The pulmonary microbial community, described only a few years ago, forms a discreet part of the human host microbiota. The airway microbiota has been found to be substantially altered in the context of numerous respiratory disorders, nonetheless its role in health and disease is as yet only poorly understood. Another important parameter to consider is the gut‐lung axis, where distal (gut) immune modulation during respiratory disease is mediated by the gut microbiota. The use of specific microbiota strains, termed “probiotics”, with beneficial effects on the host immunity and/or against pathogens, have proven successful in the treatment of intestinal disorders and is also showing promise in the context of airway diseases. In this review, we highlight the beneficial role of the body's commensal bacteria during airway infectious diseases, including recent evidence highlighting their local (lung) or distal (gut) contribution in this process.

The lungs harbor multiple resident microbial communities, otherwise known as the microbiota. There is an emerging interest in deciphering whether the pulmonary microbiota modulate local immunity, and whether this knowledge could shed light on mechanisms operating in the response to respiratory pathogens. In this study, we investigate the capacity of a pulmonary Lactobacillus strain to modulate the lung T cell compartment and assess its prophylactic potential upon infection with Mycobacterium tuberculosis, the etiological agent of tuberculosis. In naive mice, we report that a Lactobacillus murinus (Lagilactobacillus murinus) strain (CNCM I-5314) increases the presence of lung Th17 cells and of a regulatory T cell (Treg) subset known as RORγt⁺ Tregs. In particular, intranasal but not intragastric administration of CNCM I-5314 increases the expansion of these lung leukocytes, suggesting a local rather than systemic effect. Resident Th17 and RORγt⁺ Tregs display an immunosuppressive phenotype that is accentuated by CNCM I-5314. Despite the well-known ability of M. tuberculosis to modulate lung immunity, the immunomodulatory effect by CNCM I-5314 is dominant, as Th17 and RORγt⁺ Tregs are still highly increased in the lung at 42-d postinfection. Importantly, CNCM I-5314 administration in M. tuberculosis–infected mice results in reduction of pulmonary inflammation, without increasing M. tuberculosis burden. Collectively, our findings provide evidence for an immunomodulatory capacity of CNCM I-5314 at steady state and in a model of chronic inflammation in which it can display a protective role, suggesting that L. murinus strains found in the lung may shape local T cells in mice and, perhaps, in humans. Key Points Lactobacillus murinus increases lung Th17 and RORγt⁺ Tregs in naive and infected mice. L. murinus enhances the immunosuppressive phenotype of lung Th17 and RORγt⁺ Tregs. L. murinus reduces lung inflammation without affecting the bacilli burden.

The microbial populations in the gut microbiome have recently been associated with COVID-19 disease severity. However, a causal impact of the gut microbiome on COVID-19 patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. Antibiotics and other treatments during COVID-19 can potentially confound microbiome associations. We therefore first demonstrate in a mouse model that SARS-CoV-2 infection can induce gut microbiome dysbiosis, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Comparison with stool samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, paralleling our observations in the animal model. Specifically, we observed blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species in hospitalized COVID-19 patients. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data obtained from these patients indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.

Excessive cell death in the epithelium due to prolonged immune activation is associated with intestinal diseases such as Crohn’s disease. Mice with mutations in the Crohn’s disease susceptibility gene Atg16l1 are susceptible to inflammation associated with intestinal epithelial cell (IEC) death, including loss of antimicrobial Paneth cells triggered by infection with murine norovirus (MNV). Here, we show that intestinal disease downstream of MNV depends on IFN-α/β and IFN-λ signaling in IECs. In mouse organoids, IFNs synergize with TNF to induce RIPK1-dependent cell death, amplified by ATG16L1 deficiency. We further show that human intestinal organoids harboring the ATG16L1 risk allele exhibit heightened sensitivity to TNF and IFN co-stimulation and to serum from severe COVID-19 patients. Our findings reveal that virally triggered cytokines including IFNs exacerbate epithelial vulnerability in genetically predisposed hosts.

Tuberculosis (TB) is still one of the deadliest infectious diseases in humans. As TB disease is driven by exacerbation of the immune response, promising approaches include host-targeting therapies aiming at controlling the balance between pathogen eradication and limitation of the inflammation in order to prevent immunopathology. Such immune modulation has been observed through modification of the gut-microbiota compartment with oral administration of specific bacterial strains (i.e. probiotics) in other respiratory diseases. In TB, a dysbiosis of the microbiota is observed in patients, and microbiota perturbation in mice increases susceptibility to Mycobacterium tuberculosis (Mtb). Here, we assessed whether bacterial strains isolated from the recently described lung microbiota could have a local impact on Mtb infection by protecting against immune dysfunction for the host benefit. Through intranasal administration in mice, we identified different microbiota strains isolated from mouse lungs with a strong ability to modulate the lung T cell compartment. The same in vivo approach in Mtb-infected mice revealed one strain with a remarkable capacity to diminish Mtb infection-associated lung immunopathology, accompanied by a specific immune signature characterized by an increase level of regulatory T cells sharing surprisingly T-helper 17 cell markers. Collectively, this work may contribute to the design of host-directed therapies to reduce the destructive inflammatory response in TB, without further fomenting the occurrence of multiple-drug resistant Mtb strains. It will also shed light on poorly described populations in the lungs such as the RORgt+ Foxp3+ biTregs and their interactions with the microbiota.

Menopause occurs in women between the ages of 45 and 55 and often results in symptoms that can be alleviated with hormone replacement therapy (HRT). HRT improves the symptoms associated with menopause that negatively affect quality of life, such as hot flashes, difficulty sleeping, fatigue, and vaginal atrophy. HRT also prevents osteoporosis. A current HRT formulation, which includes conjugated equine estrogens (CE) and medroxyprogesterone acetate, unfortunately increases the risk of breast cancer. Over the years, the number of women taking HRT has decreased due to this perceived increased risk. A new form of HRT, which contains CE and bazedoxifene (BZA), a selective estrogen receptor modulator, has recently been approved by the FDA for treatment of moderate to severe hot flashes and for the reduction of osteoporosis development. The CE/BZA mixture has been shown to not only relieve symptoms associated with menopause, but also does not stimulate the breast or uterus. Various studies show that CE/BZA may be protective in the breast. Currently, the mechanism of action of this new combination therapy is not known. Our goal is to identify the molecular mechanism of action of CE/BZA through transcriptome and whole genome occupancy analysis in breast cancer cell lines. In addition, we are determining the effects of the combination therapy on breast cancer progression in a transgenic mouse model. The overall hypothesis of our project is that the ability of CE/BZA to delay the onset of mammary tumors and decrease the number of lesions in the polyoma middle T antigen transgenic mouse model is due to its action as an estrogen receptor α antagonist in the mammary gland. We have determined that CE stimulates gene expression in MCF7 cells at a similar rate to 17β-estradiol, and that BZA is able to decrease this stimulation. Similarly, we have found that CE increases ERα occupancy at promoters of some estrogen target genes, while a combination of CE and BZA decreases this occupancy. Through understanding the molecular mechanism of CE/BZA and by determining whether it reduces the incidence of invasive breast cancer in a transgenic mouse model, we will be able to improve quality of life for many women by relieving menopausal symptoms in a safe manner.