Background/Purpose: High-throughput sequencing of intestinal microbiota recently revealed that the composition of intestinal microbiota is perturbed in patients with new onset untreated rheumatoid arthritis (RA). In mice, both germ-free condition and administration of oral antibiotics before the onset of arthritis modulate T cell differentiation and attenuate the disease. However, it is not known whether and how modulation of intestinal microbiota after the onset of arthritis may influence the disease. Here, we investigated the involvement of commensal intestinal microbiota in the progression of established arthritis in both T cell-dependent and -independent mouse models.

Methods: Mice with established collagen-induced arthritis (CIA) as the most widely-used T cell-dependent model of RA, as well as mice with K/BxN serum-transfer arthritis as a T cell-independent model were treated orally with a cocktail of metronidazole, neomycin, ampicillin (1 g/l each) and vancomycin (0.5 g/l) for one week to partially eliminate intestinal microbiota. Arthritis was assessed macroscopically and by histologic analysis. Differentiation of Th1, Th17 and regulatory T (Treg) cells and production of their prototypic cytokines in intestinal lamina propria and joint-draining lymph nodes were assessed by flow cytometry and Luminex array. Development of anti-collagen type II antibodies was assessed in serum of CIA mice using ELISA. Intestinal and synovial expression of cytokines and serum amyloid A (SAA) isotypes was measured by qPCR.

Results: Elimination of intestinal microbiota in mice with ongoing CIA specifically suppressed intestinal Th17 cell differentiation without affecting Th1 and Treg cells. Accordingly, production of interleukin-17 (IL-17), but not interferon γ, IL-4 and IL-10, by lamina propria lymphocytes was significantly diminished in antibiotic-treated mice. Furthermore, intestinal expression of SAA isoforms and IL-22, known to promote lamina propria Th17 cell differentiation, was suppressed in antibiotic-treated CIA mice. Importantly, elimination of intestinal microbiota resulted in suppressed Th17 cell differentiation and IL-17 production in joint-draining lymph nodes and reduced the severity of established CIA. In contrast, antibiotic treatment did not influence disease severity in the T cell-independent K/BxN serum-transfer arthritis. Intriguingly, the abundance of intestinal Th17 cells strongly correlated with the severity of arthritis in the CIA mice. However, elimination of intestinal microbiota after disease onset did not affect the development of anti-collagen type II autoantibodies.  

Conclusion : These observations suggest that modulation of commensal intestinal microbiota during established arthritis specifically suppress Th17 differentiation and dampen T cell-mediated arthritic processes. While our study does not advocate the use of antibiotics as a treatment for RA, it supports the notion that inflammatory signals provided by the gut microbiota continue to promote arthritis after its onset. Understanding the exact mechanisms linking the intestinal T cell response with arthritis may help identifying novel therapeutic strategies for RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/partial-elimination-of-intestinal-microbiota-dampens-t-helper-17-cell-differentiation-and-established-collagen-induced-arthritis-in-mice/