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Taba N, Fischer K, Estonian Biobank Research Team, Org E, Aasmets O. A novel framework for assessing causal effect of microbiome on health: long-term antibiotic usage as an instrument. Gut Microbes 2025; 17:2453616. [PMID: 39849320 PMCID: PMC11776458 DOI: 10.1080/19490976.2025.2453616] [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: 02/28/2024] [Revised: 07/25/2024] [Accepted: 01/02/2025] [Indexed: 01/25/2025] Open
Abstract
Assessing causality is undoubtedly one of the key questions in microbiome studies for the upcoming years. Since randomized trials in human subjects are often unethical or difficult to pursue, analytical methods to derive causal effects from observational data deserve attention. As simple covariate adjustment is not likely to account for all potential confounders, the idea of instrumental variable (IV) analysis is worth exploiting. Here we propose a novel framework of antibiotic instrumental variable regression (AB-IVR) for estimating the causal relationships between microbiome and various diseases. We rely on the recent studies showing that antibiotic treatment has a cumulative long-term effect on the microbiome, resulting in individuals with higher antibiotic usage to have a more perturbed microbiome. We apply the AB-IVR method on the Estonian Biobank data and show that the microbiome has a causal role in numerous diseases including migraine, depression and irritable bowel syndrome. We show with a plethora of sensitivity analyses that the identified causal effects are robust and propose ways for further methodological developments.
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Affiliation(s)
- Nele Taba
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Krista Fischer
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
- Institute of Mathematics and Statistics, Faculty of Science and Technology, University of Tartu, Tartu, Estonia
| | | | - Elin Org
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Oliver Aasmets
- Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Song W, Shi J, Du M, Liang M, Zhou B, Liang L, Gao Y. Causal relationship between gut microbiota and lung squamous cell carcinoma: a bidirectional two-sample Mendelian randomization study. Postgrad Med J 2025; 101:526-534. [PMID: 39690971 DOI: 10.1093/postmj/qgae184] [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: 09/29/2024] [Revised: 11/23/2024] [Accepted: 12/03/2024] [Indexed: 12/19/2024]
Abstract
PURPOSE This study aims to explore the potential causal relationship between gut microbiota and lung squamous cell carcinoma (LUSC). METHODS A bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide association study (GWAS) data from gut microbiota and LUSC. Gut microbiota served as the exposure factor, with instrumental variables selected from a GWAS involving 18 340 participants. LUSC data were drawn from a European cohort including 29 266 LUSC cases and 56 450 controls. Inverse-variance weighted (IVW) method was used as the primary method, with the Benjamini-Hochberg method applied to adjust for multiple comparisons. An independent dataset (ieu-a-967, containing 3275 LUSC cases and 15 038 controls) was used for replication analysis to ensure robustness. RESULTS IVW analysis found that Butyricicoccus (OR = 0.79, 95% CI: 0.63-0.99, P = .042) and Coprobacter (OR = 0.85, 95% CI: 0.74-0.97, P = .018) were significantly protective against LUSC. In contrast, Victivallis (OR = 1.11, 95% CI: 1.00-1.23, P = .045) and Ruminococcus (OR = 1.28, 95% CI: 1.03-1.60, P = .028) increased LUSC risk. Replication analysis in the independent dataset confirmed significant associations for Ruminococcus and Coprobacter. No reverse causality or pleiotropy was detected. CONCLUSION This study provides evidence of a causal relationship between specific gut microbiota and LUSC risk, highlighting new microbial targets for potential prevention and treatment strategies in lung cancer. Key messages What is already known on this topic? Previous studies have suggested potential links between gut microbiota composition and the development of various cancers, including lung cancer. However, the exact causal relationship between specific gut microbiota and lung squamous cell carcinoma (LUSC) has remained unclear. Traditional observational studies have struggled to determine the direction of causality due to confounding factors, making further investigation necessary through more robust methods such as Mendelian randomization (MR). What this study adds? This bidirectional MR study provides novel genetic evidence indicating that certain gut microbiotas are causally associated with LUSC risk. Specifically, Butyricicoccus appears to reduce the risk of LUSC, while Victivallis increases the risk. These findings highlight the role of the gut-lung axis in LUSC and open up new avenues for exploring gut microbiota as potential modulators of lung cancer risk. How this study might affect research, practice, or policy? The implications of this study may significantly influence future research into cancer prevention strategies by targeting gut microbiota. Additionally, it could inform clinical practices aimed at modulating gut microbiota to lower the risk of LUSC, potentially influencing dietary or probiotic interventions to reduce cancer susceptibility. Furthermore, these results might shape public health policies that focus on the gut-lung axis as a novel avenue for cancer prevention and management.
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Affiliation(s)
- Weijian Song
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
| | - Jianwei Shi
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
| | - Minjun Du
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
| | - Mei Liang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
| | - Boxuan Zhou
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
| | - Linchuan Liang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
| | - Yushun Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing 100021, People's Republic of China
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Jiang GH, Li HY, Xie LJ, Fan JY, Li SY, Yu WQ, Xu YT, He ML, Jiang Y, Bai X, Zhou J, Wang X. Intestinal flora was associated with occurrence risk of chronic non-communicable diseases. World J Gastroenterol 2025; 31:103507. [PMID: 40124279 PMCID: PMC11924013 DOI: 10.3748/wjg.v31.i11.103507] [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: 11/25/2024] [Revised: 12/26/2024] [Accepted: 02/24/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND The intestinal flora (IF) has been linked to risks of non-communicable diseases, especially various cancers, stroke, and Alzheimer's disease. However, many uncertainties of these associations during different stages of growth, development, and aging still exist. Therefore, further in-depth explorations are warranted. AIM To explore the associations of the human IF with disease risks during different stages of growth, development, and aging to achieve more accurate and convincing conclusions. METHODS Cohort, cross-sectional, case-control, and Mendelian randomization studies published in the PubMed and Web of Science databases until December 31, 2023 were systematically reviewed to clarify the associations of the IF at the genus level with the risks of various non-communicable diseases, which were grouped in accordance with the 10th revision of the International Classification of Diseases. RESULTS In total, 57 studies were included to quantitatively examine the influence of the IF on the risks of 30 non-communicable diseases during different stages of growth, development, and aging. Population studies and Mendelian randomization studies confirmed positive associations of the abundances of Bifidobacterium and Ruminococcus with multiple sclerosis. CONCLUSION These findings contribute to a deeper understanding of the roles of the IF and provide novel evidence for effective strategies for the prevention and treatment of non-communicable diseases. In the future, it will be necessary to explore a greater variety of research techniques to uncover the specific mechanisms by which gut microbiota trigger diseases and conduct in-depth studies on the temporal relationship between microbiota alterations and diseases, so as to clarify the causal relationship more accurately.
