Emerging data suggest that host-microbe interactions, which modulate host immunity, may play an important role in the development of rheumatoid arthritis (RA). Using the well-characterized collagen-induced arthritis (CIA) model, we have published our findings that depletion of the microbiota through administration of broad- spectrum antibiotics during the phase of disease when autoantibodies are developing but observable arthritis is not present results in >95% reduction in disease severity. Preliminary data generated by our group identified the bacteria-produced metabolite indole, derived from dietary tryptophan, correlated with the development of CIA. Oral administration of indole to antibiotic-treated mice induced for CIA resulted in increased disease severity. Therefore, we hypothesize that the expansion of indole-producing bacteria exacerbate CIA through the development of mucosal germinal centers in which indole stimulates antibody glycosylation through aryl hydrocarbon receptor signaling. To understand how the microbe-derived indole modulates CIA, in Aim 1, we will first identify the bacterial source(s) of indoles during the course of CIA by using selective colonization of germ free mice.
In Aim 2, we will evaluate the mechanism by which indole affects collagen-specific Tfh and B cell differentiation during the course of CIA.
Aim 3 will then focus on how indole affects collagen autoantibody pathogenicity through the stimulation of B cell glycosylation enzymes. Completion of these studies will provide a novel insight into how intestinal bacteria modulate the development of autoimmune arthritis and inform future translational studies in humans with RA.

Public Health Relevance

Microbial interactions at mucosal surfaces are increasingly hypothesized to stimulate the development of autoantibodies relevant to rheumatoid arthritis. However, direct evidence to support this hypothesis is lacking. Evaluation of specific microbial-host interactions during the development of autoimmune arthritis will provide mechanistic insights into how rheumatoid arthritis and other autoimmune diseases develop.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR075033-02
Application #
9912724
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2019-04-10
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045