Bone Research ( IF 14.3 ) Pub Date : 2024-05-23 , DOI: 10.1038/s41413-024-00336-6 Hongzhen Chen 1 , Xuekun Fu 1, 2 , Xiaohao Wu 3, 4, 5 , Junyi Zhao 1 , Fang Qiu 1, 2 , Zhenghong Wang 6 , Zhuqian Wang 1, 2 , Xinxin Chen 1 , Duoli Xie 1, 2 , Jie Huang 1, 2 , Junyu Fan 7 , Xu Yang 8 , Yi Song 6 , Jie Li 9 , Dongyi He 7 , Guozhi Xiao 3 , Aiping Lu 2, 10, 11 , Chao Liang 1, 2, 12
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.
中文翻译:
肠道微生物代谢物靶向成纤维样滑膜细胞中的 HDAC3-FOXK1-干扰素轴以改善类风湿性关节炎
类风湿性关节炎(RA)是一种自身免疫性疾病。早期研究认为肠道微生物群是环境获得的并与 RA 易感性相关。然而,越来越多的证据表明,遗传学也塑造了肠道微生物群。众所周知,一些近交实验室小鼠品系对胶原诱导性关节炎(CIA)高度敏感,而其他品系则对 CIA 具有抵抗力。在这里,我们表明,将 CIA 耐药的 C57BL/6J 小鼠的粪便微生物群移植到 CIA 敏感的 DBA/1J 小鼠中,可以赋予 DBA/1J 小鼠 CIA 耐药性。与 DBA/1J 小鼠和 RA 患者相比,C57BL/6J 小鼠和健康人体内的脆弱拟杆菌含量更高。移植脆弱拟杆菌可预防 DBA/1J 小鼠的 CIA。我们发现脆弱拟杆菌主要产生丙酸,C57BL/6J小鼠和健康人的丙酸水平较高。 RA 中的成纤维细胞样滑膜细胞 (FLS) 被激活并发生肿瘤样转化。丙酸盐破坏 HDAC3-FOXK1 相互作用,增加 FOXK1 的乙酰化,导致 FOXK1 稳定性降低,阻断干扰素信号传导并使 RA-FLS 失活。我们用丙酸盐治疗 CIA 小鼠,结果表明丙酸盐可以减弱 CIA。此外,丙酸盐与抗TNF依那西普的组合可协同缓解CIA。这些结果表明脆弱拟杆菌或丙酸盐可能是当前疗法的替代或补充方法。