{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:59:45Z","timestamp":1780898385535,"version":"3.54.1"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Gout is increasingly recognized as a systemic metabolic disorder driven by the \u201cgut-joint axis\u201d rather than a purely localized joint disease. However, the exact mechanisms by which intestinal dysfunction causes persistent joint inflammation remain unclear. This review proposes a novel \u201cTwo-Hit\u201d theoretical framework mediated by bacterial outer membrane vesicles (OMVs) and N6-methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) epigenetic modifications. We hypothesize that the high uric acid environment in the gut exerts a metabolic stress on specific bacteria, driving the release of highly pathogenic OMVs. Following intestinal barrier damage, these OMVs, working synergistically with intestinal-derived lipopolysaccharide (LPS), act as cross-organ messengers to deliver a \u201ctwo-hit\u201d strike to the joint. First, they prime synovial macrophages (SMs) by upregulating m\n                    <jats:sup>6<\/jats:sup>\n                    A methylation (via the methyltransferase-like 3 enzyme, METTL3), creating a pro-inflammatory epigenetic memory. Second, they induce metabolic reprogramming, characterized by enhanced glycolysis and local acidification in synovial fibroblasts, which physically forces the crystallization of uric acid. Based on this theoretical model, we evaluate emerging therapeutic strategies. These include stabilizing bacterial membranes to block OMV release, using biomimetic nanotechnology to intercept circulating vesicles, and targeting m\n                    <jats:sup>6<\/jats:sup>\n                    A enzymes to erase inflammatory memory. Ultimately, this hypothesis suggests a potential framework to conceptually shift gout management from symptom relief toward source-to-epigenetic precision interventions, while highlighting the necessary directions for future experimental validation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1854522","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:33:40Z","timestamp":1780896820000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The gut-joint axis in gout: microbial outer membrane vesicles and m6A-mediated metabolic-epigenetic coupling from acute flare to chronicity"],"prefix":"10.3389","volume":"17","author":[{"given":"Yiyang","family":"Qi","sequence":"first","affiliation":[{"name":"Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jixiang","family":"Bai","sequence":"additional","affiliation":[{"name":"Hongqi Hospital Affiliated with Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dewei","family":"Liu","sequence":"additional","affiliation":[{"name":"Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Hongqi Hospital Affiliated with Mudanjiang Medical University","place":["Mudanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0333368","article-title":"Global burden of gout among young people from 1990 to 2021, with projections for 2050: A systematic analysis 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