Faculty Bibliography

Latent tuberculosis infection (LTBI) is common in people living with HIV (PLHIV) in high-TB-burden settings. Active TB is associated with specific stool taxa; however, little is known about the stool microbiota and LTBI in PLHIV. We characterised the stool microbiota of PLHIV with [interferon-γ release assay (IGRA)- and tuberculin skin test (TST)-positive] or without (IGRA- and TST-negative) LTBI (n = 25 per group). The 16S rRNA DNA sequences were analysed using QIIME2, Dirichlet-Multinomial Mixtures, DESeq2, and PICRUSt2. No α- or β-diversity differences occurred by LTBI status; however, LTBI-positive people were Faecalibacterium-, Blautia-, Gemmiger-, and Bacteroides-enriched and Moryella-, Atopobium-, Corynebacterium-, and Streptococcus-depleted. Inferred metagenome data showed that LTBI-negative-enriched pathways included several metabolite degradation pathways. Stool from LTBI-positive people demonstrated differential taxa abundance based on a quantitative response to antigen stimulation. In LTBI-positive people, older people had different β-diversities than younger people, whereas in LTBI-negative people, no differences occurred across age groups. Amongst female PLHIV, those with LTBI were, vs. those without LTBI, Faecalibacterium-, Blautia-, Gemmiger-, and Bacteriodes-enriched, which are producers of short-chain fatty acids. Taxonomic differences amongst people with LTBI occurred according to quantitative response to antigen stimulation and age. These data enhance our understanding of the microbiome's potential role in LTBI.

BACKGROUND/UNASSIGNED:The microbiome likely plays a role in tuberculosis (TB) pathogenesis. We evaluated the site-of-disease microbiome and predicted metagenome in people with presumptive tuberculous pericarditis, a major cause of mortality, and explored for the first time, the interaction between its association with C-reactive protein (CRP), a potential diagnostic biomarker and the site-of-disease microbiome in extrapulmonary TB. METHODS/UNASSIGNED:People with effusions requiring diagnostic pericardiocentesis (n=139) provided background sampling controls and pericardial fluid (PF) for 16S rRNA gene sequencing analysed using QIIME2 and PICRUSt2. Blood was collected to measure CRP. RESULTS/UNASSIGNED:-depleted). There was no correlation between enriched taxa in dTBs and CRP. CONCLUSIONS/UNASSIGNED:PF is compositionally distinct based on TB status, HIV (and ART) status and dTBs are enriched in SCFA-associated taxa. The clinical significance of these findings, including mycobacterial reads in nTBs and pTBs, requires evaluation.

OBJECTIVE:Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DESIGN/METHODS:mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation. RESULTS:family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. CONCLUSION/CONCLUSIONS:The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.

BACKGROUND/UNASSIGNED:Latent tuberculosis infection (LTBI) is common in people living with HIV (PLHIV) in high TB burden settings. Active TB is associated with specific stool taxa; however, little is known about the stool microbiota and LTBI, including in PLHIV. METHOD/UNASSIGNED:Within a parent study that recruited adult females with HIV from Cape Town, South Africa into predefined age categories (18-25, 35-60 years), we characterised the stool microbiota of those with [interferon-γ release assay (IGRA)- and tuberculin skin test (TST)-positive] or without (IGRA- and TST- negative) LTBI (n=25 per group). 16S rRNA DNA sequences were analysed using QIIME2, Dirichlet Multinomial Mixtures, DESeq2 and PICRUSt2. RESULTS/UNASSIGNED:depletion associated with higher IGRA or TST responses, respectively). In LTBI-positives, older people had different β-diversities than younger people whereas, in LTBI-negatives, no differences occurred across age groups. CONCLUSION/UNASSIGNED:-enriched, which are producers of short chain fatty acids. Taxonomic differences amongst people with LTBI occurred according to quantitative response to antigen stimulation and age. These data enhance our understanding of the microbiome's potential role in LTBI.

INTRODUCTION/UNASSIGNED:This review summarizes our current understanding of the respiratory microbiome in COPD and Bronchiectasis. We explore the interplay between microbial communities, host immune responses, disease pathology, and treatment outcomes. AREAS COVERED/UNASSIGNED:We detail the dynamics of the airway microbiome, its influence on chronic respiratory diseases, and analytical challenges. Relevant articles from PubMed and Medline (January 2010-March 2024) were retrieved and summarized. We examine clinical correlations of the microbiome in COPD and bronchiectasis, assessing how current therapies impact upon it. The potential of emerging immunotherapies, antiinflammatories and antimicrobial strategies is discussed, with focus on the pivotal role of commensal taxa in maintaining respiratory health and the promising avenue of microbiome remodeling for disease management. EXPERT OPINION/UNASSIGNED:Given the heterogeneity in microbiome composition and its pivotal role in disease development and progression, a shift toward microbiome-directed therapeutics is appealing. This transition, from traditional 'pathogencentric' diagnostic and treatment modalities to those acknowledging the microbiome, can be enabled by evolving crossdisciplinary platforms which have the potential to accelerate microbiome-based interventions into routine clinical practice. Bridging the gap between comprehensive microbiome analysis and clinical application, however, remains challenging, necessitating continued innovation in research, diagnostics, trials, and therapeutic development pipelines.

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.