Role of the gut barrier in inflammatory arthritis

PROJECT SUMMARY Antibiotic use is linked to increased risk for the onset or relapse of inflammatory arthritis, including rheumatoid arthritis and juvenile idiopathic arthritis, but the underlying basis for this and the gut-joint axis in regulation of both inflammatory and viral arthritis are not well understood. The goal of this proposal is to define how antibiotic-

mediated gut dysbiosis and loss of certain short chain fatty acids (SCFA)-producing bacteria alters local responses in the gut and distal inflammation in the joint. Heterogeneity of tissue resident synovial macrophages and fibroblasts have been described in rheumatoid arthritis but little is known about the cellular context and it

has been virtually unexplored in the context of viral arthritis. I hypothesize the antibiotic-mediated gut dysbiosis and associated loss of certain SCFA-producing bacteria alters local intestinal epithelial responses to increase gut permeability and the priming of systemic pro-inflammatory responses. Furthermore, I hypothesize that this

is linked to altered epigenetic and transcriptional programs in resident synovial cell populations that enhance synovial inflammation and worsen arthritis severity. Additionally, I propose that supplementation with exogenous SCFA can regulate these changes to temper the severity of arthritis. Using a combination of functional studies

and sequencing technologies including high resolution spatial transcriptomics and ATAC-sequencing, this proposal will address gaps in knowledge related to how SCFA-producing bacteria shape intestinal epithelial cell responses to modulate the severity of viral arthritis (Aim 1) and how antibiotic-mediated gut dysbiosis affects

tissue resident synovial macrophages and fibroblasts to enhance inflammation in Chikungunya viral arthritis (Aim 2). The elucidation of altered pathways may stimulate novel therapeutic approaches for modulation of gut dysbiosis and improved clinical management of viral and inflammatory arthritis. This proposal describes a 5-year training and mentorship plan to prepare the PI, Fang Roseanne Zhao, M.D.,

Ph.D., to become an independent physician-scientist principal investigator. The aims of the mentored research project described provide the framework for Dr. Zhao obtain additional expertise in gut immunology, synovial cell profiling, next generation sequencing, and bioinformatic skillsets in order to effectively study the complexity of

the microbiome and gut-joint link. Washington University School of Medicine is an ideal training environment with a longstanding commitment to the training of physician-scientists, outstanding resources, expertise to complete the proposed research. During the 5-year period of support provided by this K08 award, Dr. Zhao will continue

her career development through relevant coursework, collaborative learning, and mentors to allow her to obtain foundational knowledge and transition to her own independent research program as a successful physician scientist studying modulation of arthritis by the host-microbiome interface.