[Association between 473 gut microbiota and Alzheimer's disease: a Mendelian randomization mediation analysis of 233 circulating metabolites].

Assessing the Relationship between Gut Microbiota and Kidney Stones: A Two-Sample Mendelian Randomization Analysis.

Causal relationships between gut microbiota, metabolites, and chronic kidney disease: a two-step, two-sample Mendelian randomization study

Genetic evidence is provided that gut microbiota influence CKD risk partially through circulating metabolites, highlighting the gut microbiota–metabolite–CKD axis as a potential therapeutic target.

Exploring the role of gut microbiota in coronary atherosclerosis through lipoprotein-mediated cholesterol transport and distribution: A Mendelian randomization analysis.

We employed Mendelian randomization (MR) to explore causal relationships between gut microbiota (GM), coronary atherosclerotic heart disease (CAHD), and potential metabolic mediators. We utilized summary statistics from genome-wide association studies (GWAS), encompassing data on 473 GM traits from comprehensive microbiome GWAS, 61 lipoprotein-mediated cholesterol transport and distribution data from large-scale metabolic biomarker studies, and coronary atherosclerosis (CA) data from the GWAS catalog (study accession GCST90043957) involving 456,348 European participants. Bidirectional MR analyses were conducted to investigate the causal relationships between GM and CA. Two-sample Mendelian randomization analyses were performed to identify potential mediating metabolites and quantify the mediation proportion. Ultimately, the GM GCA-900066755, identified through MR as having a potential causal relationship, was selected to investigate its potential effects on CA by influencing cholesterol transport and distribution. Our results indicated that GCA-900066755 was positively associated with an increased risk of CA (odds ratio = 1.156). CA did not significantly affect the levels of GCA-900066755 (odds ratio = 1.009). GCA-900066755 was negatively correlated with total cholesterol levels in medium high-density lipoprotein, which reduced CA risk, and was positively correlated with total cholesterol levels in low-density lipoprotein (LDL), large LDL, medium LDL, and small LDL, which were positively associated with CA. Mediation analysis showed 7 data points mediating the association between GCA-900066755 and CA. Our MR study supports a causal relationship between specific GM groups and the risk of CAHD, highlighting that cholesterol traits are not merely outcomes associated with the relationship between GM and CAHD, but are important mediating factors. Understanding the biological mechanisms of these traits can provide a concrete foundation for future targeted interventions.

Dissecting the Gut Microbiota-MetaboliteCoronary Atherosclerosis Axis: Evidence from Two-Sample Mendelian Randomization.

INTRODUCTION Coronary Atherosclerosis (CAS) is a complex disease influenced by host genes, the gut microbiota, and circulating metabolites. Causal relationships and mediating effects among these factors have not yet been clarified. METHODS A two-sample Mendelian Randomization (MR) study was conducted using genomewide association study data from FinnGen, OpenGWAS, and Canadian Longitudinal Study on Aging. A total of 473 genetic instruments for gut microbial traits and 1,400 for plasma metabolites were selected. We applied bidirectional Mendelian randomization, sensitivity tests, and two-step mediation analysis to assess causal effects and identify metabolic mediators. RESULTS 18 gut microbiota taxa and 36 metabolites that are associated with coronary atherosclerosis. Protective taxa included Genus Roseibacillus and Genus Negativibacillus; Genus Geobacter C and Species Lawsonibacter sp000492175 were identified as risk. Inversely, bile acid derivatives, such as deoxycholic acid 12-sulfate, were negatively correlated, whereas guanidinoacetate was positively correlated. Mediation analysis found glutamine degradant, sphingomyelin, and 3β-hydroxy-5-cholestenoate as partially mediated by the microbial effect, with mediation proportions ranging from -30.1% to 15.8%. DISCUSSION These findings provide genetic evidence for the involvement of the gut microbiota in the development of coronary atherosclerosis, which may occur through metabolic pathways. Beneficial microbial taxa may be preferentially sustained by amino acid metabolism and anti-inflammatory mediators, whereas pathogenic taxa tend to proliferate under conditions characterized by lipid and sterol metabolic dysregulation. CONCLUSION This study emphasizes the potential central axis of gut microbiota-plasma metabolites-CAS and identifies microbial and plasma metabolite candidates that may serve as targets for early prevention and intervention of CAS. These findings provide new insights into the molecular mechanisms underlying the interactions between gut microbiota and plasma metabolites in the development and progression of C.

