Gut microbiome differences by serostatus in rheumatoid arthritis: a systematic review

Background Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease in which serological status, defined by rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA), influences disease course. Alterations of the gut microbiome have been implicated in RA, but differences between seropositive and seronegative patients, and between seropositive RA and healthy controls, have not been systematically reviewed. Methods PubMed, Scopus, Web of Science, and the Cochrane Library were searched to July 2025 for observational studies of adult RA patients reporting RF and/or ACPA status with gut microbiome analysis. Two reviewers independently screened, extracted data, and assessed quality using the Newcastle–Ottawa Scale (NOS). Results Eight studies published between 2016 and 2024 met the inclusion criteria. Six investigated both RF and ACPA, while two focused primarily on ACPA. In seropositive RA, higher abundances of Collinsella and Blautia and lower levels of Faecalibacterium were consistently reported. Several studies demonstrated reduced α-diversity in seropositive patients compared with seronegative RA or healthy controls, particularly in preclinical or early disease, while established RA showed no consistent differences. Findings for β-diversity were heterogeneous, with some cohorts reporting significant associations with serostatus, whereas others found no clear separation. Conclusions Seropositive RA, especially ACPA-positive, is frequently associated with reduced microbial diversity and distinct compositional shifts compared with seronegative RA and healthy controls. Larger standardized studies are required to validate these associations and assess their biomarker potential. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420251140715.