Microbiome-derived bile acids contribute to elevated antigenic response and bone erosion in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic, disabling and incurable autoimmune disease. It has been widely recognized that gut microbial dysbiosis is an important contributor to the pathogenesis of RA, although distinct alterations in microbiota have been associated with this disease. Yet, the metabolites that mediate the impacts of the gut microbiome on RA are less well understood. Here, with microbial profiling and non-targeted metabolomics, we revealed profound yet diverse perturbation of the gut microbiome and metabolome in RA patients in a discovery set. In the Bacteroides-dominated RA patients, differentiation of gut microbiome resulted in distinct bile acid profiles compared to healthy subjects. Predominated Bacteroides species expressing BSH and 7a-HSDH increased, leading to elevated secondary bile acid production in this subgroup of RA patients. Reduced serum fibroblast growth factor-19 and dysregulated bile acids were evidence of impaired farnesoid X receptor-mediated signaling in the patients. This gut microbiota-bile acid axis was correlated to ACPA. The patients from the validation sets demonstrated that ACPA-positive patients have more abundant bacteria expressing BSH and 7a-HSDH but less Clostridium scindens expressing 7a-dehydroxylation enzymes, together with dysregulated microbial bile acid metabolism and more severe bone erosion than ACPA-negative ones. Mediation analyses revealed putative causal relationships between the gut microbiome, bile acids, and ACPA-positive RA, supporting a potential causal effect of Bacteroides species in increasing levels of ACPA and bone erosion mediated via disturbing bile acid metabolism. These results provide insights into the role of gut dysbiosis in RA in a manifestation-specific manner, as well as the functions of bile acids in this gut-joint axis, which may be a potential intervention target for precisely controlling RA conditions.