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Objectives: Rheumatoid arthritis is an autoimmune disease with multifactorial etiopathogenesis. Among the environmental factors, mucosal infections and the inducing pathobionts are gaining increasing attention. We here set out to explore the gut-joint-axis and the impact of Clostridioides difficile infection on subsequent arthritis. Methods: We combined C. difficile infection in DBA/1J × B10.Q F1 mice with collagen induced arthritis (CIA). Mice were infected via oral gavage and infection was monitored by weight loss, colonic histology, and antibodies against bacteria. Scoring of arthritis was performed macroscopically. Intestinal microbiomes were analyzed and immune responses were monitored via quantification of transcription factor-specific mRNA isolated from the inguinal and mesenteric lymph nodes. Results: Infection with C. difficile VPI 10463 resulted in significant weight loss and severe colitis yet accelerated the reversal towards the original microbiome after antibiotic treatment. Spontaneous clearance of VPI 10463 infection reduced the incidence of subsequent CIA and led to mesenteric Treg and Th2 polarization. However, this attenuating effect was abrogated if VPI 10463 was eradicated via vancomycin followed by fecal microbiota transplantation. Moreover, VPI 10463 infection following the onset of CIA lacked therapeutic potential. Conclusion: Our results demonstrate that infection with C. difficile VPI10463 induced an inflammation of the gut that protected from subsequent arthritis development in mice. Both, microbial changes to the gut and immune cell mobilization and/or polarization may have contributed to arthritis protection. The prospect of potential therapeutic benefits resulting from C. difficile infections or some byproduct thereof call for further experiments that help elucidate exact mechanisms. [ABSTRACT FROM AUTHOR]

Objectives: Rheumatoid arthritis is an autoimmune disease with multifactorial etiopathogenesis. Among the environmental factors, mucosal infections and the inducing pathobionts are gaining increasing attention. We here set out to explore the gut-joint-axis and the impact of Clostridioides difficile infection on subsequent arthritis., Methods: We combined C. difficile infection in DBA/1J × B10.Q F1 mice with collagen induced arthritis (CIA). Mice were infected via oral gavage and infection was monitored by weight loss, colonic histology, and antibodies against bacteria. Scoring of arthritis was performed macroscopically. Intestinal microbiomes were analyzed and immune responses were monitored via quantification of transcription factor-specific mRNA isolated from the inguinal and mesenteric lymph nodes., Results: Infection with C. difficile VPI 10463 resulted in significant weight loss and severe colitis yet accelerated the reversal towards the original microbiome after antibiotic treatment. Spontaneous clearance of VPI 10463 infection reduced the incidence of subsequent CIA and led to mesenteric T reg and T h2 polarization. However, this attenuating effect was abrogated if VPI 10463 was eradicated via vancomycin followed by fecal microbiota transplantation. Moreover, VPI 10463 infection following the onset of CIA lacked therapeutic potential., Conclusion: Our results demonstrate that infection with C. difficile VPI10463 induced an inflammation of the gut that protected from subsequent arthritis development in mice. Both, microbial changes to the gut and immune cell mobilization and/or polarization may have contributed to arthritis protection. The prospect of potential therapeutic benefits resulting from C. difficile infections or some byproduct thereof call for further experiments that help elucidate exact mechanisms., (Copyright © 2020 Schmidt, Wenndorf, Ebbers, Volzke, Müller, Strübing, Kriebel, Kneitz, Kreikemeyer and Müller-Hilke.)

Septic arthritis is a medical emergency associated with high morbidity and mortality, yet hardly any novel advances exist for its clinical management. Despite septic arthritis being a global health burden, experimental data uncovering its etiopathogenesis remain scarce. In particular, any interplay between septic arthritis and preceding joint diseases are unknown as is the contribution of the synovial membrane to the onset of inflammation. Using C57BL/6 mice as a model to study sepsis, we discovered that Group A Streptococcus (GAS) - an important pathogen causing septic arthritis - was able to invade the articular microenvironment. Bacterial invasion resulted in the infiltration of immune cells and detrimental inflammation. In vitro infected fibroblast-like synoviocytes induced the expression of chemokines ( Ccl2 , Cxcl2 ), inflammatory cytokines ( Tnf , Il6 ), and integrin ligands (ICAM-1, VCAM-1). Apart from orchestrating immune cell attraction and retention, synoviocytes also upregulated mediators impacting on bone remodeling ( Rankl ) and cartilage integrity ( Mmp13 ). Using collagen-induced arthritis in DBA/1 × B10.Q F1 mice, we could show that an inflammatory joint disease exacerbated subsequent septic arthritis which was associated with an excessive release of cytokines and eicosanoids. Importantly, the severity of joint inflammation controlled the extent of bone erosions during septic arthritis. In order to ameliorate septic arthritis, our results suggest that targeting synoviocytes might be a promising approach when treating patients with inflammatory joint disease for sepsis., (Copyright © 2020 Volzke, Schultz, Kordt, Müller, Bergmann, Methling, Kreikemeyer, Müller-Hilke and KoInfekt Study Group.)