{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:03:42Z","timestamp":1790075022874,"version":"4.0.1"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"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. Pharmacol."],"abstract":"<jats:p>Difficult-to-treat rheumatoid arthritis (D2T RA) remains a major clinical problem despite treat-to-target care and an expanding range of disease-modifying antirheumatic drugs (DMARDs). D2T RA includes biologically distinct states, particularly persistent inflammatory refractory rheumatoid arthritis (PIRRA) and non-inflammatory refractory rheumatoid arthritis (NIRRA). Direct microbiome evidence in D2T RA is sparse, but studies in established RA, at-risk populations, and treatment-response cohorts suggest that intestinal ecological disruption may sustain inflammation through barrier failure, persistent microbial-product sensing, and impaired metabolite-mediated immune regulation. Gut microorganisms may also influence drug response, especially to methotrexate, while antirheumatic therapy can remodel the microbial ecosystem. We therefore synthesize the literature into three hypothesis-generating functional states, provisionally termed inflammation-amplifying, immune-tolerance-deficient, and poor-drug-response-associated microbial endotypes. These states are not validated patient classes and may overlap or evolve over time. We also propose a microbiota\u2013treatment resistance feedback loop, explicitly as an inferential model rather than an established causal pathway. Microbiota-directed adjuncts are evaluated according to evidence maturity, mechanistic fit, and safety. Overall, the gut microbiota is best considered a potential upstream modifier linking mucosal immunity, persistent inflammation, and pharmacological response, with the most coherent mechanistic relevance to PIRRA. Prospective D2T RA cohorts with objective inflammatory phenotyping, longitudinal multi-omics, and detailed drug-exposure data are needed before these concepts can inform clinical stratification or treatment.<\/jats:p>","DOI":"10.3389\/fphar.2026.1939732","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:13:11Z","timestamp":1790071991000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut dysbiosis in difficult-to-treat rheumatoid arthritis: hypothesized microbial endotypes, persistent inflammation, and pharmacological treatment resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhibo","family":"Chai","sequence":"first","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyi","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Clinical College, Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiannan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e0054125","DOI":"10.1128\/msystems.00541-25","article-title":"A hidden confounder for microbiome studies: medications used years before sample collection","volume":"10","author":"Aasmets","year":"2025","journal-title":"mSystems"},{"key":"B2","doi-asserted-by":"publisher","first-page":"keaf515","DOI":"10.1093\/rheumatology\/keaf515","article-title":"Predicting rapid radiographic progression in difficult-to-treat rheumatoid arthritis: insights from long-term follow-up","volume":"65","author":"Abacar","year":"2026","journal-title":"Rheumatol. 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