Investigating the causal relationship between gut microbiota and gastroenteropancreatic neuroendocrine neoplasms: a bidirectional Mendelian randomization study
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SUBMITTER: Zhang C
PROVIDER: S-EPMC11347282 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundObservational studies have suggested a potential link between cathepsins and major salivary gland neoplasms (MSGNs), but the causality of this relationship remains uncertain. Mendelian randomization (MR) is a significant genetic method that employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This approach reduces confounding effects, enabling the analysis of causal relationships between exposure traits and outcome diseases. This study aimed to explore the causal links between cathepsins and MSGNs by utilizing MR analysis.MethodsIn this research, we collected IVs associated with 11 different types of cathepsins (including cathepsins D, L1, B, E, F, G, H, O, S, L2, and Z) from the Medical Research Council (MRC) integrative epidemiology unit (IEU) open genome-wide association studies (GWAS) database. Data for cathepsins D and L1 were sourced from the SCALLOP consortium, which included 21,758 Europeans identified via the Olink proximity extension assay (PEA). Cathepsins B, E, F, G, H, O, S, L2, and Z were obtained from the INTERVAL study involving 3,301 European participants using the SOMAscan assay. We also collected data on benign major salivary gland neoplasms (BMSGNs) from the FinnGen database, consisting of 3,353 cases and 450,380 controls, and information on major salivary gland carcinomas (MSGCs) from the UK Biobank, which included 105 cases and 456,243 controls. Diagnostic criteria for both BMSGNs and MSGCs followed the international statistical classification of diseases and related health problems 10th revision (ICD-10) classification. A comprehensive bidirectional MR study was executed employing diverse methodologies, including inverse variance weighted (IVW), MR-Egger regression, weighted median, and weighted mode. Additionally, sensitivity analyses were conducted to emphasize the solidity of the study.ResultsIncreased levels of cathepsin F (CTSF), cathepsin O (CTSO), and cathepsin L2 (CTSL2) were associated with a higher risk of BMSGNs (CTSF: IVW: P=0.01, odds ratio (OR) =1.12, CTSO: IVW: P=0.02, OR =1.14; CTSL2: IVW: P=0.01, OR =1.17). Additionally, no causal association was found between cathepsins and MSGCs. Reverse MR analyses did not establish a causal relationship between BMSGNs and various cathepsins. However, it did reveal that a higher risk of MSGCs was associated with lower levels of CTSL2 (IVW: P=0.01, beta =-0.046).ConclusionsThe study presents compelling evidence of a correlation between elevated CTSF, CTSO, and CTSL2 levels and an increased risk of BMSGNs. Elevated CTSF, CTSO, and CTSL2 levels may serve as significant biomarkers for diagnosing BMSGNs definitively. Conversely, reduced levels of CTSL2 provide a novel foundation for diagnosing MSGCs and differentiating them from BMSGNs. Moreover, CTSF, CTSO, and CTSL2 represent potential new targets for therapeutic intervention in BMSGNs and MSGCs.
| S-EPMC11635577 | biostudies-literature
Project description:BackgroundIt has emerged that disturbances of the gut microbiota (GM) are linked to insomnia. However, the causality of the observed associations remains uncertain.MethodsWe conducted a two-sample Mendelian randomization analysis based on genome-wide association study data to explore the possible causal link between GM and insomnia. The GM data were from the MiBioGen consortium, while the summary statistics of insomnia were obtained from the FinnGen consortium R9 release data. Cochran's Q statistics were used to analyze instrumental variable heterogeneity.ResultsAccording to the inverse variance weighted estimates, the family Ruminococcaceae (odds ratio = 1.494, 95% confidence interval:1.004-2.223, p = 0.047) and the genus Lachnospiraceae (odds ratio = 1.726, 95% confidence interval: 1.191-2.501, p = 0.004) play a role in insomnia risk. In contrast, the genus Flavonifractor (odds ratio = 0.596, 95% confidence interval: 0.374-0.952, p = 0.030) and the genus Olsenella (odds ratio = 0.808, 95% confidence interval: 0.666-0.980, p = 0.031) tended to protect against insomnia. According to the reverse MR analysis, insomnia can also alter GM composition. Instrumental variables were neither heterogeneous nor horizontal pleiotropic.ConclusionIn conclusion, our Mendelian randomization study provides evidence of a causal relationship between GM and insomnia. The identified GM may be promising gut biomarkers and new therapeutic targets for insomnia. This investigation also provides a foundation for future studies examining the influence of GM on sleep disorders beyond insomnia, with potential implications for redefining the mechanisms governing sleep regulation.
