Faculty Bibliography

INTRODUCTION/UNASSIGNED:Up to 11% of patients are left with residual lung abnormalities following COVID-19 infection. It is unclear whether these changes resolve over time or progress to fibrosis. The airway microbiome is altered in interstitial lung disease, potentially contributing to pathogenesis and disease progression. We hypothesised that the airway microbiome in patients with post-COVID-19 residual lung abnormalities may be altered. METHODS/UNASSIGNED:The POST COVID-19 interstitial lung DiseasE (POSTCODE) study recruited subjects with post-COVID-19 residual lung abnormalities for bronchoscopy. 16S ribosomal RNA gene amplicon sequencing was performed on DNA extracted from bronchoalveolar lavage fluid and compared with that from patients with idiopathic pulmonary fibrosis, fibrotic hypersensitivity pneumonitis and control subjects. RESULTS/UNASSIGNED:and higher α-diversity in subjects with post-COVID-19 residual lung abnormalities. CONCLUSIONS/UNASSIGNED:The microbiome and bacterial burden in the lower airways of subjects with post-COVID-19 residual lung abnormalities do not differ from those of controls. The microbiome differs from idiopathic pulmonary fibrosis. This, and the absence of associations between microbial features and disease severity or clinical outcomes, suggests that the microbiome is unlikely to contribute to residual lung abnormalities in patients recovering from COVID-19 infection.

Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.

The role of dietary fiber in colon cancer prevention remains controversial. We investigated its impact on anti-tumor immunity and the gut microbiota in APCmin/+ mice infected with Enterotoxigenic Bacteroides fragilis. Mice were fed high-fiber, low-fiber, or chow diets, and tumor burden, survival, cytokines, microbiota, and metabolites were analyzed. Contrary to the belief that high fiber inhibits tumor progression, it had no significant impact compared to chow diet. However, the low-fiber diet significantly reduced tumor burden and improved survival. Mechanistically, high fiber increased pro-inflammatory cytokines and CD4+Foxp3+RORγt+IL-17A+ regulatory T cells, while low fiber enhanced anti-inflammatory cytokines and cytotoxic T-cells. High fiber enriched microbial taxa associated with IL-17A+RORγt+ Tregs and altered metabolites, including reduced tryptophan and increased short-chain fatty acids and bile acids. Low fiber produced opposite effects. These findings suggest that dietary fiber's effects on colon cancer depends on microbial infection and immune status, emphasizing the need for personalized dietary interventions in colon cancer management.

Non-small cell lung cancer (NSCLC) remains the most common cause for cancer-related mortality despite advances in treatment. Early detection is crucial for improving patient outcomes, yet current diagnostic and prognostic molecular biomarkers lack the sensitivity and specificity necessary to become clinically useful. Recent studies revealed that the lower airway microbiome play a role in NSCLC and that microbial signatures are associated with NSCLC development, progression, and prognosis, suggesting the potential for microbiome-based biomarkers for early diagnosis and risk stratification. Here we review recent advances in the role of the local and systemic microbiome in early-stage NSCLC. Primarily, several studies have identified specific microbial taxa associated with lung cancer suggesting novel insights into disease pathogenesis and progression. Integration of microbiome data with other 'omics' platforms, such as host transcriptomics and metabolomics, has the potential to enhance our understanding of microbial-host interactions and may provide more comprehensive biomarker signatures. While promising, challenges remain to the development of microbiome-based biomarkers such as those related to differences in samples utilized, sequencing methods, and data analysis. Here, we discuss such challenges as well as future directions for research needed to fulfil the promise of microbiome-based biomarkers for changing early detection and management strategies in NSCLC.

RATIONALE/BACKGROUND:Lower airway enrichment with oral commensals has been previously associated with grade 3 severe primary graft dysfunction (PGD) after lung transplantation (LT). We aimed to determine whether this dysbiotic signature is present across all PGD severity grades, including milder forms, and whether it is associated with a distinct host inflammatory endotype. METHODS:Lower airway samples from 96 LT recipients with varying degrees of PGD were used to evaluate the lung allograft microbiota via 16S rRNA gene sequencing. Bronchoalveolar lavage (BAL) cytokine concentrations and cell differential percentages were compared across PGD grades. In a subset of samples, we evaluated the lower airway host transcriptome using RNA sequencing methods. RESULTS:Differential analyses demonstrated lower airway enrichment with supraglottic-predominant taxa (SPT) in both moderate and severe PGD. Dirichlet Multinomial Mixtures (DMM) modeling identified two distinct microbial clusters. A greater percentage of subjects with moderate-severe PGD were identified within the dysbiotic cluster (C-SPT) than within the no PGD group (48 and 29%, respectively) though this difference did not reach statistical significance (p=0.06). PGD severity associated with increased BAL neutrophil concentration (p=0.03) and correlated with BAL concentrations of MCP-1/CCL2, IP-10/CXCL10, IL-10, and TNF-α (p<0.05). Furthermore, microbial signatures of dysbiosis correlated with neutrophils, MCP-1/CCL-2, IL-10, and TNF-α (p<0.05). C-SPT exhibited differential expression of TNF, SERPINE1 (PAI-1), MPO, and MMP1 genes and upregulation of MAPK pathways, suggesting that dysbiosis regulates host signaling to promote neutrophilic inflammation. CONCLUSIONS:Lower airway dysbiosis within the lung allograft is associated with a neutrophilic inflammatory endotype, an immune profile commonly recognized as the hallmark for PGD pathogenesis. This data highlights a putative role for lower airway microbial dysbiosis in the pathogenesis of this syndrome.