Cell‐Type‐Specific WTAP and ALKBH5 ‐Mediated m 6 A Methylation Orchestrates Mental Disorders via Gut‐Brain Axis Metabolite Signaling: Multi‐Omics Evidence and Pyroptosis‐Associated Loop Mechanism

ABSTRACT Introduction Mental disorders affect one billion people and contribute 5% of global DALYs. Although N6‐methyladenosine (m 6 A) modification, gut microbiota, cerebrospinal fluid (CSF) metabolites, and pyroptosis have been implicated in disease pathogenesis, the directionality and magnitude of causal links remain elusive. We integrated two‐sample Mendelian randomization (MR) with single‐cell eQTL data to generate hypotheses regarding these relationships. Methods Using large‐scale GWAS summary statistics, we estimated the causal effects of m 6 A regulators, gut microbiota, CSF metabolites, and pyroptosis on depression, schizophrenia (SZ), bipolar disorder (BD), attention‐deficit/hyperactivity disorder (ADHD), and post‐traumatic stress disorder (PTSD). Mediation analysis quantified hypothesized microbiota‐ and metabolite‐mediated proportions; single‐cell eQTL from 14 immune subsets localized genetic associations to cell types. Results MR analysis suggested distinct causal associations of m 6 A modifiers (WTAP/ALKBH5) with mental disorders. Gut microbiota (e.g., GCA‐900066755, Bacillus) and CSF metabolites (e.g., theophylline, isoleucine) were estimated to potentially mediate 5.06%–45.28% of these effects, forming pathways such as WTAP → GCA‐900066755 → theophylline → ADHD and ALKBH5 → CAG‐390 → isoleucine → PTSD. These represent statistically inferred associations rather than experimentally validated pathways. Notably, these proportions were not based on multiple‐testing–corrected associations. Single‐cell eQTL mapping associated WTAP's ADHD risk with XCL1‐NK cells (OR = 1.445). Bidirectional MR suggested potential reciprocal associations between mental disorders and microbial/metabolite profiles. Pyroptosis demonstrated a tentative statistical association (3.99% explanatory power), though its specific biological role remains undefined. Conclusion This multi‐omics integration generates a hypothesis regarding a potential m 6 A–microbiota–metabolite axis that may be associated with mental disorders, with pyroptosis as a potentially related peripheral factor. Should these associations prove causal, the identified relationships could suggest peripheral intervention nodes, while combinatorial targeting might provide directions for preventive psychiatry. Experimental validation is required to confirm the biological mechanisms implied by these genetic associations.