| S-EPMC10740168 | biostudies-literature
Project description:BackgroundCurrently, the influence of microbiota on the occurrence, progression, and treatment of cancer is a topic of considerable research interest. Therefore, based on the theory of the gut-brain axis proved by previous studies, our objective was to uncover the causal relationship between glioblastoma and the gut microbiome using Mendelian randomization analysis.MethodsWe conducted a bidirectional Mendelian randomization study using summary statistics of gut microbiota derived from the MiBioGen consortium, the largest database of gut microbiota. Summary statistics for glioblastoma were obtained from IEU OpenGWAS project, which included 91 cases and 218,701 controls. We assessed the presence of heterogeneity and horizontal pleiotropy in the analyzed data. We primarily employed the inverse variance weighting method to investigate the causal relationship between gut microbiota and glioblastoma after excluding cases of horizontal pleiotropy. Four other analysis methods were employed as supplementary. Excluding abnormal results based on leave-one-out sensitivity analysis. Finally, reverse Mendelian randomization analysis was performed.ResultsFour genus-level taxa and one family-level taxa exhibited causal associations with glioblastoma. And these results of reverse Mendelian randomization analysis shown glioblastoma exhibited causal associations with three genus-level taxa and one family-level taxa. However, the Prevotella7(Forward, P=0.006, OR=0.34, 95%CI:0.158-0.732; Reverse, P=0.004, OR=0.972, 95%CI:0.953-0.991) shown the causal associations with glioblastoma in the bidirectional Mendelian randomization.ConclusionsIn this bidirectional Mendelian randomization study, we identified five gut microbiota species with causal associations to glioblastoma. However, additional randomized controlled trials are required to clarify the impact of gut microbiota on glioblastoma and to reveal its precise mechanisms.
| S-EPMC10726622 | biostudies-literature
Project description:BackgroundObservational studies have demonstrated an association between gut microbiota and myasthenia gravis; however, the causal relationship between the two still lacks clarity. Our goals are to ascertain the existence of a bidirectional causal relationship between gut microbiota composition and myasthenia gravis, and to investigate how gut microbiota plays a role in reducing the risk of myasthenia gravis.MethodsWe acquired gut microbiota data at the phylum, class, order, family, and genus levels from the MiBioGen consortium (N = 18,340) and myasthenia gravis data from the FinnGen Research Project (426 cases and 373,848 controls). In the two-sample Mendelian randomization analysis, we assessed the causal relationship between the gut microbiota and myasthenia gravis. We also conducted bidirectional MR analysis to determine the direction of causality. The inverse variance weighted, mendelian randomization-Egger, weighted median, simple mode, and weighted mode were used to test the causal relationship between the gut microbiota and severe myasthenia gravis. We used MR-Egger intercept and Cochran's Q test to assess for pleiotropy and heterogeneity, respectively. Furthermore, we utilized the MR-PRESSO method to evaluate horizontal pleiotropy and detect outliers.ResultsIn the forward analysis, the inverse-variance weighted method revealed that there is a positive correlation between the genus Lachnoclostridium (OR = 2.431,95%CI 1.047-5.647, p = 0.039) and the risk of myasthenia gravis. Additionally, the family Clostridiaceae1 (OR = 0.424,95%CI 0.202-0.889, p = 0.023), family Defluviitaleaceae (OR = 0.537,95%CI 0.290-0.995, p = 0.048), family Enterobacteriaceae (OR = 0.341,95%CI 0.135-0.865, p = 0.023), and an unknown genus (OR = 0.407,95%CI 0.209-0.793, p = 0.008) all demonstrated negative correlation with the risk of developing myasthenia gravis. Futhermore, reversed Mendelian randomization analysis proved a negative correlation between the risk of myasthenia gravis and genus Barnesiella (OR = 0.945,95%CI 0.906-0.985, p = 0.008).ConclusionOur research yielded evidence of a causality connection in both directions between gut microbiota and myasthenia gravis. We identified specific types of microbes associated with myasthenia gravis, which offers a fresh window into the pathogenesis of this disease and the possibility of developing treatment strategies. Nonetheless, more studies, both basic and clinical, are necessary to elucidate the precise role and therapeutic potential of the gut microbiota in the pathogenesis of myasthenia gravis.
