Dataset Information

Causal relationship of gut microbiota with diabetic nephropathy: a Mendelian randomization analysis.

ABSTRACT:

Background

Patients with DN (diabetic nephropathy) show remarkable variations in their gut microbiota composition. However, to date, no study has shown whether a causal relationship exists between gut microbiota composition and DN.

Methods

Here, we performed a two-sample Mendelian randomization (MR) investigation for identifying causal associations of gut microbiota with DN. Gut microbiota genetic data were gathered from the recent genome-wide association study pooled data of the MiBioGen consortium, which included 24 cohorts and 18,340 individuals.

Results

IVW(Inverse variance weighting) revealed that Verrucomicrobia [odds ratio (OR) = 1.390; 95% confidence interval (CI) = 1.10-1.75; p = 0.005], Peptostreptococcaceae (OR = 1.284; 95% CI = 1.03-1.59; p = 0.012), Verrucomicrobiaceae (OR = 1.390; 95% CI = 1.10-1.75; p = 0.005), Akkermansia (OR = 1.390; 95% CI = 1.10-1.75; p = 0.005), Butyricimonas (OR = 1.261; 95% CI = 1.02-1.55; p = 0.031), Catenibacterium (OR = 1.278; 95% CI = 1.02-1.59; p = 0.030).

Conclusion

Two-sample MR analysis identified 12 microbial taxa in gut microbiota (one of which is yet to be officially named) that showed significant causal associations with DN; 8 of these taxa significantly increased the risk of DN, while the remaining 4 taxa (including the one without an official name) reduced the risk of DN. The precise mechanisms influencing the interactions of gut microbiota with DN occurrence remain unclear; hence, additional investigations should be conducted to clarify these mechanisms.

SUBMITTER: Yan W

PROVIDER: S-EPMC10792041 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Causal relationship of gut microbiota with diabetic nephropathy: a Mendelian randomization analysis.

Yan Wei W Ge Ying Y Wang Lina L Wang Yuntao Y He Daikun D

Frontiers in microbiology 20240103

<h4>Background</h4>Patients with DN (diabetic nephropathy) show remarkable variations in their gut microbiota composition. However, to date, no study has shown whether a causal relationship exists between gut microbiota composition and DN.<h4>Methods</h4>Here, we performed a two-sample Mendelian randomization (MR) investigation for identifying causal associations of gut microbiota with DN. Gut microbiota genetic data were gathered from the recent genome-wide association study pooled data of the ...[more]

PMID: 38235430

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Project description:ObjectiveEmerging evidence has provided compelling evidence linking gut microbiota (GM) and diabetic nephropathy (DN) via the "gut-kidney" axis. But the causal relationship between them hasn't been clarified yet. We perform a Two-Sample Mendelian randomization (MR) analysis to reveal the causal connection with GM and the development of DN, type 1 diabetes nephropathy (T1DN), type 2 diabetes nephropathy (T2DN), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM).MethodsWe used summary data from MiBioGen on 211 GM taxa in 18340 participants. Generalized MR analysis methods were conducted to estimate their causality on risk of DN, T1DN, T2DN, T1DM and T2DM from FinnGen. To ensure the reliability of the findings, a comprehensive set of sensitivity analyses were conducted to confirm the resilience and consistency of the results.ResultsIt was showed that Class Verrucomicrobiae [odds ratio (OR) =1.5651, 95%CI:1.1810-2.0742,PFDR=0.0018], Order Verrucomicrobiales (OR=1.5651, 95%CI: 1.1810-2.0742, PFDR=0.0018) and Family Verrucomicrobiaceae (OR=1.3956, 95%CI:1.0336-1.8844, PFDR=0.0296) had significant risk of DN. Our analysis found significant associations between GM and T2DN, including Class Verrucomimicrobiae (OR=1.8227, 95% CI: 1.2414-2.6763, PFDR=0.0139), Order Verrucomimicrobiae (OR=1.5651, 95% CI: 1.8227-2.6764, PFDR=0.0024), Rhodospirillales (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0026), and Family Verrucomicroniaceae (OR=1.8226, 95% CI: 1.2412-2.6763, PFDR=0.0083). The Eubacteriumprotogenes (OR=0.4076, 95% CI: 0.2415-0.6882, PFDR=0.0021) exhibited a protection against T1DN. Sensitivity analyses confirmed that there was no significant heterogeneity and pleiotropy.ConclusionsAt the gene prediction level, we identified the specific GM that is causally linked to DN in both T1DM and T2DM patients. Moreover, we identified distinct microbial changes in T1DN that differed from those seen in T2DN, offering valuable insights into GM signatures associated with subtype of nephropathy.

