AU-rich element (ARE)-mediated mRNA decay represents a key mechanism to avoid excessive production of inflammatory cytokines. Tristetraprolin (TTP, encoded by Zfp36) is a major ARE-binding protein, since Zfp36^−/− mice develop a complex multiorgan inflammatory syndrome that shares many features with spondyloarthritis. The role of TTP in intestinal homeostasis is not known. Herein, we show that Zfp36^−/− mice do not develop any histological signs of gut pathology. However, they display a clear increase in intestinal inflammatory markers and discrete alterations in microbiota composition. Importantly, oral antibiotic treatment reduced both local and systemic joint and skin inflammation. We further show that absence of overt intestinal pathology is associated with local expansion of regulatory T cells. We demonstrate that this is related to increased vitamin A metabolism by gut dendritic cells, and identify RALDH2 as a direct target of TTP. In conclusion, these data bring insights into the interplay between microbiota-dependent gut and systemic inflammation during immune-mediated disorders, such as spondyloarthritis.

富含非盟元素 (ARE) 介导的 mRNA 衰变是避免炎症细胞因子过度产生的关键机制。三四脯氨酸（TTP，由Zfp36编码）是一种主要的 ARE 结合蛋白，因为Zfp36 ^-/-小鼠会发展出一种复杂的多器官炎症综合征，该综合征与脊柱关节炎具有许多相同的特征。TTP 在肠道稳态中的作用尚不清楚。在此，我们表明Zfp36 ^-/-小鼠不会出现任何肠道病理学的组织学迹象。然而，它们显示出肠道炎症标志物的明显增加和微生物群组成的离散改变。重要的是，口服抗生素治疗减少了局部和全身的关节和皮肤炎症。我们进一步表明，没有明显的肠道病理学与调节性 T 细胞的局部扩张有关。我们证明这与肠道树突状细胞增加的维生素 A 代谢有关，并将 RALDH2 确定为 TTP 的直接靶标。总之，这些数据让我们深入了解微生物群依赖性肠道与免疫介导疾病（如脊柱关节炎）期间全身炎症之间的相互作用。