Moreover, abnormal Trp metabolism has also been observed in pre-RA patients, indicating its involvement in triggering early mucosal immune imbalance (88).In summary, gut flora disorders may lead to a decrease in relevant Trp metabolites, which in turn reduces the production of Treg and Tfr cells mediated by AhR signaling, leading to a disruption of immune tolerance, followed by increased antibody titers, epitope spreading, and RA-specific autoantibody production, and ultimately the development of clinically-apparent RA (Figures 4E, F). This evidence concerns the gene TFRC and rheumatoid arthritis.