Causal Relationship Between Gut Microbiota and Non‐Suicidal Self‐Injury: A Two‐Sample Mendelian Randomization Study

ABSTRACT This study aims to determine the causal relationship between gut microbiota (GM) and Non‐Suicidal Self‐Injury (NSSI) using a two‐sample Mendelian Randomization (MR) approach. By identifying Single Nucleotide Polymorphisms (SNPs) linked to both GM and NSSI, we explore bidirectional causal effects to uncover potential therapeutic pathways. A bidirectional MR analysis was conducted using GWAS data. SNPs associated with GM were used as instrumental variables (IVs) to assess the causal impact of GM on NSSI and vice versa. Forward MR analysis applied Inverse Variance Weighted (IVW) and MR‐robust adjusted profile score (MR‐RAPS) methods to address weak IVs. Sensitivity analyses, including MR‐Egger regression, weighted median, and weighted mode methods, were employed to ensure robustness and minimize bias. Reverse MR analysis evaluated the influence of NSSI on GM. Additional tests, such as heterogeneity and leave‐one‐out analyses, were used for result validation. All analyses were performed using R software (v4.3.2) and the “TwoSampleMR” package. Our analysis identified significant associations between GM and NSSI. In the forward MR analysis, 38 GM taxa at the genus level were linked to NSSI, including Dorea (OR = 1.462, p = 0.023) and Escherichia Shigella (OR = 0.731, p = 0.035), which impacted hospital treatment needs. Notable taxa like Lachnospiraceae UCG001 (OR = 0.755, p = 0.012) and Paraprevotella (OR = 1.229, p = 0.022) were associated with self‐injurious behavior. Reverse MR identified 10 significant associations, including Prevotella9 ( p = 0.001) linked to inflammation and Faecalibacterium ( p = 0.014) with protective effects. Sensitivity analyses confirmed the robustness of findings, with no pleiotropy or bias detected. This study establishes a complex relationship between GM and NSSI, revealing both risk‐enhancing and protective associations. These findings suggest that GM may influence NSSI behaviors and could serve as a target for future therapeutic interventions. Further research is needed to explore underlying mechanisms and validate these results.