P.M.R.), Brigham and Women's Hospital and Harvard Medical School; and the Clinical and Translational Epidemiology Unit (A.T.C., K.S.) and Division of Gastroenterology (A.T.C., K.S.), Massachusetts General Hospital, and Harvard Medical School, Boston, MA
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18
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Murphy AE, Beardall W, Rei M, Phuycharoen M, Skene NG. Predicting cell type-specific epigenomic profiles accounting for distal genetic effects. Nat Commun 2024; 15:9951. [PMID: 39550354 PMCID: PMC11569248 DOI: 10.1038/s41467-024-54441-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 11/06/2024] [Indexed: 11/18/2024] Open
Abstract
Understanding how genetic variants affect the epigenome is key to interpreting GWAS, yet profiling these effects across the non-coding genome remains challenging due to experimental scalability. This necessitates accurate computational models. Existing machine learning approaches, while progressively improving, are confined to the cell types they were trained on, limiting their applicability. Here, we introduce Enformer Celltyping, a deep learning model which incorporates distal effects of DNA interactions, up to 100,000 base-pairs away, to predict epigenetic signals in previously unseen cell types. Using DNA and chromatin accessibility data for epigenetic imputation, Enformer Celltyping outperforms current best-in-class approaches and generalises across cell types and biological regions. Moreover, we propose a framework for evaluating models on genetic variant effect prediction using regulatory quantitative trait loci mapping studies, highlighting current limitations in genomic deep learning models. Despite this, Enformer Celltyping can also be used to study cell type-specific genetic enrichment of complex traits.
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Affiliation(s)
- Alan E Murphy
- UK Dementia Research Institute at Imperial College London, London, W12 0BZ, UK.
- Department of Brain Sciences, Imperial College London, London, W12 0BZ, UK.
| | - William Beardall
- Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK
| | - Marek Rei
- Department of Computing, Imperial College London, London, SW7 2RH, UK
| | - Mike Phuycharoen
- Division of Informatics, Imaging & Data Sciences, University of Manchester, Manchester, M13 9PL, UK
| | - Nathan G Skene
- UK Dementia Research Institute at Imperial College London, London, W12 0BZ, UK.
- Department of Brain Sciences, Imperial College London, London, W12 0BZ, UK.
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Zhang Y, Xun L, Qiao R, Jin S, Zhang B, Luo M, Wan P, Zuo Z, Song Z, Qi J. Advances in research on the role of high carbohydrate diet in the process of inflammatory bowel disease (IBD). Front Immunol 2024; 15:1478374. [PMID: 39588368 PMCID: PMC11586370 DOI: 10.3389/fimmu.2024.1478374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/25/2024] [Indexed: 11/27/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, systemic gastrointestinal disorder characterized by episodic inflammation that requires life-long management. Although the etiology of IBD is not fully understood, it is hypothesized to involve a multifaceted interplay among genetic susceptibility, the host immune response, and environmental factors. Previous studies have largely concluded that IBD is associated with this complex interplay; however, more recent evidence underscores the significant role of dietary habits as risk factors for the development of IBD. In this review, we review the molecular mechanisms of high-sugar and high-fat diets in the progression of IBD and specifically address the impacts of these diets on the gut microbiome, immune system regulation, and integrity of the intestinal barrier, thereby highlighting their roles in the pathogenesis and exacerbation of IBD.
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Affiliation(s)
- Ying Zhang
- School of Medicine, Kunming University of Science and Technology, Kunming, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Linting Xun
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Ran Qiao
- Colleges of Letters and Science, University of Wisconsin–Madison, Madison, WI, United States
| | - Shumei Jin
- Yunnan Institute of Food and Drug Supervision and Control, Medical Products Administration of Yunnan Province, Kunming, China
| | - Bing Zhang
- Yunnan Provincial Key Laboratory of Modern Information Optics, Kunming University of Science and Technology, Kunming, China
| | - Mei Luo
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Ping Wan
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Yunnan Clinical Research Center for Geriatric Disorders, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Zan Zuo
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Zhengji Song
- School of Medicine, Kunming University of Science and Technology, Kunming, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Jialong Qi
- School of Medicine, Kunming University of Science and Technology, Kunming, China
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Yunnan Clinical Research Center for Geriatric Disorders, The First People’s Hospital of Yunnan Province, Kunming, China
- Yunnan Provincial Key Laboratory of Birth Defects and Genetic Diseases, First People’s Hospital of Yunnan Province, Kunming, China
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20
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Zheng H, Guo T, Zhao X, Wang K, Shan S, Xie S, Xu Y, Liu C, Lu W. Helicobacter pylori Infection Is Not Associated with Nonalcoholic Fatty Liver Disease: A Two-Year Cohort Study. Dig Dis 2024; 43:75-83. [PMID: 39496224 DOI: 10.1159/000542180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 10/06/2024] [Indexed: 11/06/2024]
Abstract
INTRODUCTION Previous studies reported inconsistent results of the association between Helicobacter pylori infection and nonalcoholic fatty liver disease (NAFLD). METHODS A cohort study of 2,063 adults without NAFLD at baseline, who participated in a repeated health checkup including a 13C-urea breath test and abdominal ultrasonography, was conducted to evaluate the link between H. pylori infection and NAFLD development. RESULTS During a mean follow-up period of 1.7 years, we did not find a significant association between H. pylori infection and NAFLD (hazard ratio = 1.10 (0.86, 1.40), p = 0.4689). We also found that higher age, body mass index (BMI), systolic blood pressure (systolic BP), diastolic blood pressure (diastolic BP), fasting blood glucose, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were risk factors, and high-density lipoprotein cholesterol (HDL-C) was a protective factor for NAFLD development. CONCLUSION H. pylori infection might not be positively related to NAFLD development.
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Affiliation(s)
- Huabo Zheng
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Tangmeng Guo
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofang Zhao
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Wang
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengshuai Shan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia, USA
| | - Songpu Xie
- Laboratory of Experimental Cardiology, Department Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yichen Xu
- Department of Histology and Embryology, Medicine and Life Sciences, Hainan Medical University, Haikou, China
| | - Chengyun Liu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weilin Lu
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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21
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Dai Z, Wang Q, He B, Shi F, Chen W, Jiang Q, Zhou D, Xue Z, Yang B. Causal association of plasma n-3 PUFA with peptic ulcer disease: a two-sample Mendelian randomisation study. Br J Nutr 2024; 132:1014-1021. [PMID: 39523850 DOI: 10.1017/s0007114524001752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Dietary n-3 PUFA may have potential benefits in preventing peptic ulcer disease (PUD). However, data from observational epidemiological studies are limited. Thus, we conducted a Mendelian randomisation analysis to reveal the causal impact of n-3 PUFA on PUD. Genetic variants strongly associated with plasma levels of total or individual n-3 PUFA including plant-derived α-linolenic acid and marine-derived EPA, DPA and DHA were enrolled as instrumental variables. Effect size estimates of the n-3 PUFA-associated genetic variants with PUD were evaluated using data from the UK biobank. Per one sd increase in the level of total n-3 PUFA in plasma was significantly associated with a lower risk of PUD (OR = 0·91; 95 % CI 0·85, 0·99; P = 0·020). The OR were 0·81 (95 % CI 0·67, 0·97) for EPA, 0·72 (95 % CI 0·58, 0·91) for DPA and 0·87 (95 % CI 0·80, 0·94) for DHA. Genetically predicted α-linolenic acid levels in plasma had no significant association with the risk of PUD (OR = 5·41; 95 % CI 0·70, 41·7). Genetically predicted plasma levels of n-3 PUFA were inversely associated with the risk of PUD, especially marine-based n-3 PUFA. Such findings may have offered an effective and feasible strategy for the primary prevention of PUD.
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Affiliation(s)
- Zebin Dai
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Qinjian Wang
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Bingbing He
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Fang Shi
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Wei Chen
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Qingxi Jiang
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Dan Zhou
- School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Zhanxiong Xue
- The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Bo Yang
- Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People's Republic of China
- Institute of Lipids Medicine, Wenzhou Medical University, Wenzhou, People's Republic of China
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22
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Wu W, Zeng C, Wu C, Wu T, Pang J, Zhou P, Cao Y. Antidepressant effect of carvedilol on streptozotocin-induced diabetic peripheral neuropathy mice by altering gut microbiota. Biochem Biophys Res Commun 2024; 730:150374. [PMID: 38986219 DOI: 10.1016/j.bbrc.2024.150374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/05/2024] [Accepted: 07/08/2024] [Indexed: 07/12/2024]
Abstract
RATIONALE Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain. OBJECTIVES To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota. METHODS The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation. RESULTS Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum. CONCLUSIONS Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP.