| S-EPMC10629094 | biostudies-literature
Project description:BackgroundThe etiology and pathogenesis of trigeminal neuralgia remain unclear. This study examines the connection between gut microbiota and trigeminal neuralgia using Mendelian randomization analysis to provide insights into the disorder's origin and propose potential therapies based on our findings.MethodsWe used data from the MiBioGen consortium (13,266 participants) for gut microbiota and the IEU OpenGWAS project (800 cases, 195,047 controls) for trigeminal neuralgia. We checked for heterogeneity and horizontal pleiotropy and used the inverse variance weighting method as our main approach to study the causal link between gut bacteria and trigeminal neuralgia, MR-Egger, simple mode, weighted median, and weighted mode as supplementary methods, with a sensitivity test using leave-one-out analysis. If a bacteria-trigeminal neuralgia link was found, we conducted a reverse analysis for confirmation.ResultsAccording to the final results, these groups include Butyricimonas (Genus, id = 945, p-value = 0.007, OR = 1.742, 95% CI: 1.165-2.604), unknowngenus (Genus, id = 1000005479, p-value = 0.005, OR = 1.774, 95% CI: 1.187-2.651) and Bacteroidales (Family, p-value = 0.005, OR = 1.774, 95% CI: 1.187-2.651) were causally associated with trigeminal neuralgia. No significant results according to reverse Mendelian randomization analysis.ConclusionIn our study, we identified specific gut bacteria linked to trigeminal neuralgia. To comprehensively understand their impact and mechanisms, additional randomized trials are necessary.
| S-EPMC11905160 | biostudies-literature
Project description:BackgroundGrowing evidence from observational studies and clinical trials suggests that the gut microbiota is associated with tuberculosis (TB). However, it is unclear whether any causal relationship exists between them and whether causality is bidirectional.MethodsA bidirectional two-sample Mendelian randomization (MR) analysis was performed. The genome-wide association study (GWAS) summary statistics of gut microbiota were obtained from the MiBioGen consortium, while the GWAS summary statistics of TB and its specific phenotypes [respiratory tuberculosis (RTB) and extrapulmonary tuberculosis (EPTB)] were retrieved from the UK Biobank and the FinnGen consortium. And 195 bacterial taxa from phylum to genus were analyzed. Inverse variance weighted (IVW), MR-Egger regression, maximum likelihood (ML), weighted median, and weighted mode methods were applied to the MR analysis. The robustness of causal estimation was tested using the heterogeneity test, horizontal pleiotropy test, and leave-one-out method.ResultsIn the UK Biobank database, we found that 11 bacterial taxa had potential causal effects on TB. Three bacterial taxa genus.Akkermansia, family.Verrucomicrobiacea, order.Verrucomicrobiales were validated in the FinnGen database. Based on the results in the FinnGen database, the present study found significant differences in the characteristics of gut microbial distribution between RTB and EPTB. Four bacterial taxa genus.LachnospiraceaeUCG010, genus.Parabacteroides, genus.RuminococcaceaeUCG011, and order.Bacillales were common traits in relation to both RTB and TB, among which order.Bacillales showed a protective effect. Additionally, family.Bacteroidacea and genus.Bacteroides were identified as common traits in relation to both EPTB and TB, positively associating with a higher risk of EPTB. In reverse MR analysis, no causal association was identified. No significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was found.ConclusionOur study supports a one-way causal relationship between gut microbiota and TB, with gut microbiota having a causal effect on TB. The identification of characteristic gut microbiota provides scientific insights for the potential application of the gut microbiota as a preventive, diagnostic, and therapeutic tool for TB.
| S-EPMC10765819 | biostudies-literature
Project description:BackgroundIncreasing evidence suggests that alterations in gut microbiota are associated with a variety of skin diseases. However, whether this association reflects a causal relationship remains unknown. We aimed to reveal the causal relationship between gut microbiota and skin diseases, including psoriasis, atopic dermatitis, acne, and lichen planus.MethodsWe obtained full genetic association summary data for gut microbiota, psoriasis, atopic dermatitis, acne, and lichen planus from public databases and used three methods, mainly inverse variance weighting, to analyze the causal relationships between gut microbiota and these skin diseases using bidirectional Mendelian randomization, as well as sensitivity and stability analysis of the results using multiple methods.ResultsThe results showed that there were five associated genera in the psoriasis group, seven associated genera were obtained in the atopic dermatitis group, a total of ten associated genera in the acne group, and four associated genera in the lichen planus group. The results corrected for false discovery rate showed that Eubacteriumfissicatenagroup (P = 2.20E-04, OR = 1.24, 95%CI:1.11-1.40) and psoriasis still showed a causal relationship. In contrast, in the reverse Mendelian randomization results, there was no evidence of an association between these skin diseases and gut microbiota.ConclusionWe demonstrated a causal relationship between gut microbiota and immune skin diseases and provide a new therapeutic perspective for the study of immune diseases: targeted modulation of dysregulation of specific bacterial taxa to prevent and treat psoriasis, atopic dermatitis, acne, and lichen planus.
