The gut microbiota mediates protective immunity against tuberculosis via modulation of lncRNA
Fang Yang,
Yi Yang,
Lingming Chen,
Zhiyi Zhang,
Linna Liu,
Chunmin Zhang,
Qiongdan Mai,
Yiwei Chen,
Zixu Chen,
Tao Lin,
Liang Chen,
Huixin Guo,
Lin Zhou,
Hongbo Shen,
Xinchun Chen,
Lei Liu,
Guoliang Zhang,
Hongying Liao,
Lingchan Zeng,
Gucheng Zeng
Affiliations
Fang Yang
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Yi Yang
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Lingming Chen
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Zhiyi Zhang
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Linna Liu
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Chunmin Zhang
Drepartment of Pediatric Intensive Care Unit, Guangzhou Women and Children’s Medical Center, Picu, Guangzhou China
Qiongdan Mai
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Yiwei Chen
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Zixu Chen
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Tao Lin
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
Liang Chen
Guangdong Center for Tuberculosis Control, National Clinical Research Center for Tuberculosis, Guangzhou China
Huixin Guo
Guangdong Center for Tuberculosis Control, National Clinical Research Center for Tuberculosis, Guangzhou China
Lin Zhou
Guangdong Center for Tuberculosis Control, National Clinical Research Center for Tuberculosis, Guangzhou China
Hongbo Shen
Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Institute for Advanced Study, Tongji University School of Medicine, Shanghai, China
Xinchun Chen
Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, Guangdong China
Lei Liu
Institute for Hepatology, National Clinical Research Center for Infectious Disease, Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People’s Hospital, National Clinical Research Center for Tuberculosis, Southern University of Science and Technology, National Clinical Research Center for Tuberculosis, Shenzhen, China
Guoliang Zhang
Institute for Hepatology, National Clinical Research Center for Infectious Disease, Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People’s Hospital, National Clinical Research Center for Tuberculosis, Southern University of Science and Technology, National Clinical Research Center for Tuberculosis, Shenzhen, China
Hongying Liao
De
partment of Thoracic Surgery, Thoracic Cancer Center, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
Lingchan Zeng
Clinical Research Center, Department of Medical Records Management, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China
Gucheng Zeng
Department of Microbiology Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-sen University, Guangzhou China
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 Mycobacterium tuberculosis (M. tuberculosis) infection and modulated pulmonary inflammatory responses in mouse M. tuberculosis 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 Bacteroides fragilis (B. fragilis) was a direct regulator of lncRNA-CGB, and oral administration of B. fragilis 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 M. tuberculosis 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.