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Affiliation(s)
- Weifeng Wu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Chao Zeng
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Caineng Wu
- Department of Anesthesia, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ting Wu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Jianxin Pang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Pingzheng Zhou
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
| | - Ying Cao
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China; Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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Lan Y, Shen J, Liu R, Jiang K, Qiu M, Wang S, Lin Z. Analysis of risk factors for intraoperative bleeding in patients with Siewert type II esophagogastric junction adenocarcinoma treated by two minimally invasive surgeries and its influence on prognosis: a retrospective study. Front Oncol 2024; 14:1426349. [PMID: 39416465 PMCID: PMC11479957 DOI: 10.3389/fonc.2024.1426349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 09/09/2024] [Indexed: 10/19/2024] Open
Abstract
Background The present study aimed to analyze the independent risk factors for intraoperative bleeding in Siewert II adenocarcinoma of the esophagogastric junction (AEG) using two minimally invasive surgical approaches, namely, the laparoscopy-assisted abdominal trans-hiatal (LTH) method and transthoracic-laparoscopic esophagectomy (TLE). Methods The clinical data of 100 patients with SiewertII AEG admitted to our hospital from October 2017 to October 2020 were retrospectively analyzed. According to the type of surgery, the patients were divided into LTH approach group and TLE approach group. The differences between the clinical characteristics of the patients in different groups and the differences in the intraoperative bleeding and prognosis between different surgical procedures were analyzed and compared using the t-test and chi-squared test. Multiple linear regression was used to identify the independent risk factors affecting the amount of intraoperative bleeding in patients. Results The results of this study showed that patients in the LTH group had significantly less intraoperative bleeding and operative time and significantly better postoperative recovery than the TLE group. The results of multivariate linear regression showed that the combined trans-thoracic-abdominal approach (P=0.000), advanced age (P=0.014), larger BMI (P=0.000), and larger tumor diameter (P=0.001) were the independent risk factors influencing the increase in intraoperative bleeding. Conclusion In addition to the conventional factors that affect intraoperative bleeding, such as the patient's general condition, operation time, and tumor size, LTH surgery is another way to avoid intraoperative bleeding for Siewert type II AEG patients and can significantly improve postoperative recovery.
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Affiliation(s)
- Yang Lan
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Jian Shen
- Department of Cardiothoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Ruqian Liu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Kai Jiang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Mingyuan Qiu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Shuai Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Zhou Lin
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
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24
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Chen Y, Liu S, Gong W, Guo P, Xue F, Zhou X, Wang S, Yuan Z. Protein-centric omics integration analysis identifies candidate plasma proteins for multiple autoimmune diseases. Hum Genet 2024; 143:1035-1048. [PMID: 38143258 PMCID: PMC11485194 DOI: 10.1007/s00439-023-02627-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 11/28/2023] [Indexed: 12/26/2023]
Abstract
It remains challenging to translate the findings from genome-wide association studies (GWAS) of autoimmune diseases (AIDs) into interventional targets, presumably due to the lack of knowledge on how the GWAS risk variants contribute to AIDs. In addition, current immunomodulatory drugs for AIDs are broad in action rather than disease-specific. We performed a comprehensive protein-centric omics integration analysis to identify AIDs-associated plasma proteins through integrating protein quantitative trait loci datasets of plasma protein (1348 proteins and 7213 individuals) and totally ten large-scale GWAS summary statistics of AIDs under a cutting-edge systematic analytic framework. Specifically, we initially screened out the protein-AID associations using proteome-wide association study (PWAS), followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, we performed both Mendelian randomization (MR) and colocalization analyses to further identify protein-AID pairs with putatively causal relationships. We finally prioritized the potential drug targets for AIDs. A total of 174 protein-AID associations were identified by PWAS. AIDs-associated plasma proteins were significantly enriched in immune-related biological process and pathways, such as inflammatory response (P = 3.96 × 10-10). MR analysis further identified 97 protein-AID pairs with potential causal relationships, among which 21 pairs were highly supported by colocalization analysis (PP.H4 > 0.75), 10 of 21 were the newly discovered pairs and not reported in previous GWAS analyses. Further explorations showed that four proteins (TLR3, FCGR2A, IL23R, TCN1) have corresponding drugs, and 17 proteins have druggability. These findings will help us to further understand the biological mechanism of AIDs and highlight the potential of these proteins to develop as therapeutic targets for AIDs.
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Affiliation(s)
- Yingxuan Chen
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China
| | - Shuai Liu
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China
| | - Weiming Gong
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China
| | - Ping Guo
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China
| | - Fuzhong Xue
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Shukang Wang
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China.
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China.
| | - Zhongshang Yuan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44, Wenhua West Road, Jinan, 250012, Shandong, China.
- Institute for Medical Dataology, Shandong University, 12550, Erhuan East Road, Jinan, 250003, Shandong, China.
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25
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Yeh PJ, Chen CC, Chao HC, Lai JY, Ming YC, Chen MC, Lai MW. The trends of pediatric duodenal ulcer and predictors of recurrence. J Formos Med Assoc 2024; 123:1070-1077. [PMID: 38644127 DOI: 10.1016/j.jfma.2024.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 02/27/2024] [Accepted: 04/16/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Duodenal ulcer (DU) causes various symptoms in children. The prevalence of Helicobacter pylori (Hp)-associated DU has been reducing in some regions, yet the updated trend in Taiwan is unknown. Risk factors of DU recurrence have not been comprehensively investigated in children. METHODS This retrospective study included children diagnosed with DU to evaluate the demographics, symptoms, diagnostics, treatment, and outcomes. Specific populations (infant, surgery required) were sorted for subgroup analysis. Predictors of DU recurrence was analyzed in patients who received endoscopic follow-ups. RESULTS A total of 488 children were included. Most patients were male (72.5%), school-aged (11.3 ± 4.8 years old), and with varied underlying diseases in one-fifth. The annual incidences were around 3-5%, with a declining trend of case numbers and the Hp-positive proportion. Hp infection, concurrent gastric ulcer, perforation, and mortality were noted in 32.7%, 16%, 1.6%, and 1% of patients. Patients with or without Hp infection showed different clinical features but similar outcomes. The characteristics of subpopulations were depicted respectively. Male sex, lower Hb level, and perforation were independent risk factors associated with recurrence. CONCLUSION Hp-positive DU seems to wane. Patients with male sex, lower Hb level, or perforation at diagnosis carried a higher risk of recurrence, which may warrant active surveillance and endoscopic follow-up.
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Affiliation(s)
- Pai-Jui Yeh
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Chien-Chang Chen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Hsun-Chin Chao
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Jin-Yao Lai
- Department of Pediatric Surgery, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yung-Ching Ming
- Department of Pediatric Surgery, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Mi-Chi Chen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan
| | - Ming-Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou Branch and Chang Gung University College of Medicine, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taiwan.
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26
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Nakhal MM, Yassin LK, Alyaqoubi R, Saeed S, Alderei A, Alhammadi A, Alshehhi M, Almehairbi A, Al Houqani S, BaniYas S, Qanadilo H, Ali BR, Shehab S, Statsenko Y, Meribout S, Sadek B, Akour A, Hamad MIK. The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review. Life (Basel) 2024; 14:1234. [PMID: 39459534 PMCID: PMC11508655 DOI: 10.3390/life14101234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 09/23/2024] [Accepted: 09/24/2024] [Indexed: 10/28/2024] Open
Abstract
Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.
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Affiliation(s)
- Mohammed M. Nakhal
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Lidya K. Yassin
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Rana Alyaqoubi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Sara Saeed
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Alreem Alderei
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Alya Alhammadi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Mirah Alshehhi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Afra Almehairbi
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Shaikha Al Houqani
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Shamsa BaniYas
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Haia Qanadilo
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Bassam R. Ali
- Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Safa Shehab
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
| | - Yauhen Statsenko
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
- Neuroscience Platform, ASPIRE Precision Medicine Institute in Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Sarah Meribout
- Internal Medicine Department, Maimonides Medical Center, New York, NY 11219, USA;
| | - Bassem Sadek
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Bo Box 15551, United Arab Emirates; (B.S.); (A.A.)
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 1551, United Arab Emirates
| | - Amal Akour
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Bo Box 15551, United Arab Emirates; (B.S.); (A.A.)
- Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Mohammad I. K. Hamad
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates (S.B.); (S.S.)
