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Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study
Feihong Ren1,2, Qiubai Jin1, Tongtong Liu1
1Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Background:
Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN.
Methods:
Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality.
Results:
At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found.
Conclusion:
Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".
Insights
This study used Mendelian randomization to find that the gut bacterium Enterorhabdus may protect against IgA nephropathy (IgAN), while Butyricicoccus increases IgAN risk. These findings could lead to new gut microbiota-targeted IgAN therapies.
Area of Science:
- Genetics
- Microbiology
- Nephrology
Background:
- Therapeutic targeting of the gut microbiota (GM) shows promise for IgA nephropathy (IgAN) prevention and treatment.
- Previous studies indicated a correlation between GM and IgAN, but lacked causal evidence.
Purpose of the Study:
- To investigate the causal relationship between the gut microbiota and IgA nephropathy using a bi-directional Mendelian randomization approach.
- To identify specific gut bacterial taxa causally associated with IgAN.
Main Methods:
- Utilized genome-wide association study (GWAS) data for GM (MiBioGen) and IgAN (FinnGen).
- Employed the inverse variance weighted (IVW) method as the primary analysis, supported by MR-Egger and weighted median methods.
- Conducted sensitivity analyses including Cochrane's Q test, MR-Egger, and MR-PRESSO to assess heterogeneity and pleiotropy, alongside Bayesian model averaging (MR-BMA) for result validation.
Main Results:
- Genus Enterorhabdus was identified as a protective factor for IgAN (OR: 0.456, p=0.023).
- Genus Butyricicoccus was identified as a risk factor for IgAN (OR: 3.471, p=0.0008).
- Sensitivity analyses indicated no significant heterogeneity or pleiotropy.
Conclusions:
- Established a causal link between specific gut microbiota taxa and IgAN.
- Identified Enterorhabdus and Butyricicoccus as potential biomarkers for IgAN.
- These findings advance the understanding of the gut-kidney axis and may inform targeted IgAN therapies.
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