Restoring Immune Tolerance in pre-RA: Immunometabolic Dialogue between Gut Microbiota and Regulatory T Cells

Anqi Gao ^1,2,3 Ruihe Wu ^1,2,3 Yan-Fei Mu ^1,2,3 Ruqing Jin ^1,2,3 Saixin Jiang ^1,2,3 Chong Gao ⁴ Xiao-Feng Li ^1,2,3 Caihong Wang ^1,2,3*

• ¹ Second Hospital of Shanxi Medical University, Taiyuan, China
• ² Shanxi Key Laboratory for Immunomicroecology, Taiyuan, Shanxi Province, China
• ³ Shanxi Province Engineering Research Center of Precision Medicine for Rheumatology, Taiyuan, Shanxi Province, China
• ⁴ Deaprtment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Rheumatoid arthritis (RA) is a complex chronic autoimmune disease that remains incurable for most patients. With advances in our understanding of the disease's natural history, the concept of pre-RA has emerged as a window of opportunity to intervene before irreversible joint damage occurs. Numerous studies have indicated that the key step driving autoimmunity in early pre-RA lies at an extra-articular site, which is closely related to the regulatory T (Treg) cell-established immune tolerance to the gut microbiota. The intricate immunometabolic crosstalk between Treg cells and the gut microbiota is beginning to be understood, with the re-recognition of Treg cells as metabolic sensors in recent years. In the future, deciphering their immunometabolic dialogue may help to elucidate the underlying mechanisms of pre-RA. Identifying novel biological pathways in the pre-RA stage will bring insights into restoring immune tolerance, thereby potentially curing or preventing the onset of RA.