| S-EPMC10956797 | biostudies-literature
Project description:ObjectiveEmerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs.MethodsEmploying summary statistics from the MiBioGen consortium (n=18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran's Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders.ResultsOur findings suggest that certain microbiota, identified as Ruminococcaceae_NK4A214_group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs' development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella_7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs' risk.DiscussionThis study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis's relevance. The findings advocate for the integration of GM profiles in TNs' prevention and management, offering a foundation for future research in this domain.
| S-EPMC11338761 | biostudies-literature
Project description:BackgroundGrowing evidence has shown that gut microbiome composition is associated with Biliary tract cancer (BTC), but the causality remains unknown. This study aimed to explore the causal relationship between gut microbiota and BTC, conduct an appraisal of the gut microbiome's utility in facilitating the early diagnosis of BTC.MethodsWe acquired the summary data for Genome-wide Association Studies (GWAS) pertaining to BTC (418 cases and 159,201 controls) from the Biobank Japan (BBJ) database. Additionally, the GWAS summary data relevant to gut microbiota (N = 18,340) were sourced from the MiBioGen consortium. The primary methodology employed for the analysis consisted of Inverse Variance Weighting (IVW). Evaluations for sensitivity were carried out through the utilization of multiple statistical techniques, encompassing Cochrane's Q test, the MR-Egger intercept evaluation, the global test of MR-PRESSO, and a leave-one-out methodological analysis. Ultimately, a reverse Mendelian Randomization analysis was conducted to assess the potential for reciprocal causality.ResultsThe outcomes derived from IVW substantiated that the presence of Family Streptococcaceae (OR = 0.44, P = 0.034), Family Veillonellaceae (OR = 0.46, P = 0.018), and Genus Dorea (OR = 0.29, P = 0.041) exerted a protective influence against BTC. Conversely, Class Lentisphaeria (OR = 2.21, P = 0.017), Genus Lachnospiraceae FCS020 Group (OR = 2.30, P = 0.013), and Order Victivallales (OR = 2.21, P = 0.017) were associated with an adverse impact. To assess any reverse causal effect, we used BTC as the exposure and the gut microbiota as the outcome, and this analysis revealed associations between BTC and five different types of gut microbiota. The sensitivity analysis disclosed an absence of empirical indicators for either heterogeneity or pleiotropy.ConclusionThis investigation represents the inaugural identification of indicative data supporting either beneficial or detrimental causal relationships between gut microbiota and the risk of BTC, as determined through the utilization of MR methodologies. These outcomes could hold significance for the formulation of individualized therapeutic strategies aimed at BTC prevention and survival enhancement.
| S-EPMC10978781 | biostudies-literature
Project description:BackgroundPrevious studies have shown that gut microbiota (GM) and gut microbiota-derived metabolites are associated with gestational diabetes mellitus (GDM). However, the causal associations need to be treated with caution due to confounding factors and reverse causation.MethodsThis study obtained genetic variants from genome-wide association study including GM (N = 18,340), GM-derived metabolites (N = 7,824), and GDM (5,687 cases and 117,89 controls). To examine the causal association, several methods were utilized, including inverse variance weighted, maximum likelihood, weighted median, MR-Egger, and MR.RAPS. Additionally, reverse Mendelian Randomization (MR) analysis and multivariable MR were conducted to confirm the causal direction and account for potential confounders, respectively. Furthermore, sensitivity analyses were performed to identify any potential heterogeneity and horizontal pleiotropy.ResultsGreater abundance of Collinsella was detected to increase the risk of GDM. Our study also found suggestive associations among Coprobacter, Olsenella, Lachnoclostridium, Prevotella9, Ruminococcus2, Oscillibacte, and Methanobrevibacter with GDM. Besides, eight GM-derived metabolites were found to be causally associated with GDM. For the phenylalanine metabolism pathway, phenylacetic acid was found to be related to the risk of GDM.ConclusionsThe study first used the MR approach to explore the causal associations among GM, GM-derived metabolites, and GDM. Our findings may contribute to the prevention and treatment strategies for GDM by targeting GM and metabolites, and offer novel insights into the underlying mechanism of the disease.
| S-EPMC10497006 | biostudies-literature