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While certain genes provide strong susceptibility factors, the role of environmental factors is becoming increasingly recognized. Among genetic factors, human leukocyte antigen (HLA) genes, encoded within the major histocompatibility complex (MHC), have been linked to predisposition to RA, while among environmental factors, smoking, infections and diet are the major contributors. Genetic and environmental factors impact microbial composition in the host. Based on the dysbiosis observed in the gut and lung microbiome, a mucosal origin of RA has been suggested. However, proving whether genes or microbes provide a stronger risk factor has been difficult. Studies from RA patients and various mouse models, specifically humanized mice expressing HLA class II genes, have been instrumental in defining the role of environmental factors such as smoking and endogenous small intestinal microbes in modulating arthritis severity. The consensus based on most studies support an interaction between host genetic and environmental factors in the onset and severity of disease. However, until now, no microbial markers for disease prognosis or treatment efficacy have been available. Here, the role of gut microbes as markers of disease severity, and the potential for using endogenous commensals for modulating immune responses to suppress inflammation in the context of genetic factors, are discussed.<\/jats:p>","DOI":"10.3390\/microorganisms13020255","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T04:32:22Z","timestamp":1737693142000},"page":"255","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Gut Microbes as the Major Drivers of Rheumatoid Arthritis: Our Microbes Are Our Fortune!"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2401-694X","authenticated-orcid":false,"given":"Veena","family":"Taneja","sequence":"first","affiliation":[{"name":"Department of Immunology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/B978-0-12-381300-8.00008-3","article-title":"Host-bacterial symbiosis in health and disease","volume":"107","author":"Chow","year":"2010","journal-title":"Adv. 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