AB0137 Arthritis-associated eggerthella lenta modulate disease via metabolic and microbial alterations

Background Role of environmental factors in predisposition to develop rheumatoid arthritis (RA) has gained interest due, in part, to the studies showing an association of gut microbiota with immune homeostasis. Although the etiology of RA is unknown, recent studies on the role of gut microbiota in inflammatory adaptive immune response have led to the concept that interaction between the host microbiome and genetic factors influences autoimmunity. We have shown an association of rare lineage commensals, Eggerthella lenta , with RA. Objectives In this study, we aimed to determine how human gut commensal E. lenta modulates gut epithelial integrity and inflammation via metabolites in humanised mice expressing RA-susceptible HLA-DQ8. Methods DQ8 mice following immunisation with type II collagen develop arthritis and antigen-specific cellular and humoral response. DQ8 mice orally gavaged with RA-associated E. lenta on alternate days for one week and were induced for arthritis. Gavage with microbes continued for 4 weeks. Mice were monitored for onset and progression of arthritis. Epithelial integrity was done by FITC-Dextran assay and citrulline levels in faecal and plasma samples were measured by liquid chromatography mass spectrometry Results Mice gavaged with E. lenta showed a much higher load of gut microbes compared to controls. Surprisingly, E lenta did not augment gut permeability as it was similar to non-gavaged arthritic mice. Eggerthella lenta is involved in ornithine pathway leading to generation of citrulline. To test if gavage with E. lenta accumulates citrulline in the gut, we tested citrulline levels in faecal samples by liquid chromatography mass spectrometry. Surprisingly, mice gavaged with E. lenta had lower levels of citrulline in faecal samples as compared to mice naive mice with no gavage or arthritic mice without gavage. One can speculate from these observations that there is an expansion of commensals, like E. lenta in RA, leading to production of citrulline. To determine if citrulline could be accumulated outside of gut, we measured citrulline in sera of mice in various groups, gavaged with E. lenta , naive and mice induced for arthritis but no E. lenta gavage. Surprisingly, mice gavaged with E. lenta and induced for arthritis had lower levels of citrulline as compared to controls induced for arthritis but no gavage, p E. lenta also showed significantly much lower levels compared to sera of naive mice. Conclusions This data suggests that E. lenta may be a major player in determining certain metabolic pathways. If Citrulline is being converted to arginine and used in other pathways is currently under investigation. Our studies suggest that gut commensals influence immune response in and away from the gut. Commensals and their products may provide novel targets for therapeutic strategies in arthritis. Reference [1] Chen J, Wright K, Davis J, Marietta E, Luckey D, Jeraldo P, Murray J, Nelson H, Matteson E, Taneja V. An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis Genome Medicine2016;8:43. doi:10.1186/s13073-016-0299-7 Acknowledgements The US Department of Defense grant W81XWH 15–1–0213 and the Centre of Individualised Medicine, Mayo Clinic Disclosure of Interest None declared