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Investigating the causal impact of gut microbiota on arthritis via inflammatory proteins using mendelian
Bingxiao Pan1, Qihao Guo2, Jiani Cai3
1Department of Orthopedic Surgery, Shengjing Hospital of China Medical University, Shenyang, 110000, China.
Abstract:
Previous studies have suggested a potential association between the gut microbiota and arthritis. However, the causal links between the gut microbiota and various types of arthritis, as well as the potential mediating role of inflammatory proteins, remain unclear. Mendelian randomization was used to explore the causal relationships between gut microbiota, inflammatory proteins, and various forms of arthritis (osteoarthritis, rheumatoid and psoriatic arthritis, and ankylosing spondylitis [AS]). The inverse variance-weighted method was the primary analytical approach used. Furthermore, we examined the mediating role of inflammatory proteins in the pathway linking the gut microbiota to arthritis. Sensitivity analyses were performed to verify the robustness of the findings, and enrichment analyses were conducted to investigate the biological functions and pathways involved. We identified 11 positive and 14 negative causal effects linking the genetic liability of the gut microbiota to arthritis. Similarly, 9 positive and 8 negative causal effects between inflammatory proteins and arthritis were identified. Notably, an increased abundance of the order Bacillales (odds ratio [OR] = 1.199, 95% confidence interval [CI] = 1.030-1.394, P = 0.019) and higher interleukin-7 levels (OR = 1.322, 95% CI = 1.004-1.741, P = 0.046) significantly elevated the risk of AS. Furthermore, interleukin-7 mediated 13.8% of the effect caused by the order Bacillales, with a mediation effect size of β = 0.025 (95% CI = 0.001-0.064). Sensitivity and supplementary analyses revealed no significant evidence of horizontal pleiotropy or heterogeneity. Overall, our findings demonstrate causal links between the gut microbiota, inflammatory proteins, and four arthritis types, highlighting the gut microbiota as a potential therapeutic target. Crucially, interleukin-7 not only strongly correlated with AS but also partially mediated the effect exerted by the gut microbiota on AS, suggesting that managing the gut microbiota to modulate inflammatory proteins could serve as an effective therapeutic strategy for arthritis.
Insights
This study found causal links between gut bacteria and arthritis, with specific bacteria and inflammatory proteins like interleukin-7 increasing ankylosing spondylitis risk. Modulating gut microbiota may offer a new arthritis treatment strategy.
Area of Science:
- Microbiology
- Immunology
- Genetics
Background:
- Emerging evidence suggests a connection between gut microbiota composition and arthritis development.
- However, the precise causal relationships and the role of inflammatory proteins in this association remain largely unelucidated.
- Understanding these links is crucial for developing novel therapeutic strategies for various forms of arthritis.
Purpose of the Study:
- To investigate the causal relationships between gut microbiota, inflammatory proteins, and four major types of arthritis: osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis (AS).
- To explore the potential mediating role of inflammatory proteins in the gut microbiota-arthritis pathway.
- To identify specific microbial taxa and inflammatory markers causally associated with arthritis subtypes.
Main Methods:
- Utilized Mendelian randomization (MR) analysis, a robust genetic epidemiological method, to infer causal effects.
- Employed the inverse variance-weighted (IVW) method as the primary analytical approach.
- Conducted sensitivity analyses to ensure the reliability of findings and enrichment analyses to explore underlying biological pathways.
Main Results:
- Identified significant causal effects between gut microbiota genetic liability and arthritis, with 11 positive and 14 negative associations.
- Found 9 positive and 8 negative causal effects between inflammatory proteins and arthritis.
- Specifically, increased abundance of the order Bacillales and elevated interleukin-7 levels were significantly associated with an increased risk of ankylosing spondylitis (AS).
- Demonstrated that interleukin-7 partially mediates the effect of the order Bacillales on AS, accounting for 13.8% of the causal pathway.
Conclusions:
- Established causal links between the gut microbiota, specific inflammatory proteins, and four distinct types of arthritis.
- Highlighted the gut microbiota as a promising therapeutic target for arthritis management.
- Indicated that targeting gut microbiota to modulate inflammatory proteins, such as interleukin-7, could be a viable therapeutic strategy for AS and potentially other arthritis forms.
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