Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China.
Drepartment of Pediatric Intensive Care Unit, Guangzhou Women and Children's Medical Center, Picu, Guangzhou China.
Gut Microbes. 2022 Jan-Dec;14(1):2029997. doi: 10.1080/19490976.2022.2029997.
The gut-lung axis has been implicated as a potential therapeutic target in lung disorders. While increasing evidence suggests that gut microbiota plays a critical role in regulating host immunity and contributing to tuberculosis (TB) development and progression, the underlying mechanisms whereby gut microbiota may impact TB outcomes are not fully understood. Here, we found that broad-spectrum antibiotics treatment increased susceptibility to () infection and modulated pulmonary inflammatory responses in mouse infection model. We then identified a commensal gut bacteria-regulated lncRNA, termed lncRNA-CGB, which was down-regulated by dysbiosis of gut microbiota during TB infection. Furthermore, we found that () was a direct regulator of lncRNA-CGB, and oral administration of enhanced expression of lncRNA-CGB and promoted anti-TB immunity. Genomic knock-out of lncRNA-CGB led to reduced IFN-γ expression and impaired anti-TB immunity, therefore leading to detrimental effects on infection. Mechanistically, lncRNA-CGB interacted with EZH2 and negatively regulated H3K27 tri-methylation (H3K27Me3) epigenetic programming, leading to enhanced IFN-γ expression. Thus, this work not only uncovered previously unrecognized importance of gut bacteria-lncRNA-EZH2-H3K27Me3 axis in conferring immune protection against TB but also identified a potential new paradigm to develop a microbiota-based treatment against TB and potentially other diseases.
肠-肺轴被认为是肺部疾病的潜在治疗靶点。虽然越来越多的证据表明，肠道微生物群在调节宿主免疫和促进结核病（TB）发展和进展方面起着关键作用，但肠道微生物群影响 TB 结果的潜在机制尚不完全清楚。在这里，我们发现广谱抗生素治疗增加了感染的易感性，并在小鼠感染模型中调节了肺部炎症反应。然后，我们确定了一种共生肠道细菌调节的长链非编码 RNA（lncRNA），称为 lncRNA-CGB，它在 TB 感染期间肠道微生物群失调时被下调。此外，我们发现 （）是 lncRNA-CGB 的直接调节剂，口服给药可增强 lncRNA-CGB 的表达并促进抗 TB 免疫。lncRNA-CGB 的基因组敲除导致 IFN-γ表达减少和抗 TB 免疫受损，因此对感染产生有害影响。在机制上，lncRNA-CGB 与 EZH2 相互作用，负调控 H3K27 三甲基化（H3K27Me3）表观遗传编程，从而增强 IFN-γ 表达。因此，这项工作不仅揭示了肠道细菌-lncRNA-EZH2-H3K27Me3 轴在赋予针对 TB 的免疫保护方面以前未被认识到的重要性，而且还确定了一种潜在的新范式，用于开发基于微生物组的治疗 TB 甚至其他疾病的方法。
