Abstract：
BACKGROUND: Previous observational studies have indicated a complex association between gut microbiota (GM) and neuropathic pain (NP). Nonetheless, the precise biological mechanisms underlying this association remain unclear. Therefore, we adopted a Mendelian randomization (MR) approach to investigate the causal relationship between GM and neuropathic pain including post-herpetic neuralgia (PHN), painful diabetic peripheral neuropathy (PDPN), and trigeminal neuralgia (TN), as well as to explore the potential mediation effects of immune cells.
METHODS: We performed a two-step, two-sample Mendelian randomization study with an inverse variance-weighted (IVW) approach to investigate the causal role of GM on three major kinds of NP and the mediation effect of immune cells between the association of GM and NP. In addition, we determine the strongest causal associations using Bayesian weighted Mendelian randomization (BWMR) analysis. Furthermore, we will investigate the mediating role of immune cells through a two-step Mendelian randomization design.
RESULTS: We identified 53 taxonomies and pathways of gut microbiota that had significant causal associations with NP. In addition, we also discovered 120 immune cells that exhibited significant causal associations with NP. According to the BWMR and two-step Mendelian randomization analysis, we identified the following results CD4 on CM CD4 + (maturation stages of T cell) mediated 6.7% of the risk reduction for PHN through the pathway of fucose degradation (FUCCAT.PWY). CD28 + DN (CD4-CD8-) AC (Treg) mediated 12.5% of the risk reduction for PHN through the influence on Roseburia inulinivorans. CD45 on lymphocyte (Myeloid cell) mediated 11.9% of the risk increase for TN through the superpathway of acetyl-CoA biosynthesis (PWY.5173). HLA DR + CD8br %T cell (TBNK) mediated 3.2% of the risk reduction for TN through the superpathway of GDP-mannose-derived O-antigen building blocks biosynthesis (PWY.7323). IgD-CD38-AC (B cell) mediated 7.5% of the risk reduction for DPN through the pathway of thiazole biosynthesis I in E. coli (PWY.6892).
CONCLUSIONS: These findings provided evidence supporting the causal effect of GM with NP, with immune cells playing a mediating role. These findings may inform prevention strategies and interventions directed toward NP. Future studies should explore other plausible biological mechanisms.
METHODS: We performed a two-step, two-sample Mendelian randomization study with an inverse variance-weighted (IVW) approach to investigate the causal role of GM on three major kinds of NP and the mediation effect of immune cells between the association of GM and NP. In addition, we determine the strongest causal associations using Bayesian weighted Mendelian randomization (BWMR) analysis. Furthermore, we will investigate the mediating role of immune cells through a two-step Mendelian randomization design.
RESULTS: We identified 53 taxonomies and pathways of gut microbiota that had significant causal associations with NP. In addition, we also discovered 120 immune cells that exhibited significant causal associations with NP. According to the BWMR and two-step Mendelian randomization analysis, we identified the following results CD4 on CM CD4 + (maturation stages of T cell) mediated 6.7% of the risk reduction for PHN through the pathway of fucose degradation (FUCCAT.PWY). CD28 + DN (CD4-CD8-) AC (Treg) mediated 12.5% of the risk reduction for PHN through the influence on Roseburia inulinivorans. CD45 on lymphocyte (Myeloid cell) mediated 11.9% of the risk increase for TN through the superpathway of acetyl-CoA biosynthesis (PWY.5173). HLA DR + CD8br %T cell (TBNK) mediated 3.2% of the risk reduction for TN through the superpathway of GDP-mannose-derived O-antigen building blocks biosynthesis (PWY.7323). IgD-CD38-AC (B cell) mediated 7.5% of the risk reduction for DPN through the pathway of thiazole biosynthesis I in E. coli (PWY.6892).
CONCLUSIONS: These findings provided evidence supporting the causal effect of GM with NP, with immune cells playing a mediating role. These findings may inform prevention strategies and interventions directed toward NP. Future studies should explore other plausible biological mechanisms.
摘要：
背景：先前的观察性研究表明，肠道微生物群（GM）与神经性疼痛（NP）之间存在复杂的关联。尽管如此，这种关联的确切生物学机制尚不清楚.因此,我们采用孟德尔随机化（MR）方法来研究GM与神经性疼痛（包括带状疱疹后神经痛）之间的因果关系，疼痛性糖尿病周围神经病变（PDPN），和三叉神经痛（TN），以及探索免疫细胞的潜在调解作用。
方法：我们进行了两步，采用反向方差加权（IVW）方法的双样本孟德尔随机化研究，以研究GM对三种主要NP的因果作用以及免疫细胞在GM和NP关联之间的调解作用。此外,我们使用贝叶斯加权孟德尔随机化(BWMR)分析确定最强的因果关联.此外，我们将通过两步孟德尔随机化设计研究免疫细胞的介导作用.
结果：我们确定了与NP具有显著因果关联的肠道微生物群的53个分类和途径。此外,我们还发现了120个与NP表现出显著因果关联的免疫细胞.根据BWMR和孟德尔两步随机化分析，我们确定了以下结果，CMCD4上的CD4（T细胞的成熟期）通过岩藻糖降解途径（FUCCAT。PWY）。CD28+DN(CD4-CD8-)AC(Treg)通过影响刺骨玫瑰草,介导了12.5%的PHN风险降低。淋巴细胞（髓系细胞）上的CD45通过乙酰辅酶A生物合成的超途径（PWY.5173）介导了TN风险增加的11.9％。HLADR+CD8br%T细胞(TBNK)通过GDP-甘露糖衍生的O-抗原构建块生物合成的超途径(PWY.7323)介导TN的风险降低3.2%。IgD-CD38-AC(B细胞)通过在大肠杆菌中的噻唑生物合成途径I介导7.5%的DPN风险降低(PWY.6892)。
结论：这些发现提供了证据支持GM与NP的因果效应，免疫细胞起着中介作用。这些发现可能为针对NP的预防策略和干预提供信息。未来的研究应该探索其他合理的生物学机制。
方法：我们进行了两步，采用反向方差加权（IVW）方法的双样本孟德尔随机化研究，以研究GM对三种主要NP的因果作用以及免疫细胞在GM和NP关联之间的调解作用。此外,我们使用贝叶斯加权孟德尔随机化(BWMR)分析确定最强的因果关联.此外，我们将通过两步孟德尔随机化设计研究免疫细胞的介导作用.
结果：我们确定了与NP具有显著因果关联的肠道微生物群的53个分类和途径。此外,我们还发现了120个与NP表现出显著因果关联的免疫细胞.根据BWMR和孟德尔两步随机化分析，我们确定了以下结果，CMCD4上的CD4（T细胞的成熟期）通过岩藻糖降解途径（FUCCAT。PWY）。CD28+DN(CD4-CD8-)AC(Treg)通过影响刺骨玫瑰草,介导了12.5%的PHN风险降低。淋巴细胞（髓系细胞）上的CD45通过乙酰辅酶A生物合成的超途径（PWY.5173）介导了TN风险增加的11.9％。HLADR+CD8br%T细胞(TBNK)通过GDP-甘露糖衍生的O-抗原构建块生物合成的超途径(PWY.7323)介导TN的风险降低3.2%。IgD-CD38-AC(B细胞)通过在大肠杆菌中的噻唑生物合成途径I介导7.5%的DPN风险降低(PWY.6892)。
结论：这些发现提供了证据支持GM与NP的因果效应，免疫细胞起着中介作用。这些发现可能为针对NP的预防策略和干预提供信息。未来的研究应该探索其他合理的生物学机制。
