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. 2022 Jan-Dec;14(1):2029997.
doi: 10.1080/19490976.2022.2029997.

The gut microbiota mediates protective immunity against tuberculosis via modulation of lncRNA

Fang Yang  1 , Yi Yang  1 , Lingming Chen  1 , Zhiyi Zhang  1 , Linna Liu  1 , Chunmin Zhang  2 , Qiongdan Mai  1 , Yiwei Chen  1 , Zixu Chen  1 , Tao Lin  1 , Liang Chen  3 , Huixin Guo  3 , Lin Zhou  3 , Hongbo Shen  4 , Xinchun Chen  5 , Lei Liu  6 , Guoliang Zhang  6 , Hongying Liao  7 , Lingchan Zeng  8 , Gucheng Zeng  1
Affiliations

The gut microbiota mediates protective immunity against tuberculosis via modulation of lncRNA

Fang Yang et al. Gut Microbes. 2022 Jan-Dec.

Abstract

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.

Keywords: Tuberculosis; commensal gut bacteria; gut-lung axis.

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Conflict of interest statement

G.C.Z. is a founder of Revaissant Bioscience.

Figures

Figure 1.
Figure 1.
Gut microbiota is required for the control of M. tuberculosis infection.
Figure 2.
Figure 2.
LncRNA-CGB expression was regulated by gut microbiota and involved in TB infection.
Figure 3.
Figure 3.
LncRNA-CGB knock-out (KO) mice developed more severe TB than did control mice.
Figure 4.
Figure 4.
B. fragilis was identified as a significantly altered gut microbiota to orchestrate the expression of lncRNA-CGB during TB infection.
Figure 5.
Figure 5.
Direct oral administration of B. fragilis protected mice against M. tuberculosis infection.
Figure 6.
Figure 6.
Gut microbiota and its regulated lncRNA-CGB modulate de novo IFN-γ responses during M. tuberculosis infection.
Figure 7.
Figure 7.
LncRNA-CGB negatively regulates H3K27Me3 in IFN-γ (ifng) promoter via physically interacting with EZH2.
See this image and copyright information in PMC

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