The Host Microbiota Contributes to Early Protection Against Lung Colonization by Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), caused by the airborne bacterial pathogen Mycobacterium tuberculosis, remains a major source of morbidity and mortality worldwide. So far, the study of host-pathogen interactions in TB has mostly focused on the physiology and virulence of the pathogen, as well as, on the various innate and adaptive immune compartments of the host. Microbial organisms endogenous to our body, the so-called microbiota, interact not only with invading pathogens, but also with our immune system. Yet, the impact of the microbiota on host defense against M. tuberculosis remains poorly understood. In order to address this question, we adapted a robust and reproducible mouse model of microbial dysbiosis based on a combination of wide-spectrum antibiotics. We found that microbiota dysbiosis resulted in an increased early colonization of the lungs by M. tuberculosis during the first week of infection, correlating with an altered diversity of the gut microbiota during this time period. At the cellular level, no significant difference in the recruitment of conventional myeloid cells, including macrophages, dendritic cells and neutrophils, to the lungs could be detected during the first week of infection between microbiota-competent and -deficient mice. At the molecular level, microbiota depletion did not impact the global production of pro-inflammatory cytokines, such as interferon (IFN)γ, tumor necrosis factor (TNF)α and interleukin (IL)-1β in the lungs. Strikingly, a reduced number of mucosal-associated invariant T (MAIT) cells, a population of innate-like lymphocytes whose development is known to depend on the host microbiota, was observed in the lungs of the antibiotics-treated animals after 1week of infection. These cells produced less IL-17A in antibiotics-treated mice. Notably, dysbiosis correction through the inoculation of a complex microbiota in antibiotics-treated animals reversed these phenotypes and improved the ability of MAIT cells to proliferate. Altogether, our results demonstrate that the host microbiota contributes to early protection of lung colonization by M. tuberculosis, possibly through sustaining the function(s) of MAIT cells. Our study calls for a better understanding of the impact of the microbiota on host-pathogen interactions in TB. Ultimately, this study may help to develop novel therapeutic approaches based on the use of beneficial microbes, or components thereof, to boost anti-mycobacterial immunity.

Mycobacterium tuberculosis, antimicrobials, immunity, and lung–gut microbiota crosstalk: current updates and emerging advances

“…It is worth mentioning that most of these dysbiosis-induced effects on the immune system were mainly mediated by MINCLE through DCs, and to a lesser degree, were also observed in MAIT cells. 12,13,32 The reversal of these dysbiosisinduced effects on the immune system also resulted in the partial or substantial restoration of gut eubiosis and reduction in Mtb proliferation and associated pathologies (Table 1), confirming the importance of the gut microbiome in Mtb prevention.…”

“…Thus, factors affecting microbiome stability indirectly influence susceptibility to Mtb, such that a restoration of eubiosis reverses Mtb pathogenesis, granulomas, and dissemination. 12,13,30 Therefore, the microbiome-immunity-Mtb interactions are discussed under seven main sections, according to the dysbiotic factors: (1) antimicrobials; (2) immunity; (3) pathogens; (4) Mtb; (5) smoking; (6) diet; and (7) current challenges and future perspectives.…”

“…4,5 In animal models, they drastically disrupt the microbiome within the first 7 days, allowing drug-resistant microbial species, such as Proteobacteria and Enterococcus, to subsequently proliferate, hence affecting the diversity and relative abundance of the gut microbiome. 12,13,31 Due to the importance of the microbiome in food metabolism in the intestines, their disruption affects the digestive processes, as well as the functional and biosynthetic pathways, leading to reduced biosynthesis of important metabolites and nutrients, enlarged ceca, and distorted microvilli structures. 12,32 Although fecal transplants (FTs) were able to restore much of the original diversity of the gut microbiota in animals exposed to antimicrobials, the reversal was not complete.…”

“…12,32 Although fecal transplants (FTs) were able to restore much of the original diversity of the gut microbiota in animals exposed to antimicrobials, the reversal was not complete. 12,13,32 The effects of broad-spectrum antibiotics on the gut microbiome are more drastic than narrowspectrum antibiotics, which include first-line anti-TB drugs, such as isoniazid (INH/H), pyrazinamide (PZA/Z), and ethambutol (EMB/E); rifampicin (RIF/R) is the only broad-spectrum first-line anti-TB antibiotic. 4,5 Moreover, H and Z are prodrugs, meaning they are only active once inside the Mtb host.…”

“…The effect of oral antimicrobials on the lung microbiota is not fully clear, although one study found no microbiota in the lung after antimicrobial administration. 13 Also, current studies reporting on the microbiota effect of anti-TB antibiotics focus on the gut instead of the lung microbiome. Thus, concomitant changes in the lung microbiome, alongside the gut microbiome during antimicrobial therapy, remain sketchy.…”