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Ruigrok YM, Veldink JH, Bakker MK. Drug classes affecting intracranial aneurysm risk: Genetic correlation and Mendelian randomization. Eur Stroke J 2024; 9:687-695. [PMID: 38357878 PMCID: PMC11418413 DOI: 10.1177/23969873241234134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/05/2024] [Indexed: 02/16/2024] Open
Abstract
INTRODUCTION There is no non-invasive treatment to prevent aneurysmal subarachnoid hemorrhage (ASAH) caused by intracranial aneurysm (IA) rupture. We aimed to identify drug classes that may affect liability to IA using a genetic approach. PATIENTS AND METHODS Using genome-wide association summary statistics we calculated genetic correlation between unruptured IA (N = 2140 cases), ASAH (N = 5140) or the combined group, and liability to drug usage from 23 drug classes (N up to 320,000) independent of the risk factor high blood pressure. Next, we evaluated the causality and therapeutic potential of correlated drug classes using three different Mendelian randomization frameworks. RESULTS Correlations with IA were found for antidepressants, paracetamol, acetylsalicylic acid, opioids, beta-blockers, and peptic ulcer and gastro-esophageal reflux disease drugs. MR showed no evidence that genetically predicted usage of these drug classes caused IA. Genetically predicted high responders to antidepressant drugs were at higher risk of IA (odds ratio [OR] = 1.61, 95% confidence interval (CI) = 1.09-2.39, p = 0.018) and ASAH (OR = 1.68, 95% CI = 1.07-2.65, p = 0.024) if they used antidepressant drugs. This effect was absent in non-users. For beta-blockers, additional analyses showed that this effect was not independent of blood pressure after all. A complex and likely pleiotropic relationship was found between genetic liability to chronic multisite pain, pain medication usage (paracetamol, acetylsalicylic acid, and opioids), and IA. CONCLUSIONS We did not find drugs decreasing liability to IA and ASAH but found that antidepressant drugs may increase liability. We observed pleiotropic relationships between IA and other drug classes and indications. Our results improve understanding of pathogenic mechanisms underlying IA.
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Affiliation(s)
- Ynte M Ruigrok
- Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Jan H Veldink
- Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Mark K Bakker
- Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
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28
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Shao M, Tian M, Chen K, Jiang H, Zhang S, Li Z, Shen Y, Chen F, Shen B, Cao C, Gu N. Leveraging Random Effects in Cistrome-Wide Association Studies for Decoding the Genetic Determinants of Prostate Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400815. [PMID: 39099406 PMCID: PMC11423091 DOI: 10.1002/advs.202400815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 07/09/2024] [Indexed: 08/06/2024]
Abstract
Cistrome-wide association studies (CWAS) are pivotal for identifying genetic determinants of diseases by correlating genetically regulated cistrome states with phenotypes. Traditional CWAS typically develops a model based on cistrome and genotype data to associate predicted cistrome states with phenotypes. The random effect cistrome-wide association study (RECWAS), reevaluates the necessity of cistrome state prediction in CWAS. RECWAS utilizes either a linear model or marginal effect for initial feature selection, followed by kernel-based feature aggregation for association testing is introduced. Through simulations and analysis of prostate cancer data, a thorough evaluation of CWAS and RECWAS is conducted. The results suggest that RECWAS offers improved power compared to traditional CWAS, identifying additional genomic regions associated with prostate cancer. CWAS identified 102 significant regions, while RECWAS found 50 additional significant regions compared to CWAS, many of which are validated. Validation encompassed a range of biological evidence, including risk signals from the GWAS catalog, susceptibility genes from the DisGeNET database, and enhancer-domain scores. RECWAS consistently demonstrated improved performance over traditional CWAS in identifying genomic regions associated with prostate cancer. These findings demonstrate the benefits of incorporating kernel methods into CWAS and provide new insights for genetic discovery in complex diseases.
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Affiliation(s)
- Mengting Shao
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Min Tian
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Kaiyang Chen
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Hangjin Jiang
- Center for Data ScienceZhejiang UniversityHangzhou310058P. R. China
| | - Shuting Zhang
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Zhenghui Li
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Yan Shen
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Feng Chen
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
| | - Baixin Shen
- Department of UrologyThe Second Affiliated Hospital of Nanjing Medical UniversityNanjing210011P. R. China
| | - Chen Cao
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
- Department of UrologyThe Second Affiliated Hospital of Nanjing Medical UniversityNanjing210011P. R. China
| | - Ning Gu
- Key Laboratory for Bio‐Electromagnetic Environment and Advanced Medical TheranosticsSchool of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjing211166P. R. China
- Nanjing Key Laboratory for Cardiovascular Information and Health Engineering MedicineInstitute of Clinical MedicineNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjing210093P. R. China
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29
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Xie Y, Zhao Y, Zhou Y, Jiang Y, Zhang Y, Du J, Cai M, Fu J, Liu H. Shared Genetic Architecture Among Gastrointestinal Diseases, Schizophrenia, and Brain Subcortical Volumes. Schizophr Bull 2024; 50:1243-1254. [PMID: 38973257 PMCID: PMC11349026 DOI: 10.1093/schbul/sbae099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/09/2024]
Abstract
BACKGROUND AND HYPOTHESIS The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear. STUDY DESIGN Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms. STUDY RESULTS The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes. CONCLUSIONS These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases.
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Affiliation(s)
- Yingying Xie
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yao Zhao
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yujing Zhou
- Department of Radiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yurong Jiang
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yujie Zhang
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jiaojiao Du
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Mengjing Cai
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jilian Fu
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Huaigui Liu
- Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, China
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30
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Loosen SH, Mertens A, Klein I, Leyh C, Krieg S, Kandler J, Luedde T, Roderburg C, Kostev K. Association between Helicobacter pylori and its eradication and the development of cancer. BMJ Open Gastroenterol 2024; 11:e001377. [PMID: 39181567 PMCID: PMC11344509 DOI: 10.1136/bmjgast-2024-001377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 08/02/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is a gram-negative gastrointestinal pathogen that colonises the human stomach and is considered a major risk factor for gastric cancer and mucosa-associated lymphoid tissue lymphoma. Furthermore, H. pylori is a potential trigger of a wide spectrum of extragastric cancer entities, extraintestinal chronic inflammatory processes and autoimmune diseases. In the present study, we evaluated the association between H. pylori infection and its eradication with the development of subsequent gastrointestinal and non-gastrointestinal cancer. METHODS We identified 25 317 individuals with and 25 317 matched individuals without a diagnosis of H. pylori from the Disease Analyzer database (IQVIA). A subsequent cancer diagnosis was analysed using Kaplan-Meier and conditional Cox-regression analysis as a function of H. pylori and its eradication. RESULTS After 10 years of follow-up, 12.8% of the H. pylori cohort and 11.8% of the non-H. pylori cohort were diagnosed with cancer (p=0.002). Results were confirmed in regression analysis (HR: 1.11; 95% CI 1.04 to 1.18). Moreover, a non-eradicated H. pylori status (HR: 1.18; 95% CI 1.07 to 1.30) but not an eradicated H. pylori status (HR: 1.06; 95% CI 0.97 to 1.15) was associated with a subsequent diagnosis of cancer. In subgroup analyses, H. pylori eradication was negatively associated with bronchus and lung cancer (HR: 0.60; 95% CI 0.44 to 0.83). CONCLUSION Our data from a large outpatient cohort in Germany reveal a distinct association between H. pylori infection and the subsequent development of cancer. These data might help to identify patients at risk and support eradication strategies in the future.
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Affiliation(s)
- Sven Heiko Loosen
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Alexander Mertens
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
| | | | - Catherine Leyh
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Sarah Krieg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Jennis Kandler
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital of Düsseldorf, Düsseldorf, Germany
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31
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He W, Zhang Y. Analysis of factors associated with Helicobacter pylori infection in severe pancreatitis patients and its effect on patient's prognosis. Am J Transl Res 2024; 16:4011-4019. [PMID: 39262733 PMCID: PMC11384374 DOI: 10.62347/jkef1700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/06/2024] [Indexed: 09/13/2024]
Abstract
OBJECTIVE To analyze the factors related to Helicobacter pylori (Hp) infection in patients with severe acute pancreatitis (SAP) and to observe the effect of Hp on SAP, and to provide a reference for future clinical prevention and treatment of Hp infection in SAP. METHODS A retrospective analysis was performed on 77 SAP patients admitted to Pingxiang People's Hospital between January 2020 and February 2022, with 33 Hp-infected individuals as the Hp-positive group and the other 44 patients being without Hp infection served as the Hp-negative group. First, the related factors of Hp infection in SAP patients were analyzed with multiple Logistic regression. Subsequently, the Acute Physiology and Chronic Health Evaluation II (APACHE II), Bedside Index for Severity in Acute Pancreatitis (BISAP) and Modified CT Severity Index (MCTSI) scores, as well as the levels of C-reactive protein (CRP), white blood cell (WBC), procalcitonin (PCT) and immunoglobulins A/M/G (IgA, IgM, and IgG) were recorded for inter-group comparisons. The adverse reactions and hospitalization time were also recorded. Besides, a six-month follow-up was carried out after discharge, and patients' quality of life was evaluated using the Short-Form 36 Item Health Survey (SF-36). RESULTS Logistic regression analysis identified that history of Hp infection, long-term drinking, eating habits and history of biliary tract diseases were independent risk factors for Hp infection (all P<0.05). At 2 weeks after admission, higher APACHE II, BISAP and MCTSI scores were observed in Hp-positive group compared with Hp-negative group (all P<0.05). The Hp-positive group exhibited higher CRP, WBC and PCT levels while lower IgA, IgM and IgG levels during treatment compared to the Hp-negative group (all P<0.05). No difference was found in the incidence of adverse reactions between the two groups (P>0.05), but the hospitalization time of the Hp-positive group was significantly prolonged (P<0.05). The follow-up results determined better quality of life in the Hp-negative group, which resulted in higher SF-36 scores in various dimensions (P<0.05). CONCLUSION The history of Hp infection, long-term drinking, eating habits, and history of biliary tract diseases are all independent risk factors for Hp infection. Hp infection exacerbates disease progression of SAP, adversely influences patients' recovery, impairs their immune function, and compromises their prognoses.