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Affiliation(s)
- Guo-Heng Jiang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Yu Li
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lin-Jun Xie
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jing-Yuan Fan
- China Tobacco Sichuan Industry Co. Ltd., Technology Center, Chengdu 610101, Sichuan Province, China
| | - Shi-Yi Li
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wen-Qian Yu
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi-Ting Xu
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Meng-Lin He
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi Jiang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xuan Bai
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jin Zhou
- Department of Anorectal Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, Sichuan Province, China
| | - Xin Wang
- Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Zhou D, Zhang Z, Zhang J, Lai H, Zhou Q, Pei C. Causal Relationship Between Different Sleep Traits and Dental Caries: A Bidirectional Mendelian Randomization Study. Int J Behav Med 2025:10.1007/s12529-025-10350-5. [PMID: 39870962 DOI: 10.1007/s12529-025-10350-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2025] [Indexed: 01/29/2025]
Abstract
BACKGROUND Dental caries (DC) is a significant common disease of the oral cavity. Recently, researchers have focused more on the impact of poor sleep habits on the incidence and development of DC, which aroused our interest in the study of the correlation and causal relationship between sleep and dental caries. METHODS In this study, Linkage disequilibrium score (LDSC) regression method was used to found the genetic correlation between different sleep traits and DC, while bidirectional Mendelian randomization (MR) methods were used to explore the causal relationship. The main analysis of MR was inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). RESULTS In LDSC regression analysis, genetic correlations were found between chronotype, dozing, insomnia, sleep duration and DC (P = 0.002, P = 0.026, P = 7.233E-09, P = 0.012). However, when utilizing the TSMR method, no discernible casual relationships were found between chronotype, dozing, insomnia, sleep duration and DC (P = 0.832, P = 0.129, P = 0.822, P = 0.644). This result was further substantiated through the utilization of additional validation datasets. CONCLUSIONS Our study found no causal relationship between sleep traits and DC.
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Affiliation(s)
- Dan Zhou
- Department of Stomatology, Zhejiang Hospital, Hangzhou, China
| | - Zehan Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jianxing Zhang
- Department of Stomatology, Zhejiang Hospital, Hangzhou, China
| | - Heqing Lai
- Department of Stomatology, Zhejiang Hospital, Hangzhou, China
| | - Qing Zhou
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Chao Pei
- Department of Stomatology, Zhejiang Hospital, Hangzhou, China.
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Wei LQ, Song YB, Lan D, Miao XJ, Lin CY, Yang ST, Liu DH, Chi XJ. Impact of gout on colorectal cancer and its survival: a two-sample Mendelian randomization study. Discov Oncol 2024; 15:819. [PMID: 39708204 DOI: 10.1007/s12672-024-01714-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND The relationship between gout and colorectal cancer (CRC) remains unclear, emphasizing the need for additional research to clarify the potential cumulative effect of gout on CRC development. METHODS Leveraging a single nucleotide polymorphism-based genome-wide association study, the potential causal correlation between gout and CRC was initially analyzed using Mendelian randomization (MR). Subsequently, our analysis was expanded to include an assessment of patient survival, with the aim of evaluating the potential causal correlation between gout and CRC and the impact of gout on CRC survival outcomes. RESULTS According to MR findings, a substantial relationship was observed between gout and the incidence of CRC when CRC was used as the outcome (OR = 0.954, 95% CI = 0.915-0.995). These results indicate a negative relationship between gout and the likelihood of developing CRC. In addition, when evaluating the overall survival (OS) or cancer-specific survival (CSS) of patients with CRC as outcomes, gout exhibited a significant relationship with survival. The inverse variance weighting approach demonstrated a progressive enhancement in CRC survival with the cumulative impact of gout (OS: OR = 2.000 × 10-4, 95% CI = 1.560 × 10-7-0.292; CSS: OR = 2.200 × 10-5, 95% CI = 4.660 × 10-9-0.104). CONCLUSION As gout accumulates, it exerts an inhibitory influence on CRC, indicating a potential protective effect. This study provides robust evidence that can guide the development of future clinical treatment approaches and research priorities.
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Affiliation(s)
- Li-Qiang Wei
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Yi-Bei Song
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Dong Lan
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Xue-Jing Miao
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Chun-Yu Lin
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Shu-Ting Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Deng-He Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
| | - Xiao-Jv Chi
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Key Laboratory of Clinical Laboratory Medicine of Guangxi Department of Education, 6 Shuangyong Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
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Peng S, Liu M, Zeng Y, Wang L, Man Y. Exploring the gut-inflammation connection: A Mendelian randomization study on gut microbiota, inflammatory factors, and uterine fibroids risk. Medicine (Baltimore) 2024; 103:e40514. [PMID: 39809194 PMCID: PMC11596598 DOI: 10.1097/md.0000000000040514] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 10/25/2024] [Indexed: 01/16/2025] Open
Abstract
This study employs Mendelian randomization (MR) approach to investigate the potential causal association between genetic variants associated with gut microbiota, inflammatory factors, and the risk of uterine fibroids development. We extracted data on 211 types of gut microbiota, 91 inflammatory factors, and uterine fibroids occurrence from genome-wide association studies and applied the inverse-variance weighted (IVW) method for analysis. To further assess the robustness of our MR analysis, we conducted sensitivity tests including Cochrane's Q test, the MR-Egger intercept test, the MR-PRESSO global test, and a leave-one-out analysis. IVW analysis identified a potential causal association between 14 types of gut microbiota and 8 inflammatory factors with the risk of uterine fibroids. When using 91 inflammation-related proteins as the outcome variable, 13 proteins demonstrated a potential causal association with uterine fibroids risk (IVW, all P < .05). Additionally, the MR-Egger intercept and MR-PRESSO global tests indicated no evidence of horizontal pleiotropy (P > .05), and the leave-one-out analysis confirmed the robustness of the results. This MR approach suggests that specific gut microbiota and inflammatory factors may have a causal association with the development of uterine fibroids, shedding light on the pathogenesis of uterine fibroids and potentially identifying targets for future therapeutic interventions.
