Faculty Bibliography

Idiopathic pulmonary fibrosis (IPF) is a devastating pulmonary disease with no curative treatment other than lung transplantation that results from maladaptive responses to lung epithelial injury; however, the underlying mechanisms remain unclear, and treatment options are limited. Here, we showed that deficiency in the innate immune receptor toll-like receptor 5 (TLR5) is associated with IPF in humans and with increased susceptibility to bleomycin-induced pulmonary fibrosis in mice and that activation of lung epithelial TLR5 through a synthetic flagellin analog protected mice from experimental fibrosis. Mechanistically, epithelial TLR5 activation induced antimicrobial gene expression and ameliorated lung dysbiosis after injury. In contrast, TLR5 deficiency in mice and patients with IPF was associated with lung dysbiosis. Elimination of the microbiome in mice through administration of antibiotics abolished the protective effect of TLR5, and reconstitution of the microbiome by fecal microbiota transplantation rescued the observed phenotype. In conclusion, these studies revealed that TLR5 protects against pulmonary fibrosis through effects on the lung microbiota, providing insight into therapeutic approaches that may ultimately benefit patients with IPF.

The composition of lower airway microbiome has been linked to the development and progression of non-small cell lung cancer (NSCLC). Recent research has transitioned from viewing the lung microbiome as a bystander to a central player in carcinogenesis. Enrichment of oral commensals, specifically Veillonella, Prevotella, and Streptococcus, in the lower airways is associated with upregulated oncogenic pathways and increased inflammatory immune tone. A new integrative multiomic analysis by Weinberg and colleagues involving patients with early-stage NSCLC further supports these associations. By comparing bronchoalveolar lavage fluid from tumor-affected lobes against unaffected lobes within the same patient, researchers identified a localized microbial-immunometabolic niche. Key findings include an enrichment of the Veillonella-Streptococcus-Prevotella taxa and the metabolic byproduct stearic acid (SA) in tumor-affected sites. Ex vivo, SA stimulates macrophages into a "polyfunctional" state, secreting pro-inflammatory cytokines like MIP-1β and RANTES. This secretome could induce neoplastic transformation in lung epithelial cells, facilitating anchorage-independent growth. These insights shift paradigms toward metabolically driven innate immune reprogramming induced by the lung microbiome as an early event in tumor development, offering new strategies for diagnosis, therapy monitoring, and preventive interventions. See related article by Weinberg et al., p. 229 .

RATIONALE/BACKGROUND:The discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps still remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. OBJECTIVES/OBJECTIVE:Evaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. METHODS:16S rRNA gene sequencing, cell counts, and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. MEASUREMENTS AND MAIN RESULTS/RESULTS:Lower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella and Streptococcus). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa were associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, γδT cells, PD-1+ T lymphocytes as well as higher NET levels. CONCLUSIONS:Our analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

PURPOSE OF REVIEW/OBJECTIVE:This review aggregates, analyzes, and summarizes the current understanding of the lung microbiome as it relates to pneumonia. We will review the composition and function of a healthy lung microbiome and conceptualize dysbiosis associated with pneumonia. Finally, we discuss how the lung microbiome impacts the diagnosis, prognostication and pathogenesis, and recovery from pneumonia. RECENT FINDINGS/RESULTS:The most tangible benefit of studying the lung microbiome has been the identification of pathogenic organisms in suspected pneumonia; however, as there is a growing body of evidence that suggest the lung microbiome is critical to pneumonia. Generally, detection of potential pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Escherichia coli can be found even when sampling the lung microbiome of healthy individuals, yet it is unclear what determines the transition from potential pathogens present as bystanders to pathogens driving the development of pneumonia. Analysis of the lung microbiome suggests that the loss of "oral commensals" (bacteria found in the oral microbiome) in the lower airways is associated with the development of pneumonia and may provide diagnostic and prognostic insights. SUMMARY/CONCLUSIONS:The lung microbiome is a rich and dynamic ecosystem comprised of numerous bacterial, fungal, and viral taxa that may contribute to pneumonia pathogenesis. There is increasing evidence that the lung microbiome may provide insight into factors that determine the pathogenicity of respiratory microbes and the susceptibility of individuals to those pathogens.

Despite recent advances, the underlying mechanisms of the development and progression of many chronic respiratory diseases remain to be elucidated. Factors such as heterogeneity and complexity of human diseases and difficulty interpreting large datasets hinder research into chronic respiratory diseases. Omics assesses the changes in specific biological entities, such as mRNA expression, epigenetics/epigenomics, genomics, proteomics, metagenomics and metabolomics, and provides valuable insights into the roles of these processes in chronic respiratory diseases. High-throughput omics at bulk, single-cell and spatial levels empower the exploration of disease-related changes through untargeted data-driven statistical methods. Multi-omics is the exploration and integration of multiple biological processes, which compared to a single-omics, can provide a substantially greater and more holistic overview of the pathogenic mechanisms that underpin complex diseases. Multi-omics analysis can comprehensively characterise the mechanisms that drive chronic respiratory diseases, capturing unique biological signatures and cellular interactions at different omics levels. Use of these methods has begun to identify key factors and biomarkers in chronic respiratory diseases. Here, we review current omics approaches and highlight recent advances in respiratory research achieved using multi-omics and integrative methods. Our review provides a valuable resource for researchers and clinicians in this area.

The 3rd African Microbiome Symposium was held in Cape Town, South Africa, from 20 to 22 November 2024. The symposium featured a diverse range of local and international microbiome research and provided a platform for 79 researchers, students, and industry members to engage in discussions on the microbiome within an African context and focusing on translational research. This meeting review shares highlights, findings, and recommendations derived from the event. Insights from two panel discussions revealed key barriers to microbiome research in Africa, including limited funding, infrastructure gaps, and a shortage of trained local scientists. Recommendations centered on increased investment, institutional training, adherence to ethical guidelines, and the fostering of equitable global partnerships.