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Affiliation(s)
- Wencheng He
- Department of Critical Medicine, Pingxiang People's Hospital Pingxiang 337055, Jiangxi, China
| | - Yonggen Zhang
- Department of Critical Medicine, Pingxiang People's Hospital Pingxiang 337055, Jiangxi, China
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32
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Chen W, Zhao Y, Lu H, Yi J, Li J, Song X, Zhang J, Yang S, Ni J, Wang Z, Shi Y, Ni Y, Zhang Z, Zhu S, Nie S, Liu L. Associations of dietary patterns with risk of gastrointestinal disorders: a prospective cohort study. Food Funct 2024; 15:8510-8520. [PMID: 39056582 DOI: 10.1039/d4fo01668h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Gastrointestinal (GI) disorders are highly prevalent and severely diminish life quality. It is yet unknown which dietary pattern is optimal for the prevention of GI disorders. Among 141 450 participants from UK Biobank with a median follow-up of 15 years, we comprehensively assessed 13 dietary patterns in relation to 6 GI disorders. Multivariable Cox proportional hazards models demonstrated that adherence to healthy diets was associated with lower risk of GI disorders, with the strongest associations observed for the Dietary Approaches to Stop Hypertension (DASH) diet (HRQ4 vs. Q1 = 0.85, 95% CI: 0.81, 0.88), the Alternate Mediterranean Diet (AMED) (HRQ4 vs. Q1 = 0.85, 95% CI: 0.81, 0.88), and the Alternate Healthy Eating Index-2010 (AHEI-2010) (HRQ4 vs. Q1 = 0.86, 95% CI: 0.82, 0.89). AHEI-2010 (HRs ranging from 0.76 to 0.90) and DASH (HRs ranging from 0.75 to 0.88) showed inverse associations with every individual GI disorder. Furthermore, comorbidities decreased significantly in number with higher AMED and DASH diet scores (P for trend <0.001). Finally, the associations of AHEI-2010, AMED and DASH with GI disorders diminished most intensely after removing the component of fruits or whole grains. The combined intake of fruits and whole grains was inversely associated with the risk of overall GI disorders (HRT3 vs. T1 = 0.89, 95% CI: 0.86, 0.93). In conclusion, AHEI-2010 and DASH were the most recommended dietary patterns for the prevention of GI disorders. Fruits and whole grains are the most significant contributors to the protective effect.
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Affiliation(s)
- Weiyi Chen
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Yingying Zhao
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Haojie Lu
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Jing Yi
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Jia Li
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Xuemei Song
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Jia Zhang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Shuaishuai Yang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Jingjing Ni
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Zhen Wang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Yuting Shi
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Yuxin Ni
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Zhihao Zhang
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Sijia Zhu
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Shaofa Nie
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
| | - Li Liu
- Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
- Hubei Provincial Clinical Research Center for Colorectal Cancer, Wuhan, Hubei, 430000, P.R. China
- Wuhan Clinical Research Center for Colorectal Cancer, Wuhan, Hubei, 430000, P.R. China
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Gravina AG, Pellegrino R, Iascone V, Palladino G, Federico A, Zagari RM. Impact of Helicobacter pylori Eradication on Inflammatory Bowel Disease Onset and Disease Activity: To Eradicate or Not to Eradicate? Diseases 2024; 12:179. [PMID: 39195178 PMCID: PMC11353643 DOI: 10.3390/diseases12080179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/23/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
Helicobacter pylori infection has significant epidemiological relevance due to the carcinogenic nature of this bacterium, which is potentially associated with cancer. When detected, it should ideally be eradicated using a treatment that currently involves a combination of gastric acid suppressors and multiple antibiotics. However, this treatment raises questions regarding efficacy and safety profiles in patients with specific comorbidities, including inflammatory bowel diseases (IBD). Eradication therapy for H. pylori includes components associated with adverse gastrointestinal events, such as Clostridioides difficile colitis. This necessitates quantifying this risk through dedicated studies to determine whether this antimicrobial treatment could be significantly associated with IBD relapse or exacerbation of pre-existing IBD, as well as whether it could potentially lead to the de novo onset of IBD. Although the available evidence is reassuring about the safety of eradication therapy in patients with IBD, it is limited, and there are no specific recommendations for this particular situation in the leading international IBD and H. pylori guidelines. Therefore, studies need to evaluate the efficacy and safety profiles of the available antimicrobial regimens for H. pylori eradication in patients with IBD, both in clinical trial settings and in real-life studies.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Raffaele Pellegrino
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Veronica Iascone
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Esophagus and Stomach Organic Diseases Unit, IRCSS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Giovanna Palladino
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Rocco Maurizio Zagari
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
- Esophagus and Stomach Organic Diseases Unit, IRCSS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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Tian Y, Zi J, Hu Y, Zeng Y, Li H, Luo H, Xiong J. Shared and Unique Genetic Links between Neuroticism and Gastrointestinal Tract Diseases. Depress Anxiety 2024; 2024:5515448. [PMID: 40226707 PMCID: PMC11919111 DOI: 10.1155/2024/5515448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 04/02/2024] [Accepted: 06/10/2024] [Indexed: 04/15/2025] Open
Abstract
Objective Association between neuroticism and gastrointestinal tract (GIT) diseases may not be attributable to the genetic overlaps between neuroticism and psychiatric disorders. We aim to explore the genetic links and mechanisms of neuroticism and GIT diseases. Materials and Methods We obtained European genome-wide association data of neuroticism (n = 390,278) or subclusters (depressed, n = 357,957; worry, n = 348,219) and six GIT diseases: gastroesophageal reflux disease (GERD, n = 456,327), inflammatory bowel disease (IBD, n = 456,327), peptic ulcer disease (PUD, n = 456,327), irritable bowel syndrome (IBS, n = 486,601), Crohn's disease (CD, n = 20,883), and ulcerative colitis (UC, n = 21,895). We performed genetic correlation analysis (high-definition likelihood method and cross-trait linkage disequilibrium score regression), pairwise pleiotropic analysis, single nucleic acid polymorphism annotation, Bayesian colocalization, gene-level analysis, transcriptome-wide association analysis, and gene set enrichment analysis. Results Neuroticism and its subclusters are associated with most GIT diseases (15 of 18 trait-pairs). GERD and PUD were highly correlated with depressed affect. We identified pleiotropic loci 11q23.2 (mapped gene: NCAM1/DRD2) and 18q12.2 (mapped gene: CELF4) in neuroticism and IBS/GERD, supporting the genetic overlap between neuroticism and depression. We found that 16q12.1 (mapped gene: NKD1/ZNF423/NOD2) and 2q37.1 (mapped gene: ATG16L1/SP140) are only highlighted in depressed/neuroticism CD, revealing pleiotropic loci with dissimilarities between neuroticism and different GIT diseases. MR analysis suggested that genetic liability to neuroticism is associated with increased risks of IBS, PUD, and GERD. Conclusion Our findings document the genetic links between neuroticism and six GIT diseases, highlighting the genetic overlaps and heterogeneity between neuroticism and psychiatric disorders in the context of gastrointestinal disorders. Both the shared and unique pleiotropic loci identified between neuroticism and different GIT diseases could facilitate mechanistic understandings and may stimulate further translational implications.