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Affiliation(s)
- Shaoyi Peng
- Department of Cardiology, The First People’s Hospital of Jiande, Hangzhou, China
| | - Miao Liu
- Department of Cardiology, Center Hospital of Shandong First Medical University, Jinan, China
| | - Yuhao Zeng
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lei Wang
- Department of Cardiology, Center Hospital of Shandong First Medical University, Jinan, China
| | - Yilong Man
- Department of Cardiology, Center Hospital of Shandong First Medical University, Jinan, China
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Zhou Z, Li W, Wu Y, Wang T, Zhang J, You L, Li H, Zheng C, Gao Y, Sun X. Bidirectional Mendelian randomization links gut microbiota to primary biliary cholangitis. Sci Rep 2024; 14:28301. [PMID: 39550468 PMCID: PMC11569131 DOI: 10.1038/s41598-024-79227-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: 12/12/2023] [Accepted: 11/07/2024] [Indexed: 11/18/2024] Open
Abstract
Primary biliary cholangitis (PBC) and gut microbiota (GM) are epidemiologically correlated but the causal inter-relationships remain poorly understood. We aim to explore the causal relationships between GM and PBC. Using the MiBioGen consortium, GWAS data for GM at the species level and the largest publicly available PBC GWAS data to date, we performed a bidirectional two-sample Mendelian randomization by the inverse variance weighted, MR-Egger, weighted median, weighted model and MR-PRESSO to elucidate the potential causal role of GM in PBC. To measure the heterogeneity of instrumental variables (IV), Cochran's Q statistic and MR-Egger intercept test were used. Genetically instrumented order Coriobacteriales (odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.30-3.66, P = 0.004) significantly increased the risk for PBC, while genetically driven class Deltaproteobacteria (OR = 0.52, 95% CI 0.36-0.74, P = 0.002) causally decrease the NAFLD risk. Reverse MR analysis showed no significant association between PBC and the two specific GM. However, it indicated that PBC progression significantly increases the abundance of the class Bacteroidia, order Bacteroidales, and phylum Bacteroidetes (OR = 1.02, 95% CI 1.002-1.03, P = 0.026), while decreasing the abundance of the genus Lachnospiraceae UCG010 (OR = 0.98, 95% CI 0.96-0.995, P = 0.026). Our study demonstrated that genetically driven order Coriobacteriales and class Deltaproteobacteria were causally related to PBC risk. This causality provided a new perspective on ameliorating PBC by modulating GM. Our study demonstrated that genetically driven order Coriobacteriales and class Deltaproteobacteria were causally related to PBC risk. PBC was causally related to the abundance of four GM taxa(class Bacteroidia, order Bacteroidales, phylum Bacteroidetes and genus Lachnospiraceae UCG010). This causality provided a new perspective on ameliorating PBC by modulating GM.
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Affiliation(s)
- Zhijia Zhou
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenxuan Li
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuelan Wu
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tao Wang
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinghao Zhang
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Liping You
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Haoran Li
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chao Zheng
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Yueqiu Gao
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Xuehua Sun
- Department of Hepatology, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Liu X, Liu L, Zhang J. Causal role of the pyrimidine deoxyribonucleoside degradation superpathway mediation in Guillain-Barré Syndrome via the HVEM on CD4 + and CD8 + T cells. Sci Rep 2024; 14:27418. [PMID: 39521826 PMCID: PMC11550458 DOI: 10.1038/s41598-024-78996-x] [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: 06/16/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
Immune system regulation is a key indicator of the gut microbiota (GM) influencing disease development. The causal role of the GM in Guillain-Barré syndrome (GBS) and whether it can be mediated by immune cells is unknown. Genome-wide association study (GWAS) summary statistics for the GM were obtained from the Dutch Microbiota Project (n = 7,738) and the FINRISK 2002 (FR02) cohort (n = 5,959). Inverse variance weighting method (IVW) were used as the main method to evaluate the causal relationship between GM and GBS. Subsequently, the mediating effects of 731 immune traits were evaluated. Additionally, we also executed the Bayesian Weighting algorithm for verification. Mendelian randomization (MR) analysis determined the protective effect of the pyrimidine deoxyribonucleoside degradation superpathway on GBS (IVW: P = 0.0019, OR = 0.4508). It is worth noting that in the causal effects of pyrimidine deoxyribonucleoside degradation superpathway on GBS, the mediated proportions of herpesvirus entry mediator (HVEM) ( HVEM on CM CD4 + , HVEM on naive CD4 + , HVEM on CD45RA - CD4 + , HVEM on CM CD8br) in the T cell maturation stage on GBS were -0.0398, -0.0452, -0.0414, -0.0425, accounting for 5.00%, 5.67%, 5.19% and 5.34% of the total effect. 11 types of intestinal bacteria might be involved in the pyrimidine deoxyriboside degradation superpathway, including Staphylococcus A fleurettii, AR31,CAG-274 sp000432155, Photobacterium, Acetobacteraceae, Dysgonomonadaceae, NK4A144,Leptospirae, CAG-81 sp000435795, Leptospirales and CAG-873 sp001701165. This study suggests that there is a causal relationship between pyrimidine deoxyribonucleoside degradation superpathway and GBS, which may be mediated by HVEM on CD4 + and CD8 + T cells. As a bidirectional molecular switch, HVEM plays an important role in T cell regulation. 11 intestinal flora were found to be involved in pyrimidine deoxyribonucleoside degradation superpathway, and their changes may be related to the occurrence of GBS. However, extensive research is still warranted before microbiome sequencing can be used for prevention and targeted treatment of GBS.
