Infection With Clostridioides difficile Attenuated Collagen-Induced Arthritis in Mice and Involved Mesenteric Treg and Th2 Polarization.

Christian Johann Schmidt,Katja Kriebel,Susanne Kneitz,Meinolf Ebbers,Katharina Wenndorf,Johann Volzke,Bernd Kreikemeyer,Michael Müller,Julia Strübing,Brigitte Müller-Hilke

doi:10.3389/fimmu.2020.571049

Abstract

ObjectivesRheumatoid 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.MethodsWe 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.ResultsInfection 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.ConclusionOur 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.

Highlights

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and primarily affects the joints, even though it can develop into a systemic disease with various extra-articular manifestations [1]
Spontaneous clearance of VPI 10463 infection reduced the incidence of subsequent collagen induced arthritis (CIA) and led to mesenteric Treg and Th2 polarization
Our results demonstrate that infection with C. difficile VPI10463 induced an inflammation of the gut that protected from subsequent arthritis development in mice

Summary

Introduction

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and primarily affects the joints, even though it can develop into a systemic disease with various extra-articular manifestations [1]. RA is a multifactorial disease and the genetic factors contributing to disease occurrence were estimated to range between 53 and 65% [4]. This in turn means that at least one third of RA susceptibility is due to environmental variation. The quest for an infectious micro-organism that triggers the pathogenicity of RA has been the target of considerable study the absence of a clustering of the disease in time or place and the likelihood of a delay between infection and disease onset have hampered conclusive evidence. The many clinical facets of RA, the diversity of responses to targeted therapies as well as the broad range of genes associated with it leave space for more than one infectious agent as a trigger [7]

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