Abstract
Hypertrophic scars (HS), classified as abnormal scarring, result from an overactive tissue response during wound healing following dermal trauma. Nonetheless, the precise mechanistic pathway underlying its occurrence remains elusive. The principal aim of this study is to elucidate the causal relationship among gut microbiota (GM), immune cell function, and hypertrophic scarring in a European demographic. Leveraging the genome-wide association analysis (GWAS) database, we conducted a two-sample Mendelian randomization (MR) study on gut microbiota (GM), immune cells, and HS. To ascertain the causality between GM, immune cells, and HS, we utilized the inverse variance weighted (IVW) method while employing multiple approaches to negate the effects of pleiotropy and heterogeneity. Furthermore, we quantitatively evaluated the influences of immune cells-mediated GM on hypertrophic scar through a two-step MR analysis. The two-sample MR analysis demonstrated a potential causality between 5 genera of gut microbiotas and 23 immune cell traits with respect to hypertrophic scarring. Further, our results showed that the causal pathway from the genus Subdoligranulum to hypertrophic scar (HS) was mediated by B cell-activating factor receptor (BAFF-R) on CD20- CD38- B cell, with a beta value of 0.034 (95% CI [0.002, 0.066]; P = 0.004), contributing to 7.60% of the total effect of Subdoligranulum on HS. Similarly, CD24 on IgD + CD38 + B cell exhibited a causal impact in the pathway from genus Coprococcus 1 to HS, with a beta value of -0.015 (95% CI [-0.029, -0.001]; P = 0.023), constituting 6.70% of the total effect of Coprococcus 1 on HS. Additionally, the CD8 + T cell %T cell mediated the causal pathway from the genus Adlercreutzia to HS with a beta value of 0.075 (95% CI [0.017, 0.133]; P = 0.024), contributing to 10.10% of the total effect of Adlercreutzia on HS. Our study indicates that the development of hypertrophic scars might be influenced by specific gut microbiota and immune cells. We highlight the possible role of two distinct immune cell genotypes as mediators in this relationship. However, most statistical significance of these findings was not maintained after FDR correction, suggesting our results should be viewed as preliminary and interpreted with caution. Further research is needed to confirm these associations.