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Affiliation(s)
- Xianghua Liu
- Jining No. 1 People's Hospital, Jining, Shandong, China
| | - Lingling Liu
- Clinical Laboratory Department, Jiangnan University Medical Center, JUMC, Wuxi, Jiangsu, China
| | - Jiuchang Zhang
- The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
- Jining No. 1 People's Hospital, Jining, Shandong, China.
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9
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Wu C, Zhu Y, Xi H. Causation between the gut microbiota and inguinal hernia: a two-sample double-sided Mendelian randomization study. Sci Rep 2024; 14:20526. [PMID: 39227644 PMCID: PMC11372202 DOI: 10.1038/s41598-024-71253-1] [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: 03/11/2024] [Accepted: 08/26/2024] [Indexed: 09/05/2024] Open
Abstract
Inguinal hernias are the most common type of enterocele and are frequently caused by defects in the abdominal wall muscles in the groin area. Numerous animal models and human studies have shown that the gut microbiota is associated with skeletal muscle aging and loss. However, the causation between the gut microbiota and inguinal hernia remains unclear. To reveal the causal association between the gut microbiota and inguinal hernia, we conducted a two-sample double-sided Mendelian randomization analysis. We used genome-wide association analysis (GWAS) summary statistics of the gut microbiota from the MiBioGen consortium and GWAS statistics of inguinal hernia from the FinnGen R10 database. The causation between the gut microbiota and inguinal hernia was explored through the inverse variance weighted (IVW) method, MR Egger regression method, weighted median method, weighted model method, and simple model method. Sensitivity analysis was used to test whether the Mendelian randomization analysis results were reliable. Reverse Mendelian randomization was used to conduct effect analysis and sensitivity analysis using the entire gut microbiota as the outcome. The IVW results indicated that Verrucomicrobia, Lactobacilliales, Clostridiaceae1, Butyricococcus, Categorybacter, Hungatella, Odoribacter, and Olsenella had a direct negative causation with the gut microbiota. The reverse Mendelian Randomization results showed that Eubacterium brachygroup, Eubacterium eligensgroup, Eubacterium xylanophilumgroup, Coprococcus3, Ruminococcus1, and Senegalimassilia were directly related to inguinal hernia. The bilateral sensitivity analysis revealed no heterogeneity or horizontal pleiotropy. The results confirmed that 8 bacterial traits had a negative causation with inguinal hernia. Reverse MR analysis revealed a positive correlation between inguinal hernia and 6 bacterial traits. Modulating the diversity and components of the gut microbiota is envisaged to contribute to improving the incidence and prognosis of inguinal hernia.
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Affiliation(s)
- Changyuan Wu
- Department of Pediatrics, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Yujin Zhu
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Hongwei Xi
- Department of General Surgery, Shanxi Children's Hospital, Taiyuan, People's Republic of China.
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10
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Trivedi A, Bose D, Moffat K, Pearson E, Walsh D, Cohen D, Skupsky J, Chao L, Golier J, Janulewicz P, Sullivan K, Krengel M, Tuteja A, Klimas N, Chatterjee S. Gulf War Illness Is Associated with Host Gut Microbiome Dysbiosis and Is Linked to Altered Species Abundance in Veterans from the BBRAIN Cohort. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2024; 21:1102. [PMID: 39200711 PMCID: PMC11354743 DOI: 10.3390/ijerph21081102] [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: 06/10/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/02/2024]
Abstract
Gulf War Illness (GWI) is a debilitating condition marked by chronic fatigue, cognitive problems, pain, and gastrointestinal (GI) complaints in veterans who were deployed to the 1990-1991 Gulf War. Fatigue, GI complaints, and other chronic symptoms continue to persist more than 30 years post-deployment. Several potential mechanisms for the persistent illness have been identified and our prior pilot study linked an altered gut microbiome with the disorder. This study further validates and builds on our prior preliminary findings of host gut microbiome dysbiosis in veterans with GWI. Using stool samples and Multidimensional Fatigue Inventory (MFI) data from 89 GW veteran participants (63 GWI cases and 26 controls) from the Boston biorepository, recruitment, and integrative network (BBRAIN) for Gulf War Illness, we found that the host gut bacterial signature of veterans with GWI showed significantly different Bray-Curtis beta diversity than control veterans. Specifically, a higher Firmicutes to Bacteroidetes ratio, decrease in Akkermansia sp., Bacteroides thetaiotamicron, Bacteroides fragilis, and Lachnospiraceae genera and increase in Blautia, Streptococcus, Klebsiella, and Clostridium genera, that are associated with gut, immune, and brain health, were shown. Further, using MaAsLin and Boruta algorithms, Coprococcus and Eisenbergiella were identified as important predictors of GWI with an area under the curve ROC predictive value of 74.8%. Higher self-reported MFI scores in veterans with GWI were also significantly associated with an altered gut bacterial diversity and species abundance of Lachnospiraceae and Blautia. These results suggest potential therapeutic targets for veterans with GWI that target the gut microbiome and specific symptoms of the illness.
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Affiliation(s)
- Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.)
