The role of gut microbiota in tristetraprolin regulated inflammation

Tristetraprolin (TTP) is an RNA-binding protein that plays a crucial role in regulating inflammation. TTP-deficiency causes a systemic sterile inflammation syndrome characterized by immunosenescence, gut dysbiosis, and severe bone loss. We hypothesized that the dysbiotic microbiota is a key transmissible driver of this pathology. Using specific pathogen-free (SPF) and germ-free (GF) co-housing mouse models, we investigated this hypothesis. Co-housing successfully transmitted a dysbiotic microbiota that bidirectionally modulated systemic inflammation (TNF-alpha) and the expansion of monocytic myeloid-derived suppressor cells (M-MDSCs). This transmissible phenotype extended to the skeleton, where co-housing was sufficient to induce a significant deterioration of trabecular bone microarchitecture in healthy mice without transmitting gross osteopenia. All transmissible pathologies were entirely microbiota-dependent, as they were abrogated in GF conditions. Our findings demonstrate that the gut microbiota acts as a critical amplifier in a feedback loop that exacerbates TTP-mediated disease, proving that specific microbial communities can transmit complex inflammatory and bone pathologies. This highlights the microbiome as a potential therapeutic target for managing inflammatory diseases linked to host genetic defects.

Tristetraprolin（TTP）是一种RNA结合蛋白，在炎症调控中发挥关键作用。TTP缺陷会引发全身性无菌炎症综合征，其特征为免疫衰老、肠道菌群失调与严重骨丢失。本研究提出假说：失调菌群是该病理过程的关键可传播驱动因素。我们采用无特定病原体（SPF）与无菌（GF）共饲养小鼠模型验证该假说。结果显示，共饲养成功传递了失调菌群，该菌群可双向调控全身性炎症（肿瘤坏死因子-α，TNF-α）以及单核细胞样髓系来源抑制细胞（M-MDSCs）的扩增。这种可传播的表型同样累及骨骼系统：共饲养足以诱导健康小鼠的骨小梁微结构出现显著恶化，但未引发明显骨质减少。所有可传播的病理改变均完全依赖菌群，在无菌环境下这些改变会被完全阻断。本研究结果表明，肠道菌群在加剧TTP介导疾病的反馈环路中发挥关键放大作用，证实特定微生物群落可传播复杂的炎症与骨骼病理改变。这提示微生物组可作为治疗宿主遗传缺陷相关炎症性疾病的潜在治疗靶点。