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Affiliation(s)
- Ye Tian
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jing Zi
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yifan Hu
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Yaxian Zeng
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Haoqi Li
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Hang Luo
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jingyuan Xiong
- Department of Occupational and Environmental Health, Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
- Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu 610041, China
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Chen H, Zhang L, Li Y, Meng X, Chi Y, Liu M. Gut Microbiota and Its Metabolites: The Emerging Bridge Between Coronary Artery Disease and Anxiety and Depression? Aging Dis 2024; 16:1265-1284. [PMID: 39012662 PMCID: PMC12096936 DOI: 10.14336/ad.2024.0538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 06/19/2024] [Indexed: 07/17/2024] Open
Abstract
The increasing studies indicated that cardiovascular diseases, such as coronary artery disease (CAD), usually induce and exacerbate psychological problems, including anxiety and depression. These psychological issues are admitted as independent risk factors of heart disease as well. The interaction between CAD and anxiety and depression deteriorates the development and prognosis of CAD, which severely threatens the quality of life of patients. Although the existing mechanisms revealed the pathological relationship between CAD and anxiety and depression, there are few studies investigating the correlation between CAD and anxiety and depression from the aspect of gut microbiota (GM) and its metabolites. Therefore, in this review, we summarized whether GM and its metabolites are the emergent bridge between CAD and anxiety and depression. The results showed that there are four kinds of jointly up-regulated bacteria (i.e., Staphylococcus, Escherichia coli, Helicobacter pylori, and Shigella) and five kinds of jointly down-regulated bacteria (i.e., Prevotella, Lactobacillus, Faecalibacterium prausnitzii, Collinsella, and Bifidobacterium) in CAD as well as anxiety and depression. In addition, in CAD and anxiety and depression, the dysbiosis of the former four kinds of bacterium frequently leads to the outburst of inflammatory response, and the dysbiosis of the latter five kinds of bacterium is usually related to the metabolic abnormality of short-chain fatty acids, bile acids, and branched-chain amino acids. Therefore, we believe that GM and its metabolites act as the emergent bridge between CAD and anxiety and depression. The findings of this review provide novel insights and approaches for the clinical treatment of patients with both CAD and anxiety and depression.
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Affiliation(s)
- Haiyang Chen
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Lijun Zhang
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Yanwei Li
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
- School of Clinical Medicine, Henan University, Kaifeng, China.
| | - Xiangxi Meng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Yunpeng Chi
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Meiyan Liu
- Department of Psycho-cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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Adewuyi EO, Porter T, O'Brien EK, Olaniru O, Verdile G, Laws SM. Genome-wide cross-disease analyses highlight causality and shared biological pathways of type 2 diabetes with gastrointestinal disorders. Commun Biol 2024; 7:643. [PMID: 38802514 PMCID: PMC11130317 DOI: 10.1038/s42003-024-06333-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 05/15/2024] [Indexed: 05/29/2024] Open
Abstract
Studies suggest links between diabetes and gastrointestinal (GI) traits; however, their underlying biological mechanisms remain unclear. Here, we comprehensively assess the genetic relationship between type 2 diabetes (T2D) and GI disorders. Our study demonstrates a significant positive global genetic correlation of T2D with peptic ulcer disease (PUD), irritable bowel syndrome (IBS), gastritis-duodenitis, gastroesophageal reflux disease (GERD), and diverticular disease, but not inflammatory bowel disease (IBD). We identify several positive local genetic correlations (negative for T2D - IBD) contributing to T2D's relationship with GI disorders. Univariable and multivariable Mendelian randomisation analyses suggest causal effects of T2D on PUD and gastritis-duodenitis and bidirectionally with GERD. Gene-based analyses reveal a gene-level genetic overlap between T2D and GI disorders and identify several shared genes reaching genome-wide significance. Pathway-based study implicates leptin (T2D - IBD), thyroid, interferon, and notch signalling (T2D - IBS), abnormal circulating calcium (T2D - PUD), cardiovascular, viral, proinflammatory and (auto)immune-mediated mechanisms in T2D and GI disorders. These findings support a risk-increasing genetic overlap between T2D and GI disorders (except IBD), implicate shared biological pathways with putative causality for certain T2D - GI pairs, and identify targets for further investigation.
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Affiliation(s)
- Emmanuel O Adewuyi
- Centre for Precision Health, Edith Cowan University, Joondalup, 6027, Western, Australia.
- Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, 6027, Western, Australia.
| | - Tenielle Porter
- Centre for Precision Health, Edith Cowan University, Joondalup, 6027, Western, Australia
- Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, 6027, Western, Australia
- Curtin Medical School, Curtin University, Bentley, 6102, Western, Australia
| | - Eleanor K O'Brien
- Centre for Precision Health, Edith Cowan University, Joondalup, 6027, Western, Australia
- Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, 6027, Western, Australia
| | - Oladapo Olaniru
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, UK
| | - Giuseppe Verdile
- Curtin Medical School, Curtin University, Bentley, 6102, Western, Australia
- Curtin Health Innovation Research Institute, Curtin University, Bentley, 6102, Western, Australia
| | - Simon M Laws
- Centre for Precision Health, Edith Cowan University, Joondalup, 6027, Western, Australia.
- Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, 6027, Western, Australia.
- Curtin Medical School, Curtin University, Bentley, 6102, Western, Australia.
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Camilleri M, Jencks K. Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets and metabolism. Expert Opin Drug Metab Toxicol 2024; 20:319-332. [PMID: 38785066 PMCID: PMC11139426 DOI: 10.1080/17425255.2024.2349716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/26/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION Medications are frequently prescribed for patients with irritable bowel syndrome (IBS) or disorders of gut brain interaction. The level of drug metabolism and modifications in drug targets determine medication efficacy to modify motor or sensory function as well as patient response outcomes. AREAS COVERED The literature search included PubMed searches with the terms: pharmacokinetics, pharmacogenomics, epigenetics, clinical trials, irritable bowel syndrome, disorders of gut brain interaction, and genome-wide association studies. The main topics covered in relation to irritable bowel syndrome were precision medicine, pharmacogenomics related to drug metabolism, pharmacogenomics related to mechanistic targets, and epigenetics. EXPERT OPINION Pharmacogenomics impacting drug metabolism [CYP 2D6 (cytochrome P450 2D6) or 2C19 (cytochrome P450 2C19)] is the most practical approach to precision medicine in the treatment of IBS. Although there are proof of concept studies that have documented the importance of genetic modification of transmitters or receptors in altering responses to medications in IBS, these principles have rarely been applied in patient response outcomes. Genome-wide association (GWAS) studies have now documented the association of symptoms with genetic variation but not the evaluation of treatment responses. Considerably more research, particularly focused on patient response outcomes and epigenetics, is essential to impact this field in clinical medicine.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Kara Jencks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Zhang J, Shi X, Wang Y. Exploring causality in the association between gut microbiota and irritable bowel syndrome risk: a large Mendelian randomization study. Aging (Albany NY) 2024; 16:7448-7459. [PMID: 38669090 PMCID: PMC11087118 DOI: 10.18632/aging.205771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 03/18/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND In the past, some observational studies have highlighted the correlation between gut microbiota and irritable bowel syndrome (IBS). However, it is still unknown if the composition of gut microbiota shows a causal effect on the risk of IBS. AIM To conduct Mendelian randomization (MR) analysis of the samples to study the probable causal relationship between the gut microbiota, their taxonomic groups, and the risk of IBS. MATERIALS AND METHODS In this study, the summarized data regarding 211 gut microbiota and their IBS genome-wide association studies (GWAS) were collected from public databases. The causal estimates were determined using five MR techniques, where Inverse Variance Weighted (IVW) regression was employed as the major MR technique. Herein, MR-PRESSO and MR-Egger intercept tests were conducted to prevent horizontal pleiotropy. Cochran's Q test was used to evaluate heterogeneity using the IVW and MR-Egger techniques. RESULTS IVW results showed that gut microbes, belonging to Class Gammaproteobacteria (P = 0.04; OR = 1.45), Family XIII (P = 0.03; OR = 1.34), Family Prevotellaceae (P = 0.003; OR =1.24), and Lachnospiraceae UCG004 (P = 0.049; OR = 1.19) increased the risk of IBS, while Alcaligenaceae (P = 0.03; OR = 0.83, 95% CI: 0.69-0.98) and Coprobacter (P = 0.02; OR = 0.86, 95% CI: 0.76-0.98) decreased the risk of IBS. CONCLUSIONS This study presented novel insights that highlighted the causal relationship between gut microbiota and IBS, and offered new treatment strategies for preventing or treating IBS.