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.)
| | - Kelly Moffat
- CosmosID, Germantown, MD 20874, USA; (K.M.); (D.W.)
| | | | - Dana Walsh
- CosmosID, Germantown, MD 20874, USA; (K.M.); (D.W.)
| | - Devra Cohen
- Miami VA Healthcare System, Miami, FL 33125, USA;
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA;
| | - Jonathan Skupsky
- VA Research and Development, VA Long Beach Health Care, Long Beach, CA 90822, USA;
| | - Linda Chao
- San Francisco Veterans Affairs Health Care System, San Francisco, CA 94121, USA
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94143, USA
- Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA 94143, USA
| | - Julia Golier
- J. Peters VA Medical Center, Bronx, NY 10468, USA;
- Psychiatry Department, Icahn School of Medicine at Mount Sinai, 1428 Madison Ave, New York, NY 10029, USA
| | - Patricia Janulewicz
- Department of Environmental Health, Boston University School of Public Health, 715 Albany St. T4W, Boston, MA 02130, USA; (P.J.)
| | - Kimberly Sullivan
- Department of Environmental Health, Boston University School of Public Health, 715 Albany St. T4W, Boston, MA 02130, USA; (P.J.)
| | - Maxine Krengel
- Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02130, USA;
| | - Ashok Tuteja
- Division of Gastroenterology, School of Medicine, University of Utah, Salt Lake City, UT 84132, USA;
| | - Nancy Klimas
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA;
- Geriatric Research and Education Clinical Center, Miami VA Heathcare System, Miami, FL 33125, USA
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.)
- Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA;
- Department of Medicine, Infectious Disease, UCI School of Medicine, Irvine, CA 92697, USA
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11
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Gryaznova M, Smirnova Y, Burakova I, Morozova P, Lagutina S, Chizhkov P, Korneeva O, Syromyatnikov M. Fecal Microbiota Characteristics in Constipation-Predominant and Mixed-Type Irritable Bowel Syndrome. Microorganisms 2024; 12:1414. [PMID: 39065182 PMCID: PMC11278693 DOI: 10.3390/microorganisms12071414] [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: 06/20/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a common condition that affects the lifestyle of patients. It is associated with significant changes in the composition of the gut microbiome, but the underlying microbial mechanisms remain to be fully understood. We study the fecal microbiome of patients with constipation-predominant IBS (IBS-C) and mixed-type IBS (IBS-M). METHODS We sequenced the V3 region of the 16S rRNA on the Ion Torrent PGM sequencing platform to study the microbiome. RESULTS In the patients with IBS-C and IBS-M, an increase in alpha diversity was found, compared to the healthy group, and differences in beta diversity were also noted. At the phylum level, both IBS subtypes showed an increase in the Firmicutes/Bacteroidetes ratio, as well as an increase in the abundance of Actinobacteria and Verrucomicrobiota. Changes in some types of bacteria were characteristic of only one of the IBS subtypes, while no statistically significant differences in the composition of the microbiome were detected between IBS-C and IBS-M. CONCLUSIONS This study was the first to demonstrate the association of Turicibacter sanguinis, Mitsuokella jalaludinii, Erysipelotrichaceae UCG-003, Senegalimassilia anaerobia, Corynebacterium jeikeium, Bacteroides faecichinchillae, Leuconostoc carnosum, and Parabacteroides merdae with IBS subtypes.
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Affiliation(s)
- Mariya Gryaznova
- Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies, 394036 Voronezh, Russia; (M.G.); (Y.S.); (I.B.); (P.M.); (O.K.)
| | - Yuliya Smirnova
- Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies, 394036 Voronezh, Russia; (M.G.); (Y.S.); (I.B.); (P.M.); (O.K.)
| | - Inna Burakova
- Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies, 394036 Voronezh, Russia; (M.G.); (Y.S.); (I.B.); (P.M.); (O.K.)
| | - Polina Morozova
- Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies, 394036 Voronezh, Russia; (M.G.); (Y.S.); (I.B.); (P.M.); (O.K.)
- Department of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, Russia;
| | - Svetlana Lagutina
- Department of Polyclinic Therapy, Voronezh State Medical University Named after N.N. Burdenko, 394036 Voronezh, Russia;
| | - Pavel Chizhkov
- Department of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, Russia;
| | - Olga Korneeva
- Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies, 394036 Voronezh, Russia; (M.G.); (Y.S.); (I.B.); (P.M.); (O.K.)
| | - Mikhail Syromyatnikov
- Laboratory of Metagenomics and Food Biotechnology, Voronezh State University of Engineering Technologies, 394036 Voronezh, Russia; (M.G.); (Y.S.); (I.B.); (P.M.); (O.K.)
- Department of Genetics, Cytology and Bioengineering, Voronezh State University, 394018 Voronezh, Russia;
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12
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Montgomery TL, Wang Q, Mirza A, Dwyer D, Wu Q, Dowling CA, Martens JWS, Yang J, Krementsov DN, Mao-Draayer Y. Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis. Sci Rep 2024; 14:15292. [PMID: 38961134 PMCID: PMC11222390 DOI: 10.1038/s41598-024-64369-x] [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: 12/21/2023] [Accepted: 06/07/2024] [Indexed: 07/05/2024] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.
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Affiliation(s)
- Theresa L Montgomery
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05401, USA
| | - Qin Wang
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Ali Mirza
- Pharmacoepidemiology in Multiple Sclerosis Research Group, The University of British Columbia, Vancouver, BC, V6T 2B5, Canada
| | - Deanna Dwyer
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Qi Wu
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Catherine A Dowling
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Jacob W S Martens
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Jennifer Yang
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Dimitry N Krementsov
- Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT, 05401, USA.
