Role of the Gut Microbiome in Modulating Arthritis Progression in Mice

Abstract

Genetics alone cannot explain most cases of rheumatoid arthritis (RA). Thus, investigating environmental factors such as the gut microbiota may provide new insights into the initiation and progression of RA. In this study, we performed 16S rRNA sequencing to characterise the gut microbiota of DBA1 mice that did or did not develop arthritis after induction with collagen. We found that divergence in the distribution of microbiota after induction was pronounced and significant. Mice susceptible to collagen-induced arthritis (CIA) showed enriched operational taxonomic units (OTUs) affiliated with the genus Lactobacillus as the dominant genus prior to arthritis onset. With disease development, the abundance of OTUs affiliated with the families Bacteroidaceae, Lachnospiraceae, and S24-7 increased significantly in CIA-susceptible mice. Notably, germ-free mice conventionalized with the microbiota from CIA-susceptible mice showed a higher frequency of arthritis induction than those conventionalized with the microbiota from CIA-resistant mice. Consistently, the concentration of the cytokine interleukin-17 in serum and the proportions of CD8+T cells and Th17 lymphocytes in the spleen were significantly higher in the former group, whereas the abundances of dendritic cells, B cells, and Treg cells in the spleen were significantly lower. Our results suggest that the gut microbiome influences arthritis susceptibility.

Modulation of Inflammatory Arthritis in Mice by Gut Microbiota Through Mucosal Inflammation and Autoantibody Generation

“…Early after induction of CIA by day 14, we observed a reduction in the abundance of the Bacteroidetes class S24‐7 and an increase in Lactobacillaceae; however, by day 35 Lactobacillaceae and S24‐7 returned to day 0–7 levels, while Lachnospiraceae significantly increased in abundance. These are consistent with a previous study showing the same trends in Lactobacillaceae and Lachnospiraceae in mice with advanced CIA compared to nonimmunized mice .…”

“…Microbial communities and mucosal inflammation change continuously through the course of CIA. Because dysbiosis is observed in individuals with symptomatic RA and in mice with clinical arthritis , we queried when dysbiosis developed during the CIA disease process. CIA was induced by immunization of 6‐week‐old male DBA/1J mice with CII in CFA on days 0 and 21, with arthritis first observed on days 23 and 24.…”

“…Recently, others have described intestinal dysbiosis at the terminal time point of this model in mice that developed disease compared to those that were immunized but did not develop observable joint swelling . Transfer of fecal material from arthritic mice but not from nonarthritic, immunized mice into germ‐free mice followed by CII immunization resulted in disease induction . However, questions from that study remain unanswered regarding microbial changes over time and whether there is a time‐dependent role for microbiota in pathogenesis.…”

Immunopathogenesis of Rheumatoid Arthritis

“…For example, arthritis susceptibility and severity in a variety of rodent strains is decreased when maintained germ-free or in environments with a restricted bacterial flora (Lui et al 2016). These data suggest that bacteria provide complex adjuvant functions that enhance autoimmunity, either directly (e.g., bacterial cell walls or lipopolysaccharides) or by critically altering the immunoregulatory mucosal environment.…”

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases

“…Data from murine studies support the role of microbiota in influencing arthritis susceptibility. Liu X et al [10] performed 16S rRNA sequencing to characterize the gut microbiota of DBA1 mice that did or did not develop collagen-induced arthritis and demonstrated marked and significant divergence in the distribution of microbiota after arthritis induction. Mice susceptible to collagen-induced arthritis (CIA) showed enriched operational taxonomic units (OTUs) affiliated with the genus Lactobacillus prior to arthritis onset.…”