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Although N6\u2010methyladenosine (m\n                      <jats:sup>6<\/jats:sup>\n                      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\u2010sample Mendelian randomization (MR) with single\u2010cell eQTL data to generate hypotheses regarding these relationships.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using large\u2010scale GWAS summary statistics, we estimated the causal effects of m\n                      <jats:sup>6<\/jats:sup>\n                      A regulators, gut microbiota, CSF metabolites, and pyroptosis on depression, schizophrenia (SZ), bipolar disorder (BD), attention\u2010deficit\/hyperactivity disorder (ADHD), and post\u2010traumatic stress disorder (PTSD). Mediation analysis quantified hypothesized microbiota\u2010 and metabolite\u2010mediated proportions; single\u2010cell eQTL from 14 immune subsets localized genetic associations to cell types.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analysis suggested distinct causal associations of m\n                      <jats:sup>6<\/jats:sup>\n                      A modifiers (WTAP\/ALKBH5) with mental disorders. Gut microbiota (e.g., GCA\u2010900066755, Bacillus) and CSF metabolites (e.g., theophylline, isoleucine) were estimated to potentially mediate 5.06%\u201345.28% of these effects, forming pathways such as WTAP \u2192 GCA\u2010900066755 \u2192 theophylline \u2192 ADHD and ALKBH5 \u2192 CAG\u2010390 \u2192 isoleucine \u2192 PTSD. These represent statistically inferred associations rather than experimentally validated pathways. Notably, these proportions were not based on multiple\u2010testing\u2013corrected associations. Single\u2010cell eQTL mapping associated WTAP's ADHD risk with XCL1\u2010NK cells (OR\u2009=\u20091.445). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This multi\u2010omics integration generates a hypothesis regarding a potential m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2013microbiota\u2013metabolite 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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70840","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T04:01:38Z","timestamp":1773633698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cell\u2010Type\u2010Specific\n                    <scp>WTAP<\/scp>\n                    and\n                    <scp>ALKBH5<\/scp>\n                    \u2010Mediated\n                    <scp>\n                      m\n                      <sup>6<\/sup>\n                      A\n                    <\/scp>\n                    Methylation Orchestrates Mental Disorders via Gut\u2010Brain Axis Metabolite Signaling: Multi\u2010Omics Evidence and Pyroptosis\u2010Associated Loop Mechanism"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9530-5072","authenticated-orcid":false,"given":"Jingjing","family":"Zhang","sequence":"first","affiliation":[{"name":"Qilu Aerospace Information Research Istitute  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Liu","sequence":"additional","affiliation":[{"name":"Geriatric Medicine Center Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Geriatric Medicine Center Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7298-6476","authenticated-orcid":false,"given":"Junjie","family":"Bi","sequence":"additional","affiliation":[{"name":"Geriatric Medicine Center Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,15]]},"reference":[{"key":"e_1_2_13_2_1","volume-title":"Preventing Relapse: Depression in Adults: Evidence Review C","year":"2022"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0230363"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.3109\/15622970209150605"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2022.1142"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/schbul\/sbn074"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.4103\/0253\u20107176.198955"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1017\/S2045796019000313"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1017\/S2045796017000476"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpsychores.2022.110788"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291724001077"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.13649"},{"issue":"11","key":"e_1_2_13_13_1","first-page":"30","article-title":"Our Current Understanding of Adult ADHD","volume":"11","author":"Targum S. 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