Microbial drivers and pathogenic mechanisms in rheumatoid arthritis natural history - IT is now known that the great majority of individuals who ultimately develop seropositive rheumatoid arthritis…

The National Institute of Allergy and Infectious Diseases awarded The Regents of The University of Colorado (University of Colorado-Denver) $2.322 million on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate microbial drivers and pathogenic mechanisms in rheumatoid arthritis natural history.

The project, titled MOSAIC, examines longitudinal inter-relationships between site-specific mucosal inflammation and bacterial dysbiosis in the development of systemic autoimmunity and clinical rheumatoid arthritis. The research focuses on understanding how causal mucosal bacterial strains initiate and promote progression to clinical RA in at-risk individuals through distinct immunologic drivers of autoimmunity. The program includes three integrated projects and two cores. Project 1 investigates how causally associated mucosal bacterial microbiota evolve over time in at-risk individuals. The work addresses findings from prior cross-sectional studies demonstrating that subsets of pre-RA individuals exhibit mucosal inflammation at gut, lung, and oral/periodontal sites associated with bacterial dysbiosis, with murine models indicating pathogenic relevance.

Performance occurs at Aurora, Colorado. The award runs through May 31, 2031. This is a Project Grant assistance type supporting collaborative, multi-institutional research led by a highly interactive group of investigators across institutions.

Microbial drivers and pathogenic mechanisms in rheumatoid arthritis natural history - IT is now known that the great majority of individuals who ultimately develop seropositive rheumatoid arthritis (RA) pass through a multi-year pre-RA period characterized by the asymptomatic presence of RA-related autoantibodies. In cross-sectional studies, subsets of pre-RA individuals have been shown to exhibit sites of mucosal inflammation, including GUT, lung and oral/periodontal, that are associated with bacterial dysbiosis, and with murine models demonstrating likely pathogenic relevance of these findings. To understand the longitudinal inter-relationships between the presence of site-specific mucosal inflammation and dysbiosis to the development of systemic autoimmunity and ultimately clinical RA, a highly interactive group of investigators across institutions have come together through this program project proposal, entitled "mosaic: microbial drivers and pathogenic mechanisms in rheumatoid arthritis natural history". One of the most important outcomes of the recent collaborative efforts of this group has been the demonstration that bacterial dysbiosis and chronic inflammation at these specific mucosal sites appear to promote the initial development of the RA disease-specific loss of tolerance to autoantigens. Thus, the central hypothesis of this proposal, upon which the mosaic investigators will focus in a highly collaborative and synergistic manner, is that causal mucosal bacterial strains initiate and promote the transition to clinical RA in at-risk individuals through the development of distinct and definable immunologic drivers of autoimmunity. The mosaic project and core focus, activities, synergies, and inter-relationships are described within this overall section. Included within mosaic are three projects and two cores. Project 1 will investigate how the specific causally associated mucosal bacterial microbiota evolve over time in individual at-risk individuals who then develop RA. In parallel, project 2 will address the hypothesis that immune responses to mucosal microbiota promote molecular mimicry and epitope spreading, resulting in autoimmunity to citrullinated autoantigens. In project 3, classification and disease development models will be built that enhance the understanding of how the identified specific bacterial microbiota and citrullinated autoantigen responses interact to drive subsequent arthritis. Through these efforts, project 3 will also work to improve prediction for transitions from pre-RA to the development of clinical RA. To support the projects, two cores will be utilized. The administrative core will organize synergistic study activities across sites as well as manage the budget and publication strategies and interactions with NIH/niaid. In addition, the population and data management core will maintain cohorts and data generated within mosaic. DR. Michael holers will serve as the contact PI of mosaic and director of the administrative core. He will be joined by DRS. Kristi kuhn and jane bucker as leaders of project 1 and project 2, respectively, as well as constituting the multiple PI team. DRS. Fan zhang and kevin deane will lead project 3 and the population and data management core, respectively. Finally, an external advisory committee will be formed.