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Page 2 of 23 Poznyak et al. Microbiome Res Rep. 2026;5:3

microRNA networks in regulating epithelial integrity and systemic immune activation. Taken together, the literature
supports a mechanistic link between gut dysbiosis and the onset of RA. It points to microbiota-targeted strategies as
promising avenues for delaying or preventing disease progression. Future studies should prioritize longitudinal
analyses and interventional trials focusing specifically on individuals at risk for RA.

INTRODUCTION
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by polyarthritis, leading to
damage of cartilage and bone and significantly impairing an individual’s mobility. The progression of RA
begins with an initial susceptibility phase influenced by genetic factors, followed by a preclinical stage
marked by a breakdown in immunological tolerance, ultimately resulting in the onset of clinical arthritis .
[1,2]
The primary objectives in treating RA are to achieve long-term remission or maintain low disease activity,
prevent joint damage and disability, and reduce the risk of complications. Current pharmacological options
for RA include glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying
anti-rheumatic drugs (DMARDs), and small molecule inhibitors . Despite the advancement of treatment
[3-5]
strategies such as treat-to-target, the application of DMARDs, and early intervention, more than 60% of RA
patients do not reach true remission following the onset of clinical arthritis. Initiating treatment during the
preclinical phase of RA, before the onset of clinical symptoms, could prevent substantial joint damage and
foster sustained remission. This indicates that the preclinical stage may represent a critical window for
effective intervention . It is important to note that remission rates vary across patient populations. Several
[6-9]
studies indicate that certain subgroups - such as individuals with early-onset disease, seropositive patients,
smokers, older adults, and some ethnic minorities - exhibit lower response rates to conventional and biologic
therapies. Women also tend to have lower rates of sustained remission compared to men, likely due to
differences in immune regulation and genetic background . These findings suggest that the commonly cited
[10]
60% non-remission rate represents an overall average and may obscure poorer outcomes in specific high-risk
subgroups .
[11]

Preclinical RA is characterized by the presence of autoantibodies - such as those targeting citrullinated
proteins and rheumatoid factors - resulting from a loss of immunological tolerance [12-14] . However, it is
important to note that the definition of ‘pre-clinical RA’ is not fully standardized. Different studies and
guidelines apply varying criteria - such as seropositivity for anti-citrullinated protein antibodies (ACPAs) or
Rheumatoid Factor (RF), genetic risk factors, musculoskeletal symptoms without clinical arthritis, or
subclinical synovitis on imaging - resulting in heterogeneity across cohorts . This ambiguity complicates
[15]
the identification of truly at-risk individuals and may influence both the timing and interpretation of
preventive intervention strategies.

Emerging evidence from human cohorts and experimental models indicates that the gut microbiota
contributes to the transition from preclinical to clinically manifest RA. Microbial dysbiosis has been
implicated in the breakdown of immunological self-tolerance and in the amplification of inflammatory
pathways through mechanisms such as molecular mimicry [16-19] . Bacterial peptides that share structural
similarity with established RA autoepitopes may promote autoantibody generation through cross-reactive
immune responses, thereby contributing to joint tissue damage. Integrated microbiome and metabolomics
studies have further demonstrated that microbially derived metabolites act as immunomodulatory signals
that influence immune cell differentiation and effector functions [20-22] . In addition, microbiota-driven
alterations in intestinal barrier integrity during the preclinical phase may facilitate trafficking of immune
cells from the gut to synovial tissues, promoting disease progression .
[23]