Host-Microbiome Interactions Influence Pulmonary Disease Development

The human microbiome, defined as the communities of microorganisms that inhabit various bodily niches, has been considered a novel essential organ system. Prior work has identified links between colonizing organisms, innate immunity and adaptive immunity in the regulation of inflammatory processes. The lungs, previously thought to be devoid of commensal organisms, represent a novel target for microbiome research given their environmental exposure. The analyses performed in this work sought to delineate the role of host-microbiome interactions in sarcoidosis and bronchiolitis obliterans syndrome (BOS), two respiratory diseases with poorly defined etiologies. In sarcoidosis, deficient expression of genes associated with lymphocyte mediated immunity was associated with disease progression and loss of pulmonary function, despite increased expression of cytokine and interferon response elements. Strikingly, expression of these pathways was linked to systemic exposure of Streptococcaceae, Sphingomonadaceae, and Burkholderiaceae families. Additionally, airway exposure to Micrococcaceae was associated with increased lymphocyte counts in newly diagnosed sarcoidosis patients. In the study of BOS, an airway microbiome phenotype composed largely of gram-positive organisms promoted resilience towards BOS in lung transplant populations. This phenotype was associated with reduced airway inflammation and reduced neutrophilic infiltration of the airway. Collectively, these analyses suggest that microbial exposures influence innate and adaptive immunity in the lung, promoting or protecting against pathogenesis and disease progression

Why the kidney glomerulus does not clog: A gel permeation/diffusion hypothesis of renal function

Current interpretations of kidney function in terms of a coarse filter followed by a fine filter have difficulty explaining why the glomerulus does not clog. I propose, as an alternative, a semiquantitative hypothesis that assumes that the size-selective property of the glomerulus is a consequence of the limited fraction of space in the glomerular basement membrane (a concentrated gel) into which macromolecules can permeate. The glomerular epithelial cell slits and slit diaphragms are assumed to impose substantial resistance to liquid flow across the glomerulus without acting as a molecular sieve. Calculations based on gel behavior show that proteins cross the glomerular basement membrane mainly by diffusion rather than by liquid flow, whereas water crosses entirely by flow. Thus, diffusion provides most of the protein, whereas flow provides the diluent. As a result, the single-nephron glomerular filtration rate (GFR) becomes a prime factor in (inversely) determining the concentration of proteins in early proximal tubular fluid. Because the reabsorption of proteins from the tubules is a saturable process, the gel permeation/diffusion hypothesis readily accounts for the albuminuria observed when single-nephron GFR is substantially reduced by severe pathological decreases in slit diaphragm length, such as occur in minimal-change nephrotic syndrome in humans, in animals treated with puromycin aminonucleoside, or in humans or animals with mutations in the gene coding for nephrin. My hypothesis predicts that albuminuria will ensue, even with a normal kidney, if the single-nephron GFR falls below ≈50% of normal

Bronchiolitis obliterans syndrome susceptibility and the pulmonary microbiome

BackgroundLung transplantation outcomes remain complicated by bronchiolitis obliterans syndrome (BOS), a major cause of mortality and retransplantation for patients. A variety of factors linking inflammation and BOS have emerged, meriting further exploration of the microbiome as a source of inflammation. In this analysis, we determined features of the pulmonary microbiome associated with BOS susceptibility.MethodsBronchoalveolar lavage (BAL) samples were collected from 25 patients during standard of care bronchoscopies before BOS onset. Microbial DNA was isolated from BAL fluid and prepared for metagenomics shotgun sequencing. Patient microbiomes were phenotyped using k-means clustering and compared to determine effects on BOS-free survival.ResultsClustering identified 3 microbiome phenotypes: Actinobacteria dominant (AD), mixed, and Proteobacteria dominant. AD microbiomes, distinguished by enrichment with Gram-positive organisms, conferred reduced odds and risks for patients to develop acute rejection and BOS compared with non-AD microbiomes. These findings were independent of treatment models. Microbiome findings were correlated with BAL cell counts and polymorphonuclear cell percentages.ConclusionsIn some populations, features of the microbiome may be used to assess BOS susceptibility. Namely, a Gram-positive enriched pulmonary microbiome may predict resilience to BOS