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Inflammatory Proteins Mediate the Effect of Gut Microbiota on Graves' Ophthalmopathy: A Mendelian Randomization Study
Yipao Li1,2, Lu Chen1,2, Shaokai Lin1,2
1National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Purpose:
This study investigates the causal relationship between gut microbiota (GM) and Graves' ophthalmopathy (GO) and explores the mediating role of circulating inflammatory proteins (IPs) in this association.
Methods:
A two-step, two-sample Mendelian randomization (MR) analysis was performed using GM data from MiBioGen (N = 18,340), GO data from the FinnGen Research Project (691 cases, 411,490 controls), and IP data from a genome-wide association study (N = 14,824). The primary MR analysis utilized the inverse variance-weighted approach, supplemented by MR Egger, weighted median, maximum likelihood, and MR robust adjusted profile score methods. Mediation MR was used to assess the mediating role of IPs.
Results:
We identified 26 GM taxa causally associated with GO. Notably, the genus Parabacteroides exhibited a protective effect on GO (odds ratio = 0.29; 95% confidence interval, 0.16-0.51; P < 0.001). Additionally, five circulating IPs demonstrated protective effects, while three IPs (CXCL10, CXCL11, EN-RAGE) were associated with increased GO risk. Mediation MR showed that CXCL10 mediated the pathway from Parabacteroides to GO (mediation effect = -0.07), accounting for 5.27% of the total effect.
Conclusions:
This study supports a causal link between GM and GO, mediated by circulating IPs. These findings offer new insights into GO pathogenesis and potential targets for clinical intervention.
Translational Relevance:
Our findings reveal how gut microbiota influences Graves' ophthalmopathy through inflammatory proteins, providing potential therapeutic targets for disease prevention and treatment.
Insights
The gut microbiome influences Graves' ophthalmopathy (GO) through inflammatory proteins. Specific bacteria like Parabacteroides may protect against GO, offering potential therapeutic targets.
Area of Science:
- Genetics
- Immunology
- Microbiology
Background:
- Graves' ophthalmopathy (GO) is an autoimmune condition affecting the eyes.
- The gut microbiota's role in GO pathogenesis is not fully understood.
- Inflammatory proteins are implicated in GO development.
Purpose of the Study:
- To investigate the causal relationship between gut microbiota (GM) and GO.
- To explore the mediating role of circulating inflammatory proteins (IPs) in the GM-GO association.
Main Methods:
- Two-step, two-sample Mendelian randomization (MR) analysis.
- Utilized large-scale genetic data for GM, GO, and IPs.
- Employed various MR methods including inverse variance-weighted and mediation MR.
Main Results:
- Identified 26 GM taxa causally associated with GO.
- The genus Parabacteroides showed a protective effect against GO.
- CXCL10 mediated the pathway from Parabacteroides to GO, suggesting a specific mechanism.
Conclusions:
- Establishes a causal link between GM and GO, mediated by IPs.
- Highlights potential therapeutic targets for GO prevention and treatment.
- Provides novel insights into GO pathogenesis.
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