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Affiliation(s)
- Jishi Zhang
- Department of General Surgery, Huangdao District People’s Hospital, Qingdao, Shandong, China
| | - Xinlin Shi
- Department of General Surgery, Huangdao District People’s Hospital, Qingdao, Shandong, China
| | - Yun Wang
- Department of Hepatology/Infectious Diseases, Huangdao District People’s Hospital, Qingdao, Shandong, China
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Camargo Tavares L, Lopera-Maya EA, Bonfiglio F, Zheng T, Sinha T, Zanchetta Marques F, Zhernakova A, Sanna S, D'Amato M. Rome III Criteria Capture Higher Irritable Bowel Syndrome SNP-Heritability and Highlight a Novel Genetic Link With Cardiovascular Traits. Cell Mol Gastroenterol Hepatol 2024; 18:101345. [PMID: 38643935 PMCID: PMC11176963 DOI: 10.1016/j.jcmgh.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 04/10/2024] [Accepted: 04/10/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND & AIMS Irritable bowel syndrome (IBS) shows genetic predisposition, and large-scale genome-wide association studies (GWAS) are emerging, based on heterogeneous disease definitions. We investigated the genetic architecture of IBS defined according to gold standard Rome Criteria. METHODS We conducted GWAS meta-analyses of Rome III IBS and its subtypes in 24,735 IBS cases and 77,149 asymptomatic control subjects from 2 independent European cohorts (UK Biobank and Lifelines). Single-nucleotide polymorphism (SNP)-based heritability (h2SNP) and genetic correlations (rg) with other traits were calculated. IBS risk loci were functionally annotated to identify candidate genes. Sensitivity and conditional analyses were conducted to assess impact of confounders. Polygenic risk scores were computed and tested in independent datasets. RESULTS Rome III IBS showed significant SNP-heritability (up to 13%) and similar genetic architecture across subtypes, including those with manifestations at the opposite ends of the symptom spectrum (rg = 0.48 between IBS-D and IBS-C). Genetic correlations with other traits highlighted commonalities with family history of heart disease and hypertension, coronary artery disease, and angina pectoris (rg = 0.20-0.45), among others. Four independent GWAS signals (P < 5×10-8) were detected, including 2 novel loci for IBS (rs2035380) and IBS-mixed (rs2048419) that had been previously associated with hypertension and coronary artery disease. Functional annotation of GWAS risk loci revealed genes implicated in circadian rhythm (BMAL1), intestinal barrier (CLDN23), immunomodulation (MFHAS1), and the cyclic adenosine monophosphate pathway (ADCY2). Polygenic risk scores allowed the identification of individuals at increased risk of IBS (odds ratio, 1.34; P = 1.1×10-3). CONCLUSIONS Rome III Criteria capture higher SNP-heritability than previously estimated for IBS. The identified link between IBS and cardiovascular traits may contribute to the delineation of alternative therapeutic strategies, warranting further investigation.
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Affiliation(s)
| | | | - Ferdinando Bonfiglio
- Department of Chemical, Materials and Production Engineering, University of Naples Federico II, Naples, Italy; CEINGE Biotecnologie Avanzate s.c.ar.l., Naples, Italy
| | - Tenghao Zheng
- School of Biological Sciences, Monash University, Clayton, Australia
| | - Trishla Sinha
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Francine Zanchetta Marques
- School of Biological Sciences, Monash University, Clayton, Australia; Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Alexandra Zhernakova
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Serena Sanna
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Institute for Genetic and Biomedical Research, National Research Council, Cagliari, Italy
| | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Department of Medicine and Surgery, LUM University, Casamassima, Italy
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Li J, He C, Ying J, Hua B, Yang Y, Chen W, Liu W, Ye D, Sun X, Mao Y, Chen K. Air pollutants, genetic susceptibility, and the risk of incident gastrointestinal diseases: A large prospective cohort study. ENVIRONMENTAL RESEARCH 2024; 247:118182. [PMID: 38218525 DOI: 10.1016/j.envres.2024.118182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/10/2023] [Accepted: 01/10/2024] [Indexed: 01/15/2024]
Abstract
A comprehensive overview of the associations between air pollution and the risk of gastrointestinal (GI) diseases has been lacking. We aimed to examine the relationships of long-term exposure to ambient particulate matter (PM) with aerodynamic diameter ≤2.5 μm (PM2.5), 2.5-10 μm (PMcoarse), ≤10 μm (PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx), with the risk of incident GI diseases, and to explore the interplay between air pollution and genetic susceptibility. A total of 465,703 participants free of GI diseases in the UK Biobank were included at baseline. Land use regression models were employed to calculate the residential air pollutants concentrations. Cox proportional hazard models were used to evaluate the associations of air pollutants with the risk of GI diseases. The dose-response relationships of air pollutants with the risk of GI diseases were evaluated by restricted cubic spline curves. We found that long-term exposure to ambient air pollutants was positively associated with the risk of peptic ulcer (PM2.5 : Q4 vs. Q1: hazard ratio (HR) 1.272, 95% confidence interval (CI) 1.179-1.372, NO2: 1.220, 1.131-1.316, and NOx: 1.277, 1.184-1.376) and chronic gastritis (PM2.5: 1.454, 1.309-1.616, PM10 : 1.232, 1.112-1.366, NO2: 1.456, 1.311-1.617, and NOx: 1.419, 1.280-1.574) after Bonferroni correction. Participants with high genetic risk and high air pollution exposure had the highest risk of peptic ulcer, compared to those with low genetic risk and low air pollution exposure (PM2.5: HR 1.558, 95%CI 1.384-1.754, NO2: 1.762, 1.395-2.227, and NOx: 1.575, 1.403-1.769). However, no significant additive or multiplicative interaction between air pollution and genetic risk was found. In conclusion, long-term exposure to ambient air pollutants was associated with increased risk of peptic ulcer and chronic gastritis.
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Affiliation(s)
- Jiayu Li
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chunlei He
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiacheng Ying
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Baojie Hua
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yudan Yang
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weiwei Chen
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wei Liu
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ding Ye
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaohui Sun
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Yingying Mao
- Department of Epidemiology, School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Kun Chen
- Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Wu H, Li J, Li F, Lun W. Causal association of gastroesophageal reflux disease on irritable bowel syndrome: a two-sample Mendelian randomization study. Front Genet 2024; 15:1328327. [PMID: 38601073 PMCID: PMC11004226 DOI: 10.3389/fgene.2024.1328327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 03/11/2024] [Indexed: 04/12/2024] Open
Abstract
Background Recently, observational studies have reported that gastroesophageal reflux disease (GERD) is commonly associated with irritable bowel syndrome (IBS), but the causal relationship is unclear. Methods We conducted a two-sample Mendelian randomization study using summary data from genome-wide association studies (GWASs) to explore a causal relationship between GERD (N cases = 129,080) and IBS (N cases = 4,605) of European ancestry. Furthermore, the inverse-variance weighted (IVW) method and a series of sensitivity analyses were used to assess the accuracy and confidence of our results. Results We found a significant association of GERD with IBS (NSNP = 74; OR: 1.375; 95% CI: 1.164-1.624; p < 0.001). Reverse MR analysis showed no evidence of a causal association for IBS with GERD (NSNP = 6; OR: 0.996; 95% CI: 0.960-1.034; p = 0.845). Conclusion This study provides evidence that the presence of GERD increases the risk of developing IBS, and it is observed from the reverse MR results that IBS did not increase the risk of GERD.
