Lou Jiaqi,
Li Jiliang,
Cui Shengyong,
Huang Neng,
Jin Guoying,
Xu Sida,
Yu Yaohua,
Xu Pei,
Le Xin,
Pan Yanyan,
Fan Youfen
Abstract:
Objective To investigate the causal relationships between human gut microbiota features, immune cell phenotypes, and hypertrophic scar (HS). Methods This was a study based on two-step two-sample mediation Mendelian randomization (MR) analysis. Data on human gut microbiota characteristics, immune cell phenotypes, and HS were retrieved from the genome-wide association research database. The inverse variance weighted method was used to assess the causal relationships between 119 gut microbiota features, 731 immune cell phenotypes, and HS. Heterogeneity and horizontal pleiotropy were evaluated using Cochran's Q test and MR-Egger regression test, respectively. A two-step MR approach was employed to quantify the mediating effect of immune cell phenotypes in the association between gut microbiota features and HS. Results Seven gut microbiota features showed significant causal relationships with HS formation risk (P<0.05). Actinobacteria-Actinobacteria-Bifidobacteriales, Actinobacteria-Actinobacteria-Bifidobacteriales-Bifidobacteriaceae, Bacteroidetes-Bacteroidia-Bacteroidales-Rikenellaceae-Alistipes-Alistipes senegalensis, Firmicutes-Clostridia-Clostridiales-Clostridiaceae, superpathway of heme biosynthesis from glycine, and peptidoglycan biosynthesis I (containing meso-diaminopimelate) were significantly negatively associated with HS formation risk (with OR of 0.804, 0.804, 0.784, 0.820, 0.864, and 0.686, respectively, 95% CI of 0.649-0.996, 0.649-0.996, 0.623-0.988, 0.687-0.980, 0.759-0.984, and 0.491-0.959, respectively, P<0.05). Firmicutes-Clostridia-Clostridiales-Eubacteriaceae-Eubacterium-Eubacterium eligens was significantly positively associated with HS formation risk (OR=1.239, with 95% CI of 1.007-1.525, P<0.05). Twenty-three immune cell phenotypes showed significant causal relationships with HS formation risk. IgD⁻CD38⁻ B cell %B cell, CD11c⁺ human leukocyte antigen DR (HLA-DR)⁺⁺ monocyte absolute count, IgD⁻CD27⁻ B cell %B cell, CD25 expression on IgD⁻CD27⁻ B cells, CD8⁺ T cell %T cell, HLA-DR⁺⁺ monocyte %monocyte, HLA-DR expression on CD14⁺CD16⁻ monocytes, HLA-DR expression on CD14⁺ monocytes, CD20 expression on IgD⁺CD38⁺ B cells, programmed death-ligand 1 (PD-L1) expression on CD14⁻CD16⁺ monocytes, CD28⁺CD45RA⁻CD8dim T cell %, effector memory CD8⁺ T cell %T cell, CD25⁺⁺CD45RA⁻ CD4 non-regulatory T cell %, and CD45 expression on immature myeloid-derived suppressor cells were significantly negatively associated with HS fomation risk (with OR of 0.847, 0.878, 0.891, 0.894, 0.894, 0.903, 0.908, 0.911, 0.911, 0.916, 0.931, 0.932, 0.940, and 0.942, respectively, 95% CI of 0.731-0.982, 0.776-0.994, 0.798-0.995, 0.804-0.994, 0.824-0.970, 0.830-0.982, 0.848-0.971, 0.849-0.976, 0.851-0.976, 0.846-0.992, 0.886-0.977, 0.876-0.991, 0.886-0.997, and 0.889-0.998, respectively, P<0.05). HLA-DR expression on CD14⁺CD16⁺ monocytes, memory B cell absolute count, CD25 expression on CD45RA⁻ CD4 non-regulatory T cells, CD24 expression on IgD⁺CD38⁺ B cells, side scatter light area expression on natural killer (NK) cells, PD-L1 expression on CD14⁻CD16⁻ cells, CD25⁺⁺CD4⁺ T cell %T cell, CD16⁻CD56 expression on NK cells, and T cell absolute count were significantly positively associated with HS formation risk (with OR of 1.040, 1.056, 1.077, 1.100, 1.102, 1.102, 1.104, 1.113, and 1.156, respectively, 95% CI of 1.001-1.080, 1.001-1.114, 1.020-1.138, 1.030-1.174, 1.008-1.205, 1.024-1.187, 1.016-1.200, 1.034-1.198, and 1.047-1.276, respectively, P<0.05). No significant heterogeneity or horizontal pleiotropy was observed for the aforementioned associations (P>0.05). The significant overall protective effect of Firmicutes-Clostridia-Clostridiales-Clostridiaceae on HS (total effect β=-0.198, with 95% CI of -0.375--0.021, P<0.05) was partially mediated by HLA-DR⁺⁺ monocyte % and HLA-DR expression on CD14⁺CD16⁻ monocytes (with mediation effect β values of -0.016 and -0.020, respectively, 95% CI of -0.035--0.001 and -0.050--0.001, respectively, P values both <0.05), with mediation proportions of 8.333% and 13.333%, respectively. Conclusions Seven gut microbiota features and 23 immune cell phenotypes are significantly associated with HS formation risk. Specific gut microbiota, such as Clostridiaceae and Bifidobacteriales, may reduce HS formation risk potentially by modulating immune cell phenotypes like monocyte HLA-DR expression.
Lou Jiaqi,Li Jiliang,Cui Shengyong,et al.Two-step two-sample mediation Mendelian randomization analysis of causal relationships between human gut microbiota features, immune cell phenotypes, and hypertrophic scar[J].Chin J Burns Wounds,2026,42(4):1-10.DOI: 10.3760/cma.j.cn501225-20241226-00509.
Abstract
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