MicroRNA-31 mediated by interferon regulatory factor 7 signaling facilitates control of Mycobacterium tuberculosis infection.

Tuberculosis (TB) induced by Mycobacterium tuberculosis (M. tuberculosis) infection remains a global most deadly infectious disease. While development of more effective TB vaccines and therapeutics relies on identifications of true biomarkers designating an immune protection against M. tuberculosis infection, exact protective immune components against M. tuberculosis infection remain largely unidentified. We previously found that severe TB induced remarkable up-regulation of interferon regulatory factor 7 (IRF7) and IRF7-related gene signatures, implicating that some unknown downstream molecules in IRF7 signaling cascades may determine the M. tuberculosis infection outcomes and serve as a protective immune component against M. tuberculosis infection. Indeed, here, we observe that genetic ablation of IRF7 leads to more severe lung pathology, increased M. tuberculosis burdens, impaired differentiation of effector/memory T subsets, and extensively elevated expression of pro-inflammatory cytokines in lungs. Importantly, IRF7 is vital for sustaining expression of PD-1/PD-L1 and PD-1/PD-L1-modulated miRNA-31. Moreover, interventions of miRNA-31 expressions via administration of miRNA-31 agomir reduces lung pathology and bacilli burdens via inducing up-regulation of gene sets involved in biological processes of defense response or cellular and chemical homeostasis in lungs. Thus, this study uncovers previously unrecognized importance and mechanisms of IRF7-mediated miRNA-31 as a protective immune component against M. tuberculosis infection.

Dietary palmitoleic acid reprograms gut microbiota and improves biological therapy against colitis.

Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn's disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.

Ifnar gene variants influence gut microbial production of palmitoleic acid and host immune responses to tuberculosis.

Both host genetics and the gut microbiome have important effects on human health, yet how host genetics regulates gut bacteria and further determines disease susceptibility remains unclear. Here, we find that the gut microbiome pattern of participants with active tuberculosis is characterized by a reduction of core species found across healthy individuals, particularly Akkermansia muciniphila. Oral treatment of A. muciniphila or A. muciniphila-mediated palmitoleic acid strongly inhibits tuberculosis infection through epigenetic inhibition of tumour necrosis factor in mice infected with Mycobacterium tuberculosis. We use three independent cohorts comprising 6,512 individuals and identify that the single-nucleotide polymorphism rs2257167 'G' allele of type I interferon receptor 1 (encoded by IFNAR1 in humans) contributes to stronger type I interferon signalling, impaired colonization and abundance of A. muciniphila, reduced palmitoleic acid production, higher levels of tumour necrosis factor, and more severe tuberculosis disease in humans and transgenic mice. Thus, host genetics are critical in modulating the structure and functions of gut microbiome and gut microbial metabolites, which further determine disease susceptibility.

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

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.

MiR-21 Is Remotely Governed by the Commensal Bacteria and Impairs Anti-TB Immunity by Down-Regulating IFN-γ.

Tuberculosis (TB), which is a frequent and important infectious disease caused by Mycobacterium tuberculosis, has resulted in an extremely high burden of morbidity and mortality. The importance of intestinal dysbacteriosis in regulating host immunity has been implicated in TB, and accumulating evidence suggests that microRNAs (miRNAs) might act as a key mediator in maintaining intestinal homeostasis through signaling networks. However, the involvement of miRNA in gut microbiota, TB and the host immune system remains unknown. Here we showed that intestinal dysbacteriosis increases the susceptibility to TB and remotely increased the expression of miR-21 in lung. Systemic antagonism of miR-21 enhanced IFN-γ production and further conferred immune protection against TB. Molecular experiments further indicated that miR-21a-3p could specifically target IFN-γ mRNA. These findings revealed regulatory pathways implicating intestinal dysbacteriosis induced-susceptibility to TB: intestinal dysbiosis→lung miRNA→targeting IFN-γ→impaired anti-TB immunity. This study also suggested that deregulated miRNAs by commensal bacteria could become promising targets as TB therapeutics.