| | - Yang Mao-Draayer
- Autoimmunity Center of Excellence, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
- Autoimmunity Center of Excellence, Multiple Sclerosis Center of Excellence, Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
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13
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Xu B, Zhu L, Hu P, Yao W, Ke M, Zhu Z. Exploring the Mediation Effect of Metabolite Levels on the Association Between Gut Microbiota and HCC: A two-step, two-sample bidirectional Mendelian Randomization. J Cancer 2024; 15:3975-3983. [PMID: 38911378 PMCID: PMC11190768 DOI: 10.7150/jca.96579] [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: 03/24/2024] [Accepted: 05/19/2024] [Indexed: 06/25/2024] Open
Abstract
Background: Although the gut microbiota is one of the risk factors for liver cancer, it remains unclear whether the level of metabolites mediates this association. Methods: Utilizing summary data from genome-wide association studies (GWAS), we conducted a two-sample Mendelian Randomization (MR) analysis to explore the causal links between GM, metabolites, and HCC. A two-step MR analysis quantitatively assessed the effect of metabolite-mediated GM on HCC. Results: In our study, we demonstrated that Clostridium leptum was identified as a protective factor against HCC, with no evidence of reverse causality (Inverse-variance weighted [IVW], OR: 0.62 [95% CI, 0.42-0.91]; p = 0.016). Our study also found that the potential connection between the GM and HCC may be mediated by the level of metabolites. An increase of one standard deviation in C. leptum abundance led to a 38% decrease in HCC risk (OR: 0.62 [95% CI, 0.42-0.91]), with a 9% reduction in phosphoethanolamine (PE) levels (OR: 0.91 [95% CI: 0.84-0.99]). PE's mediation proportion was established as -6.725% (95% CI, 12.96% to -26.41%). Conclusion: Our results demonstrate that increasing specific GM abundance can lower HCC risk, mediated by PE levels. We offer new prevention and treatment targets for HCC by adjusting GM.
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Affiliation(s)
- Bingchen Xu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Department of Minimally Invasive Intervention, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Department of Thoracic Surgery, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Lianxin Zhu
- Medical College of Nanchang University, Nanchang 330088, P.R. China; Queen Mary University of London, London, United Kingdom
| | - Pan Hu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Department of Minimally Invasive Intervention, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Wang Yao
- The First Affiliated Hospital of Sun Yat-sen University, Department of Interventional Oncology, Guangzhou 510080, P.R. China
| | - Miaola Ke
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Department of Blood Transfusion, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 510080, P.R. China
| | - Zhihua Zhu
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Department of Thoracic Surgery, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
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14
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Cui C, Yang T, Wang S, Jia Z, Zhao L, Han X, Sun X, Zong J, Wang S, Chen D. Discussion on the relationship between gut microbiota and glioma through Mendelian randomization test based on the brain gut axis. PLoS One 2024; 19:e0304403. [PMID: 38809931 PMCID: PMC11135782 DOI: 10.1371/journal.pone.0304403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 05/11/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND In the realm of Gut-Brain axis research, existing evidence points to a complex bidirectional regulatory mechanism between gut microbiota and the brain. However, the question of whether a causal relationship exists between gut microbiota and specific types of brain tumors, such as gliomas, remains unresolved. To address this gap, we employed publicly available Genome-Wide Association Study (GWAS) and MIOBEN databases, conducting an in-depth analysis using Two-Sample Mendelian Randomization (MR). METHOD We carried out two sets of MR analyses. The preliminary analysis included fewer instrumental variables due to a high genome-wide statistical significance threshold (5×10-8). To enable a more comprehensive and detailed analysis, we adjusted the significance threshold to 1×10-5. We performed linkage disequilibrium analysis (R2 <0.001, clumping distance = 10,000kb) and detailed screening of palindromic SNPs, followed by MR analysis and validation through sensitivity analysis. RESULTS Our findings reveal a causal relationship between gut microbiota and gliomas. Further confirmation via Inverse Variance Weighting (IVW) identified eight specific microbial communities related to gliomas. Notably, the Peptostreptococcaceae and Olsenella communities appear to have a protective effect, reducing glioma risk. CONCLUSION This study not only confirms the causal link between gut microbiota and gliomas but also suggests a new avenue for future glioma treatment.
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Affiliation(s)
- Chenzhi Cui
- Graduate school, Dalian Medical University, Dalian, Dalian, China
- Department of Neurosurgery, Dalian Municipal Central Hospital, Dalian, China
| | - Tianke Yang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- College of Integrative Medicine, Dalian Medical University, Dalian, China
| | - ShengYu Wang
- Medical Laboratory Technology, College of Medical Laboratory, Dalian Medical University, Dalian, China
| | - Zhuqiang Jia
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Naqu People’s Hospital, Tibet, China
| | - Lin Zhao
- Department of Quality Management, Dalian Municipal Central Hospital, Dalian, China
| | - Xin Han
- Naqu People’s Hospital, Tibet, China
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaohong Sun
- Department of Nursing, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Junwei Zong
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shouyu Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dong Chen
- Graduate school, Dalian Medical University, Dalian, Dalian, China
- Department of Neurosurgery, Dalian Municipal Central Hospital, Dalian, China
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15
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Xu R, Li S, Zhang Y, Pu Y, Luo G, Wang X. Causal effects of gut microbiota on the risk of osteomyelitis: a Mendelian randomization study. Front Microbiol 2024; 15:1342172. [PMID: 38863758 PMCID: PMC11166080 DOI: 10.3389/fmicb.2024.1342172] [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: 11/22/2023] [Accepted: 05/14/2024] [Indexed: 06/13/2024] Open
Abstract
Background Osteomyelitis is characterized by an inflammatory process initiated by microorganisms, leading to infection and subsequent degradation of bone tissue. Several studies have indicated a potential link between gut microbiota and the occurrence of osteomyelitis. Utilizing the benefits of Mendelian randomization, which mitigates issues of confounding and reverse causation, we employed this approach to ascertain the presence of a causal connection between gut microbiota and osteomyelitis. Additionally, we aimed to pinpoint gut microbiota that could potentially exert substantial influence. Methods We performed a rigorous screening of single nucleotide polymorphisms in GWAS summary statistics for gut microbiota and osteomyelitis. The 2,542 instrumental variables obtained after screening were subjected to MR analyses, including inverse variance weighting, weighted median, weighted mode, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier test. We then validated the reliability of the results by performing sensitivity analyses on the MR of 196 well-defined gut microbiota. Result We established a causal relationship between gut microbiota and osteomyelitis through MR analysis. Additionally, we identified a taxon of significant importance and six taxons with nominal significance. Specifically, the family Bacteroidales S24.7 group exhibited an association with a diminished risk of osteomyelitis development. Conversely, the class Bacilli, class Bacteroidia, order Bacteroidales, order Lactobacillales, family Streptococcaceae, and genus Coprococcus3 displayed an increased risk of developing osteomyelitis. The MR outcomes for these seven taxa remained stable throughout a series of sensitivity analyses. Conclusion This study demonstrated a causal relationship between gut microbiota and osteomyelitis by Mendelian randomization. We hope that this study will provide a new direction for the treatment of osteomyelitis, which has a paucity of therapeutic options.