Project description:ObjectivePrevious observational studies suggest a potential link between gut microbiota, metabolites, and diabetic nephropathy. However, the exact causal relationship among these factors remains unclear.MethodWe conducted a two-sample bidirectional Mendelian randomization study using summary statistics from the IEU OpenGWAS Project database to investigate gut microbiota, metabolites, and diabetic nephropathy. A range of methods, including inverse variance weighting, MR-Egger, weighted median, and simple median, were applied to examine causal associations. Sensitivity analyses were performed to assess the robustness of the results. Additionally, reverse Mendelian randomization analysis was conducted, treating significant gut microbiota as the outcome, to evaluate effects and perform sensitivity testing. This comprehensive approach provided an in-depth assessment of the interactions among gut microbiota, metabolites, and diabetic nephropathy.ResultThe Inverse Variance Weighted estimates revealed that the abundance of Lachnospiraceae, Parasutterella, and Eubacterium exhibited negative causal effects on diabetic nephropathy, while Coprococcus, Sutterella, Faecalibacterium prausnitzii, and Bacteroides vulgatus showed protective causal effects against the condition. However, reverse Mendelian randomization analysis did not identify any significant associations between diabetic nephropathy and the identified gut microbiota. Furthermore, the estimates indicated that Cholesterol, Pyridoxate, Hexanoylcarnitine, X-12007, Octanoylcarnitine, 10-nonadecenoate (19:1n9), X-12734, and the average number of double bonds in a fatty acid chain had negative causal effects on diabetic nephropathy. In contrast, Methionine, Glycodeoxycholate, X-06351, 1-stearoylglycerol (1-monostearin), 5-dodecenoate (12:1n7), X-13859, 2-hydroxyglutarate, Glycoproteins, Phospholipids in IDL, and the concentration of small HDL particles demonstrated protective causal effects. Notably, sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy, ensuring the robustness of the findings.ConclusionModulating gut microbiota diversity and composition offers a promising strategy for improving the incidence and prognosis of diabetic nephropathy. This highlights the need for future clinical trials focusing on microbiome-based interventions, potentially utilizing microbiome-dependent metabolites. Such approaches could transform the treatment and management of diabetic nephropathy and its associated risk factors, paving the way for more effective therapeutic strategies to combat this debilitating condition.