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Affiliation(s)
- Huihuan Wu
- Department of Gastroenterology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, Guangdong, China
| | - Jingwei Li
- Department of Gastroenterology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - FeiFei Li
- Department of Cardiology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Weijian Lun
- Department of Gastroenterology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, Guangdong, China
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Fischbach W, Bornschein J, Hoffmann JC, Koletzko S, Link A, Macke L, Malfertheiner P, Schütte K, Selgrad DM, Suerbaum S, Schulz C. Update S2k-Guideline Helicobacter pylori and gastroduodenal ulcer disease of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:261-321. [PMID: 38364851 DOI: 10.1055/a-2181-2225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2024]
Affiliation(s)
| | - Jan Bornschein
- Translational Gastroenterology Unit John, John Radcliffe Hospital Oxford University Hospitals, Oxford, United Kingdom
| | - Jörg C Hoffmann
- Medizinische Klinik I, St. Marien- und St. Annastiftskrankenhaus, Ludwigshafen, Deutschland
| | - Sibylle Koletzko
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU-Klinikum Munich, Munich, Deutschland
- Department of Paediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, 10-719 Olsztyn, Poland
| | - Alexander Link
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburg, Magdeburg, Deutschland
| | - Lukas Macke
- Medizinische Klinik und Poliklinik II Campus Großhadern, Universitätsklinikum Munich, Munich, Deutschland
- Deutsches Zentrum für Infektionsforschung, Standort Munich, Munich, Deutschland
| | - Peter Malfertheiner
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburg, Magdeburg, Deutschland
- Medizinische Klinik und Poliklinik II Campus Großhadern, Universitätsklinikum Munich, Munich, Deutschland
| | - Kerstin Schütte
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Niels-Stensen-Kliniken Marienhospital Osnabrück, Osnabrück, Deutschland
| | - Dieter-Michael Selgrad
- Medizinische Klinik Gastroenterologie und Onkologie, Klinikum Fürstenfeldbruck, Fürstenfeldbruck, Deutschland
- Klinik für Innere Medizin 1, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Sebastian Suerbaum
- Universität Munich, Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Munich, Deutschland
- Nationales Referenzzentrum Helicobacter pylori, Pettenkoferstr. 9a, 80336 Munich, Deutschland
- Deutsches Zentrum für Infektionsforschung, Standort Munich, Munich, Deutschland
| | - Christian Schulz
- Medizinische Klinik und Poliklinik II Campus Großhadern, Universitätsklinikum Munich, Munich, Deutschland
- Deutsches Zentrum für Infektionsforschung, Standort Munich, Munich, Deutschland
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Liao OL, Xie SY, Ye J, Du Q, Lou GC. Association between inflammatory bowel disease and all-cause dementia: A two-sample Mendelian randomization study. World J Psychiatry 2024; 14:15-25. [PMID: 38327884 PMCID: PMC10845233 DOI: 10.5498/wjp.v14.i1.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/03/2023] [Accepted: 12/26/2023] [Indexed: 01/19/2024] Open
Abstract
BACKGROUND Numerous observational studies have documented a correlation between inflammatory bowel disease (IBD) and an increased risk of dementia. However, the causality of their associations remains elusive. AIM To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization (MR) method. METHODS Genetic variants extracted from the large genome-wide association study (GWAS) for IBD (the International IBD Genetics Consortium, n = 34652) were used to identify the causal link between IBD and dementia (FinnGen, n = 306102). The results of the study were validated via another IBD GWAS (United Kingdom Biobank, n = 463372). Moreover, MR egger intercept, MR pleiotropy residual sum and outlier, and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity. Finally, multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia, with the inverse variance wei-ghted approach adopted as the primary analysis. RESULTS The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS. No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted [odds ratio (OR) = 0.980, 95%CI : 0.942-1.020, P value = 0.325], weighted median (OR = 0.964, 95%CI : 0.914-1.017, P value = 0.180), and MR-Egger (OR = 0.963, 95%CI : 0.867-1.070, P value = 0.492) approaches. Consistent results were observed in validation analyses. Reverse MR analysis also showed no effect of dementia on the development of IBD. Furthermore, MR analysis suggested that IBD and its subtypes did not causally affect all-cause dementia and its four subtypes, including dementia in Alzheimer's disease, vascular dementia, dementia in other diseases classified elsewhere, and unspecified dementia. CONCLUSION Taken together, our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes. Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.
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Affiliation(s)
- Ou-Lan Liao
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Si-Yuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Jun Ye
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Qin Du
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Department of Gastroenterology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Guo-Chun Lou
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
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Wang W, Wang M, Peng H, Huang J, Wu T. Association of major depressive disorder and increased risk of irritable bowel syndrome: A population-based cohort study and a two-sample Mendelian randomization study in the UK biobank. J Affect Disord 2024; 345:419-426. [PMID: 37852586 DOI: 10.1016/j.jad.2023.10.111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/08/2023] [Accepted: 10/15/2023] [Indexed: 10/20/2023]
Abstract
OBJECTIVE To examine the association between depression and the risk of incident irritable bowel syndrome (IBS). METHODS We included 98,564 participants free of IBS in the UK biobank. Depression was defined by self-report and Hospital Episode Statistics. The main outcome was incident IBS. Cox proportional hazards regression models and two-sample mendelian randomization were performed to estimate the risk of incident IBS. RESULTS Among 98,564 participants, 8770 (8.9 %) participants had a depression diagnosis at baseline. During a median of 12.9-year follow-up, 224 cases of incident IBS were identified in patients with depression (2.0 per 1000 person-years), compared with 1625 cases in reference individuals (1.5 per 1000 person-years). After adjustment, the hazard ratio of incident IBS associated with depression was 1.26 (95 % CI: 1.01-1.41). Sensitivity analysis indicated similar results. The two-sample mendelian randomization based on the inverse variance weighted method provided evidence for the harmful role of depression in an increased risk of IBS with an OR of 1.57 (95 % CI: 1.24-1.99). LIMITATIONS Depression was mainly measured by self-report online CIDI-SF in the current study, rather than the gold diagnostic criteria including clinical structured interview, which might lead to potential measurement error. Lifestyle behaviors might change during the long-term follow-up, and time-varying covariates (i.e., smoking and alcohol status) may bias the estimate. CONCLUSIONS Depression is associated with an increased risk of incident IBS. Further studies are warranted to confirm the role of depression on incident IBS and elucidate the underlying mechanisms.
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Affiliation(s)
- Weiwei Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders, National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, 5 Ankang Lane, Xicheng District, Beijing 100088, China
| | - Mengying Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing 100191, China
| | - Hexiang Peng
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing 100191, China
| | - Jie Huang
- School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China.
| | - Tao Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Key Laboratory of Epidemiology of Major Diseases, Peking University, Ministry of Education, Beijing 100191, China.
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Liu M, Fan G, Liu H. Integrated bioinformatics and network pharmacology identifying the mechanisms and molecular targets of Guipi Decoction for treatment of comorbidity with depression and gastrointestinal disorders. Metab Brain Dis 2024; 39:183-197. [PMID: 37847347 DOI: 10.1007/s11011-023-01308-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/04/2023] [Indexed: 10/18/2023]
Abstract
BACKGROUND Guipi decoction (GPD) not only improves gastrointestinal (GI) function, but also depressive mood. The bioinformatics study aimed to reveal potential crosstalk genes and related pathways between depression and GI disorders. A network pharmacology approach was used to explore the molecular mechanisms and potential targets of GPD for the simultaneous treatment of depression comorbid GI disorders. METHODS Differentially expressed genes (DEGs) of major depressive disorder (MDD) were identified based on GSE98793 and GSE19738, and GI disorders-related genes were screened from the GeneCards database. Overlapping genes between MDD and GI disorders were obtained to identify potential crosstalk genes. Protein-protein interaction (PPI) network was constructed to screen for hub genes, signature genes were identified by LASSO regression analysis, and single sample gene set enrichment analysis (ssGSEA) was performed to analyze immune cell infiltration. In addition, based on the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, we screened the active ingredients and targets of GPD and identified the intersection targets of GPD with MDD and GI disorder-related genes, respectively. A "component-target" network was constructed using Cytoscape, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. RESULTS The MDD-corrected dataset contained 2619 DEGs, and a total of 109 crosstalk genes were obtained. 14 hub genes were screened, namely SOX2, CRP, ACE, LEP, SHH, CDH2, CD34, TNF, EGF, BDNF, FN1, IL10, PPARG, and KIT. These genes were identified by LASSO regression analysis for 3 signature genes, including TNF, EGF, and IL10. Gamma.delta.T.cell was significantly positively correlated with all three signature genes, while Central.memory.CD4.T.cell and Central.memory.CD8.T.cell were significantly negatively correlated with EGF and TNF. GPD contained 134 active ingredients and 248 targets, with 41 and 87 relevant targets for the treatment of depression and GI disorders, respectively. EGF, PPARG, IL10 and CRP overlap with the hub genes of the disease. CONCLUSION We found that GPD may regulate inflammatory and oxidative stress responses through EGF, PPARG, IL10 and CRP targets, and then be involved in the treatment of both depression and GI disorders.
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Affiliation(s)
- Menglin Liu
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Genhao Fan
- Tianjin University of Chinese Medicine, Tianjin, China
| | - Huayi Liu
- Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China.
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Wang R, Tang S, Huang L, Chen Z, Li Y, Liu S, Song F, Men L, Liu Z. Integrated ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry-based components analysis and network pharmacology strategy of Gancao Xiexin Decoction in treating gastric ulcer. J Sep Sci 2024; 47:e2300751. [PMID: 38234032 DOI: 10.1002/jssc.202300751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/15/2023] [Accepted: 12/18/2023] [Indexed: 01/19/2024]
Abstract
Gancao Xiexin Decoction (GCXXD) is a traditional Chinese decoction that is often used in treating gastric ulcers. However, the substance basis and mechanism of action remain unclear. In this study, in vivo and in vitro components of GCXXD were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry. The compound Discover platform was used to ultimately enable rapid identification of compounds. Acquire X intelligent data acquisition technology software was innovatively adopted. In the process of collecting drug-containing plasma, all components detected in blank plasma samples were excluded to eliminate the interference and influence of endogenous components in plasma, making the analysis results more accurate and reliable. At the same time, the possibility of selecting precursor parent ions with low concentration levels within the chromatographic peak can be increased, improving the coverage and integrality of the detection of components in vivo. Also, the targeted network pharmacology strategy combined with molecular docking was established to explore the mechanism of GCXXD in treating gastric ulcers. As a result, 113 components were identified, 41 of which could enter the bloodstream and exert therapeutic effects in vivo. The main effective components are glycyrrhizic acid, 6-gingerol, jatrorrhizine, wogonin, palmatine, and liquiritigenin, main targets in vivo were related to ALB, IL6, and VEGF, which play an important role in anti-inflammatory and promoting angiogenesis. In summary, this study adopted a comprehensive analysis strategy to reveal the pharmacodynamic material basis and mechanism of GCXXD against gastric ulcers, providing a scientific basis for its clinical application.
