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Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.\n                  <\/jats:p>","DOI":"10.1172\/jci202262","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:01:13Z","timestamp":1784052073000},"source":"Crossref","is-referenced-by-count":1,"title":["Gut microbe\u2013derived short-chain fatty acids regulate alphavirus arthritis and macrophage activation in mice"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5059-0833","authenticated-orcid":true,"given":"Fang R.","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Medicine and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksim","family":"Kleverov","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, 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