Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease. Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility. However, accumulating evidence demonstrates that genetics also shape the gut microbiota. It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis (CIA), while the others are resistant to CIA. Here, we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice. C57BL/6J mice and healthy human individuals have enriched B. fragilis than DBA/1J mice and RA patients. Transplantation of B. fragilis prevents CIA in DBA/1J mice. We identify that B. fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate. Fibroblast-like synoviocytes (FLSs) in RA are activated to undergo tumor-like transformation. Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1, resulting in reduced FOXK1 stability, blocked interferon signaling and deactivation of RA-FLSs. We treat CIA mice with propionate and show that propionate attenuates CIA. Moreover, a combination of propionate with anti-TNF etanercept synergistically relieves CIA. These results suggest that B. fragilis or propionate could be an alternative or complementary approach to the current therapies.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(82172386)

Department of Education of Guangdong Province (Guangdong Province Education Department)(2021KTSCX104)

Guangdong Basic and Applied Basic Research Foundation (2022A1515012164 to CL) the Science, Technology and Innovation Commission of Shenzhen (JCYJ20210324104201005 to CL

the Guangdong Basic and Applied Basic Research Foundation (2023A1515012000 to XF)