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Affiliation(s)
- Rongjin Wang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Shoufang Tang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Limei Huang
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Ziyi Chen
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Yuwen Li
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
| | - Shu Liu
- National Center of Mass Spectrometry in Changchun and Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Fengrui Song
- National Center of Mass Spectrometry in Changchun and Jilin Provincial Key Laboratory of Chinese Medicine Chemistry and Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
| | - Lihui Men
- College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Zhongying Liu
- School of Pharmaceutical Sciences, Jilin University, Changchun, China
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Andriolo IRL, Longo B, de Melo DM, de Souza MM, Prediger RD, da Silva LM. Gastrointestinal Issues in Depression, Anxiety, and Neurodegenerative Diseases: A Systematic Review on Pathways and Clinical Targets Implications. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:1371-1391. [PMID: 38500273 DOI: 10.2174/0118715273289138240306050532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/26/2024] [Accepted: 02/06/2024] [Indexed: 03/20/2024]
Abstract
INTRODUCTION Multiple illnesses commonly involve both the Central Nervous System (CNS) and the Gastrointestinal Tract (GI) simultaneously. Consistent evidence suggests that neurological disorders impair GI tract function and worsen the symptomatology and pathophysiology of digestive disorders. On the other hand, it has been proposed that early functional changes in the GI tract contribute to the genesis of several CNS illnesses. Additionally, the role played by the gut in these diseases can be seen as a paradigm for how the gut and the brain interact. METHODS We mentioned significant GI symptoms and discussed how the GI tract affects central nervous system illnesses, including depression, anxiety, Alzheimer's disease, and Parkinson's disease in this study. We also explored potential pathophysiological underpinnings and novel targets for the creation of future therapies targeted at gut-brain connections. RESULTS & DISCUSSION In this situation, modulating the gut microbiota through the administration of fecal microbiota transplants or probiotics may represent a new therapeutic option for this population, not only to treat GI problems but also behavioral problems, given the role that dysbiosis and leaky gut play in many neurological disorders. CONCLUSION Accurate diagnosis and treatment of co-existing illnesses also require coordination between psychiatrists, neurologists, gastroenterologists, and other specialties, as well as a thorough history and thorough physical examination.
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Affiliation(s)
| | - Bruna Longo
- Graduate Program in Pharmaceutical Sciences, University of Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Dayse Machado de Melo
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Márcia Maria de Souza
- Graduate Program in Pharmaceutical Sciences, University of Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Rui Daniel Prediger
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Luisa Mota da Silva
- Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil
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Jiang M, Hao X, Jiang Y, Li S, Wang C, Cheng S. Genetic and observational associations of lung function with gastrointestinal tract diseases: pleiotropic and mendelian randomization analysis. Respir Res 2023; 24:315. [PMID: 38102678 PMCID: PMC10724909 DOI: 10.1186/s12931-023-02621-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND The two-way communications along the gut-lung axis influence the immune function in both gut and lung. However, the shared genetic characteristics of lung function with gastrointestinal tract (GIT) diseases remain to be investigated. METHODS We first investigated the genetic correlations between three lung function traits and four GIT diseases. Second, we illustrated the genetic overlap by genome-wide pleiotropic analysis (PLACO) and further pinpointed the relevant tissue and cell types by partitioning heritability. Furthermore, we proposed pleiotropic genes as potential drug targets by drug database mining. Finally, we evaluated the causal relationships by epidemiologic observational study and Mendelian randomization (MR) analysis. RESULTS We found lung function and GIT diseases were genetically correlated. We identified 258 pleiotropic loci, which were enriched in gut- and lung-specific regions marked by H3K4me1. Among these, 16 pleiotropic genes were targets of drugs, such as tofacitinib and baricitinib targeting TYK2 for the treatment of ulcer colitis and COVID-19, respectively. We identified a missense variant in TYK2, exhibiting a shared causal effect on FEV1/FVC and inflammatory bowel disease (rs12720356, PPLACO=1.38 × 10- 8). These findings suggested TYK2 as a promising drug target. Although the epidemiologic observational study suggested the protective role of lung function in the development of GIT diseases, no causalities were found by MR analysis. CONCLUSIONS Our study suggested the shared genetic characteristics between lung function and GIT diseases. The pleiotropic variants could exert their effects by modulating gene expression marked by histone modifications. Finally, we highlighted the potential of pleiotropic analyses in drug repurposing.
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Affiliation(s)
- Minghui Jiang
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xingjie Hao
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yi Jiang
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Si Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Chaolong Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shanshan Cheng
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Hu JY, Lv M, Zhang KL, Qiao XY, Wang YX, Wang FY. Evaluating the causal relationship between human blood metabolites and gastroesophageal reflux disease. World J Gastrointest Oncol 2023; 15:2169-2184. [PMID: 38173433 PMCID: PMC10758654 DOI: 10.4251/wjgo.v15.i12.2169] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/01/2023] [Accepted: 10/30/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Gastroesophageal reflux disease (GERD) affects approximately 13% of the global population. However, the pathogenesis of GERD has not been fully elucidated. The development of metabolomics as a branch of systems biology in recent years has opened up new avenues for the investigation of disease processes. As a powerful statistical tool, Mendelian randomization (MR) is widely used to explore the causal relationship between exposure and outcome. AIM To analyze of the relationship between 486 blood metabolites and GERD. METHODS Two-sample MR analysis was used to assess the causal relationship between blood metabolites and GERD. A genome-wide association study (GWAS) of 486 metabolites was the exposure, and two different GWAS datasets of GERD were used as endpoints for the base analysis and replication and meta-analysis. Bonferroni correction is used to determine causal correlation features (P < 1.03 × 10-4). The results were subjected to sensitivity analysis to assess heterogeneity and pleiotropy. Using the MR Steiger filtration method to detect whether there is a reverse causal relationship between metabolites and GERD. In addition, metabolic pathway analysis was conducted using the online database based MetaboAnalyst 5.0 software. RESULTS In MR analysis, four blood metabolites are negatively correlated with GERD: Levulinate (4-oxovalerate), stearate (18:0), adrenate (22:4n6) and p-acetamidophenylglucuronide. However, we also found a positive correlation between four blood metabolites and GERD: Kynurenine, 1-linoleoylglycerophosphoethanolamine, butyrylcarnitine and guanosine. And bonferroni correction showed that butyrylcarnitine (odd ratio 1.10, 95% confidence interval: 1.05-1.16, P = 7.71 × 10-5) was the most reliable causal metabolite. In addition, one significant pathways, the "glycerophospholipid metabolism" pathway, can be involved in the pathogenesis of GERD. CONCLUSION Our study found through the integration of genomics and metabolomics that butyrylcarnitine may be a potential biomarker for GERD, which will help further elucidate the pathogenesis of GERD and better guide its treatment. At the same time, this also contributes to early screening and prevention of GERD. However, the results of this study require further confirmation from both basic and clinical real-world studies.
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Affiliation(s)
- Jia-Yan Hu
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Mi Lv
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Kun-Li Zhang
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Xi-Yun Qiao
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Yu-Xi Wang
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
| | - Feng-Yun Wang
- Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China
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Liu B, Qian Y, Li Y, Shen X, Ye D, Mao Y, Sun X. Circulating levels of cytokines and risk of inflammatory bowel disease: evidence from genetic data. Front Immunol 2023; 14:1310086. [PMID: 38149258 PMCID: PMC10750389 DOI: 10.3389/fimmu.2023.1310086] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 11/27/2023] [Indexed: 12/28/2023] Open
Abstract
Background Prior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research. Objective We aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach. Materials and methods We selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn's disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation. Results Genetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn's disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines. Conclusion Our study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.
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Affiliation(s)
- Bin Liu
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Yu Qian
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
- Diseases & Population (DaP) Geninfo Lab, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Yanan Li
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Xiangting Shen
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Ding Ye
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Yingying Mao
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
| | - Xiaohui Sun
- Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, China
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