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Affiliation(s)
- Ran Xu
- Department of Urology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Si Li
- Department of Pediatric Surgery, Women and Children’s Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Ying Zhang
- Department of Urology, Zhongshan Hospital Xiamen University, The School of Clinical Medicine, Fujian Medical University, Xiamen, China
| | - Yue Pu
- Department of Urology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Guangcheng Luo
- Department of Urology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Urology, Zhongshan Hospital Xiamen University, The School of Clinical Medicine, Fujian Medical University, Xiamen, China
| | - Xinjun Wang
- Department of Urology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Urology, Zhongshan Hospital Xiamen University, The School of Clinical Medicine, Fujian Medical University, Xiamen, China
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16
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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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17
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Wang Z, Han S, Xiao Y, Zhang Y, Ge Y, Liu X, Gao J. Genetically supported causality between gut microbiota and frailty: a two-sample Mendelian randomization study. Front Microbiol 2024; 15:1324209. [PMID: 38741737 PMCID: PMC11089315 DOI: 10.3389/fmicb.2024.1324209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 03/25/2024] [Indexed: 05/16/2024] Open
Abstract
Background A mounting body of evidence suggests a strong connection between gut microbiota and the risk of frailty. However, the question of causality remains unanswered. In this study, we employed a Mendelian randomization (MR) approach to assess potential causal relationships between gut microbiota and the risk of frailty. Materials and methods Summary statistics for the gut microbiome were obtained from a genome wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). Our primary analysis utilized the inverse variance weighted (IVW) method. To enhance the robustness of our results, we also applied weighted median methods, MR Egger regression, and MR pleiotropy residual sum and outlier test. Finally, we conducted reverse MR analysis to investigate the potential for reverse causality. Results IVW method identified 7 bacterial taxa nominally associated with the risk of FI. Class Bacteroidia (p = 0.033) and genus Eubacterium ruminantium group (p = 0.028) were protective against FI. In addition, class Betaproteobacteria (p = 0.042), genus Allisonella (p = 0.012), genus Bifidobacterium (p = 0.013), genus Clostridium innocuum group (p = 0.036) and genus Eubacterium coprostanoligenes group (p = 0.003) were associated with a higher risk of FI. No pleiotropy or heterogeneity were found. Conclusion The MR analysis indicates a causal relationship between specific gut microbiota and FI, offering new insights into the mechanisms underlying FI mediated by gut microbiota.
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Affiliation(s)
- Zi Wang
- Yangzhou University Medical College, Yangzhou, China
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Shuai Han
- Yangzhou University Medical College, Yangzhou, China
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Yinggang Xiao
- Yangzhou University Medical College, Yangzhou, China
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Yang Zhang
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Yali Ge
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Xin Liu
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Ju Gao
- Department of Anesthesiology, Institute of Anesthesia, Emergency and Critical Care, Yangzhou University Affiliated Northern Jiangsu People’s Hospital, Yangzhou, China
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Li J, Gao X, Sun X, Li H, Wei J, Lv L, Zhu L. Investigating the causal role of the gut microbiota in esophageal cancer and its subtypes: a two-sample Mendelian randomization study. BMC Cancer 2024; 24:416. [PMID: 38575885 PMCID: PMC10996172 DOI: 10.1186/s12885-024-12205-w] [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: 12/31/2023] [Accepted: 03/29/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Through research on the gut microbiota (GM), increasing evidence has indicated that the GM is associated with esophageal cancer (ESCA). However, the specific cause-and-effect relationship remains unclear. In this study, Mendelian randomization (MR) analysis was applied to investigate the causal relationship between the GM and ESCA, including its subtypes. METHODS We collected information on 211 GMs and acquired data on ESCA and its subtypes through genome-wide association studies (GWASs). The causal relationship was primarily assessed using the inverse variance weighted (IVW) method. Additionally, we applied the weighted median estimator (WME) method, MR-Egger method, weighted mode, and simple mode to provide further assistance. Subsequent to these analyses, sensitivity analysis was conducted using the MR-Egger intercept test, MR-PRESSO global test, and leave-one-out method. RESULT Following our assessment using five methods and sensitivity analysis, we identified seven GMs with potential causal relationships with ESCA and its subtypes. At the genus level, Veillonella and Coprobacter were positively correlated with ESCA, whereas Prevotella9, Eubacterium oxidoreducens group, and Turicibacter were negatively correlated with ESCA. In the case of esophageal adenocarcinoma (EAC), Flavonifractor exhibited a positive correlation, while Actinomyces exhibited a negative correlation. CONCLUSION Our study revealed the potential causal relationship between GM and ESCA and its subtypes, offering novel insights for the advancement of ESCA diagnosis and treatment.
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Affiliation(s)
- Jia Li
- Thoracic Surgery Department, Jinan Central Hospital, Shandong University, Jinan, 250000, China
| | - Xuedi Gao
- Thoracic Surgery Department, Jinan Mingshui Eye Hospital, Jinan, 250000, China
| | - Xiaoming Sun
- Thoracic Surgery Department, Jinan Central Hospital, Jinan, 250000, China
| | - Hao Li
- Thoracic Surgery Department, Jinan Central Hospital, Shandong First Medical University, Jinan, 250000, China
| | - Jiaheng Wei
- Thoracic Surgery Department, Weifang Medical University, Weifang, 261000, China
| | - Lin Lv
- Thoracic Surgery Department, Jinan Central Hospital, Shandong University, Jinan, 250000, China
| | - Liangming Zhu
- Thoracic Surgery Department, Jinan Central Hospital, Shandong University, Jinan, 250000, China.