Exploring the Causal Role of Circulating Inflammatory Proteins in Multiple Sclerosis: A Mendelian Randomization Study and Druggability Analysis.

INTRODUCTION To evaluate the causal effects of circulating inflammatory proteins on the development of Multiple Sclerosis (MS) and to discover potential therapeutic targets for the disease. METHODS Two-sample Mendelian randomization analysis was used to evaluate causal relationships between levels of 91 inflammatory proteins in serum and the risk of MS. For each circulating protein, genetic variation data were from a genome-wide association study of 14,736 individuals of European ancestry. The MS dataset included 47,429 cases and 68,374 controls. Additional sensitivity, colocalization, functional enrichment, and protein-protein interaction analyses were performed to assess the robustness and biological relevance of the findings. Soluble proteins causally associated with MS were assessed for their therapeutic target potentials using the Drug-Gene Interaction Database. RESULTS The analysis identified 9 circulating inflammatory proteins with nominal evidence of association with MS risk. Among them, CD40 (Odds Ratio [OR]: 0.907) and VEGFA (OR: 0.971) appear protective, while IL1A (OR: 1.139), CD6 (OR: 1.047), TNF (OR: 1.058), LIF-R (OR: 1.052), CCL25 (OR: 1.032), CD244 (OR: 1.057) and CXCL10 (OR: 1.061) were associated with higher risks of MS. After correcting for multiple testing, associations with MS risks remained significant only for CD40. Supportive analyses highlighted immune- and inflammationrelated pathways, particularly cytokine signaling, as mediators of the risks of MS. Six circulating proteins were identified as candidates in an exploratory assessment of druggability. DISCUSSION These results offered new insight into the inflammatory landscape of MS, reinforcing the pathogenic relevance of immune signaling pathways. The robust statistical significance of CD40 highlighted it as a primary candidate for further investigation, while the additional eight proteins provided a foundation for future hypothesis-generating studies. While the findings strengthened the biological plausibility of inflammation-driven disease mechanisms, the presence of nominal significance and potential pleiotropy for certain markers necessitated a cautious interpretation. CONCLUSION Genetic evidence linking inflammatory proteins to MS pathogenesis was uncovered, offering clues for novel therapeutic targets for this condition.

Causal relationships between oral-gut microbiome and bone neoplasm-related phenotypes

The human oral and gut microbiota are the 4 largest microbial communities in the body and play crucial roles in maintaining homeostasis and influencing disease. Observational studies have suggested links between these microbiota and bone neoplasm-related phenotypes, but establishing causality has been challenging due to confounding factors and reverse causality. We conducted a bidirectional, 2-sample Mendelian randomization (MR) study to investigate evidence consistent with a potential causal association between the saliva and gut microbiota and various bone neoplasm-related phenotypes. Genetic instruments for saliva and gut microbiota were sourced from large genome-wide association studies. Inverse variance weighted was the primary MR method, supplemented by 4 other MR techniques. Sensitivity analyses, including MR-Egger regression, were performed to assess pleiotropy and heterogeneity. In the forward MR analysis, Veillonella parvula from the saliva microbiota was associated with a decreased risk of bone and connective tissue neoplasms (β: −0.236, 95% CI: [−0.275, −0.197], P = 8.20E−33). MR analyses identified genetically predicted associations between several microbial taxa and bone neoplasm-related phenotypes. Reverse MR analyses showed that genetic liability to bone neoplasm-related phenotypes was associated with variation in the composition of the oral (e.g., Order Bacteroidales, Rothia mucilaginosa) and gut microbiota (e.g., Class Methanobacteria, Genus Eubacterium oxidoreducens group). Sensitivity analyses confirmed the robustness of these findings, as no statistical evidence of substantial heterogeneity or directional horizontal pleiotropy was detected. This study provides genetic evidence supporting a bidirectional causal relationship between specific saliva and gut microbiota and bone neoplasm-related phenotypes. Our findings identify several microbial taxa as potential candidates for future biomarker development and therapeutic investigation in bone neoplasm-related phenotypes. However, these genetically informed associations require further mechanistic, experimental, and prospective clinical validation before clinical application.