Project description:ObjectiveThe aim of this study was to investigate the causal relationship between microbiota, diabetic nephropathy, and blood metabolites through a randomized Mendelian study.MethodsIn this study, we used 412 microbiota as exposures, 1,400 blood metabolites as intermediaries, and diabetic nephropathy as the outcome. We conducted a two-way Mendelian randomization (MR) analysis to explore the causal relationship between microbiota and diabetic nephropathy, followed by mediation analyses and two-step MR to identify potential blood metabolites.ResultsThere is a causal relationship between microbiota and diabetic nephropathy. Specific bacteria and metabolites, such as Escherichia coli str. K-12 substr. MG1655, Listeria monocytogenes 10403S, g_Adlercreutzia, g_Haemophilus, g_Bacteroides, and Escherichia coli CFT073, and metabolites like pyrraline, glycocholenate sulfate, alpha-ketoglutarate, tetradecadienoate (14:2), Cys-gly oxidized, methylsuccinate, and various others, were identified. Escherichia coli str. K-12 substr. MG1655 is positively related to alpha-ketoglutarate levels, while alpha-ketoglutarate levels and Sphingomyelin (d18:1/18:1, d18:2/18:0) are negatively related. The bacterial microbiota involved in fatty acid oxidation is associated with diabetic kidney disease (DKD) progression, positively correlated with glycocholenate sulfate levels, and negatively correlated with the phosphate linoleyl-tetraenyl-glycerol (18:2 to 20:4) ratio. Additionally, Listeria monocytogenes 10403S is positively correlated with N-acetyl-isoputreanine and negatively correlated with X-12462. Anaerobic fermentation-related bacteria were positively related to N-acetylcarnitine and 5-acetylamino-6-formyluracil and negatively correlated with 5-acetamino-6-amino-3-methyluracil (X-24243). Escherichia coli CFT073 was positively associated with X-16580. Interactions between Bacillus species and metabolites such as d18:1/18:1, d18:2/18:0, 2-aminophenol sulfate, and cholate were negative when compared to tetradecadienoate (14:2). g_Adlercreutzia is positively correlated with N-delta-acetylornithine, methylsuccinate, and N-acetyl-isoputreanine but negatively correlated with N-acetylglucosamine and N-acetylgalactosamine. g_Haemophilus was positively associated with arachidoylcarnitine but negatively correlated with X-24531. The results were heterogeneous and multi-efficacious.ConclusionsFor the first time, MR analysis provides supportive evidence for a bidirectional causal relationship between microbiota and diabetic nephropathy and identifies specific genes associated with the disease. The results suggest that probiotic therapy may play a significant role in preventing diabetic nephropathy and improving the quality of life and survival rates of affected patients. Furthermore, this study provides additional evidence of a causal relationship between specific microbiota, diabetic nephropathy, and blood metabolites.

Project description:BackgroundThe correlation between diabetic nephropathy (DN) and gut microbiota (GM) has been suggested in numerous animal experiments and cross-sectional studies. However, a causal association between GM and DN has not been ascertained.MethodsThis research adopted MR analysis to evaluate the causal link between GM and DN derived from data acquired through publicly available genome-wide association studies (GWAS). The study utilized the inverse variance weighted (IVW) approach to assess causal association between GM and DN. Four additional methods including MR-Egger, weighted median, weighted mode, and simple mode were employed to ensure comprehensive analysis and robust results. The Cochran's Q test and the MR-Egger method were conducted to identify heterogeneity and horizontal pleiotropy, respectively. The leave-one-out approach was utilized to evaluate the stability of MR results. Finally, a reverse MR was performed to identify the reverse causal association between GM and DN.ResultsAccording to IVW analysis, Class Verrucomicrobiae (p = 0.003), Order Verrucomicrobiales (p = 0.003), Family Verrucomicrobiaceae (p = 0.003), Genus Akkermansia (p = 0.003), Genus Catenibacterium (p = 0.031), Genus Coprococcus 1 (p = 0.022), Genus Eubacterium hallii group (p = 0.018), and Genus Marvinbryantia (p = 0.023) were associated with a higher risk of DN. On the contrary, Class Actinobacteria (p = 0.037), Group Eubacterium ventriosum group (p = 0.030), Group Ruminococcus gauvreauii group (p = 0.048), Order Lactobacillales (p = 0.045), Phylum Proteobacteria (p = 0.017) were associated with a lower risk of DN. The sensitivity analysis did not identify any substantial pleiotropy or heterogeneity in the outcomes. We found causal effects of DN on 11 GM species in the reverse MR analysis. Notably, Phylum Proteobacteria and DN are mutually causalities.ConclusionThis study identified the causal association between GM and DN with MR analysis, which may enhance the understanding of the intestinal-renal axis and provide novel potential targets for early non-invasive diagnosis and treatment of DN.

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.

Dataset Information

Causal relationship of gut microbiota with diabetic nephropathy: a Mendelian randomization analysis.

Background

Methods

Results

Conclusion

Publications

Causal relationship of gut microbiota with diabetic nephropathy: a Mendelian randomization analysis.

Similar Datasets

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