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Gao C. Investigating the association between blood metabolites and telomere length: A mendelian randomization study. PLoS One 2024; 19:e0298172. [PMID: 38457472 PMCID: PMC10923442 DOI: 10.1371/journal.pone.0298172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/19/2024] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND Telomere length refers to the protective cap at the end of chromosomes, and it plays a crucial role in many diseases. The objective of this study is to explore the relationship between blood metabolites and telomere length, aiming to identify novel biological factors that influence telomere length. METHODS In this study, we extracted genome-wide association study (GWAS) data for blood metabolites from a sample of 7824 Europeans. Additionally, GWAS data for telomere length were obtained from the Open GWAS database (GWAS ID: ieu-b-4879). The primary analysis of this study utilized the random inverse variance weighted (IVW) method. Complementary analyses were also conducted using the MR-Egger and weighted median approaches. Sensitivity analyses were performed to assess the robustness of the findings. These included the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. To investigate the possibility of reverse causation, reverse MR analysis was conducted. Additionally, multivariable MR was utilized to evaluate the direct effect of metabolites on telomere length. RESULTS The results suggested a potential association between 15-methylpalmitate, taurocholate, levulinate, and X-12712 and telomere length. MVMR analysis further showed that 15-methylpalmitate, taurocholate, and levulinate can directly influence telomere length, regardless of other metabolites. CONCLUSIONS This study suggests that 15-methylpalmitate, taurocholate, and levulinate are likely factors correlated with telomere length. These findings will contribute to the development of strategies for protecting telomeres, preventing related diseases, and establishing a new biological foundation for achieving healthy aging.
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Affiliation(s)
- Chen Gao
- Head and Neck Surgeons, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fujian, China
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20
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Zhang Z, Xu W, Zheng Y, Chen C, Kang X, Chen D, Cheng F, Wang X. Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis. Exp Dermatol 2024; 33:e14984. [PMID: 37997526 DOI: 10.1111/exd.14984] [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: 07/18/2023] [Revised: 10/26/2023] [Accepted: 11/13/2023] [Indexed: 11/25/2023]
Abstract
Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level.
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Affiliation(s)
- Zehan Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Wenxiu Xu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuxiao Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Congai Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiangdong Kang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Dan Chen
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fafeng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xueqian Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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21
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Nordin E, Hellström PM, Dicksved J, Pelve E, Landberg R, Brunius C. Effects of FODMAPs and Gluten on Gut Microbiota and Their Association with the Metabolome in Irritable Bowel Syndrome: A Double-Blind, Randomized, Cross-Over Intervention Study. Nutrients 2023; 15:3045. [PMID: 37447371 DOI: 10.3390/nu15133045] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/30/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND A mechanistic understanding of the effects of dietary treatment in irritable bowel syndrome (IBS) is lacking. Our aim was therefore to investigate how fermentable oligo- di-, monosaccharides, and polyols (FODMAPs) and gluten affected gut microbiota and circulating metabolite profiles, as well as to investigate potential links between gut microbiota, metabolites, and IBS symptoms. METHODS We used data from a double-blind, randomized, crossover study with week-long provocations of FODMAPs, gluten, and placebo in participants with IBS. To study the effects of the provocations on fecal microbiota, fecal and plasma short-chain fatty acids, the untargeted plasma metabolome, and IBS symptoms, we used Random Forest, linear mixed model and Spearman correlation analysis. RESULTS FODMAPs increased fecal saccharolytic bacteria, plasma phenolic-derived metabolites, 3-indolepropionate, and decreased isobutyrate and bile acids. Gluten decreased fecal isovalerate and altered carnitine derivatives, CoA, and fatty acids in plasma. For FODMAPs, modest correlations were observed between microbiota and phenolic-derived metabolites and 3-indolepropionate, previously associated with improved metabolic health, and reduced inflammation. Correlations between molecular data and IBS symptoms were weak. CONCLUSIONS FODMAPs, but not gluten, altered microbiota composition and correlated with phenolic-derived metabolites and 3-indolepropionate, with only weak associations with IBS symptoms. Thus, the minor effect of FODMAPs on IBS symptoms must be weighed against the effect on microbiota and metabolites related to positive health factors.
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Affiliation(s)
- Elise Nordin
- Department of Life Sciences, Food and Nutrition Science, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
| | - Per M Hellström
- Department of Medical Sciences, Gastroenterology/Hepatology, Uppsala University, SE-75185 Uppsala, Sweden
| | - Johan Dicksved
- Department of Animal Nutrition and Management, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden
| | - Erik Pelve
- Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, SE-75007 Uppsala, Sweden
| | - Rikard Landberg
- Department of Life Sciences, Food and Nutrition Science, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
| | - Carl Brunius
- Department of Life Sciences, Food and Nutrition Science, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
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Montgomery TL, Wang Q, Mirza A, Dwyer D, Wu Q, Dowling CA, Martens JW, Yang J, Krementsov DN, Mao-Draayer Y. Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.06.26.23291875. [PMID: 37425956 PMCID: PMC10327224 DOI: 10.1101/2023.06.26.23291875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
Background Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. Methods In a longitudinal study, disability status and associated clinical features in 60 MS patients were tracked over 4.2 ± 0.97 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. Results We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 45 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia , Lachnospiraceae, and Oscillospiraceae , with an expansion of Alloprevotella , Prevotella-9 , and Rhodospirillales . Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed a significant enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K 2 production (linked to Akkermansia ), and a depletion in SCFA metabolism (linked to Lachnospiraceae and Oscillospiraceae ). Further, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to robustly predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. Conclusions These results demonstrate the utility of the gut microbiome for predicting disease progression in MS. Further, analysis of the inferred metagenome revealed that oxidative stress, vitamin K 2 and SCFAs are associated with progression. Abstract Figure
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