The gut microbiota of people with asthma influences lung inflammation in gnotobiotic mice.

The gut microbiota in early childhood is linked to asthma risk, but may continue to affect older patients with asthma. Here, we profile the gut microbiota of 38 children (19 asthma, median age 8) and 57 adults (17 asthma, median age 28) by 16S rRNA sequencing and find individuals with asthma harbored compositional differences from healthy controls in both adults and children. We develop a model to aid the design of mechanistic experiments in gnotobiotic mice and show enterotoxigenic Bacteroides fragilis (ETBF) is more prevalent in the gut microbiota of patients with asthma compared to healthy controls. In mice, ETBF, modulated by community context, can increase oxidative stress in the lungs during allergic airway inflammation (AAI). Our results provide evidence that ETBF affects the phenotype of airway inflammation in a subset of patients with asthma which suggests that therapies targeting the gut microbiota may be helpful tools for asthma control.

Airway Microbiota-Host Interactions Regulate Secretory Leukocyte Protease Inhibitor Levels and Influence Allergic Airway Inflammation.

Homeostatic mucosal immune responses are fine-tuned by naturally evolved interactions with native microbes, and integrating these relationships into experimental models can provide new insights into human diseases. Here, we leverage a murine-adapted airway microbe, Bordetella pseudohinzii (Bph), to investigate how chronic colonization impacts mucosal immunity and the development of allergic airway inflammation (AAI). Colonization with Bph induces the differentiation of interleukin-17A (IL-17A)-secreting T-helper cells that aid in controlling bacterial abundance. Bph colonization protects from AAI and is associated with increased production of secretory leukocyte protease inhibitor (SLPI), an antimicrobial peptide with anti-inflammatory properties. These findings are additionally supported by clinical data showing that higher levels of upper respiratory SLPI correlate both with greater asthma control and the presence of Haemophilus, a bacterial genus associated with AAI. We propose that SLPI could be used as a biomarker of beneficial host-commensal relationships in the airway.

Substituted tryptophans at amyloid-ß(1-40) residues 19 and 20 experience different environments after fibril formation.

Amyloid-ß protein (Aß) is the principal component of the neuritic plaques found in Alzheimer's disease. The predominant Aß morphology in the plaques is fibrillar which has prompted substantial in vitro work to better understand the molecular organization of Aß fibrils. In the current study, tryptophan substitutions were made at Aß(1-40) position 19 (F19W) or 20 (F20W) to ascertain environmental differences between the two residues in the fibril structure. Kinetic studies revealed similar rates of fibril formation between Aß(1-40) F19W and F20W and both peptides formed typical amyloid fibril structures. Aß(1-40) F19W fibrils displayed a significant tryptophan fluorescence blue-shift in λ(max) (33nm) compared to monomer while Aß(1-40) F20W fibrils had a much smaller shift (9nm). Fluorescence quenching experiments with water-soluble acrylamide and KI demonstrated that both W19 and W20 were much less accessible to quenching in fibrils compared to monomer. Lipid-soluble TEMPO quenched the fluorescence of Aß(1-40) F19W fibrils more effectively than F20W fibrils in agreement with the fluorescence blue-shift results. These findings demonstrate distinct environments between Aß(1-40) residues 19 and 20 fibrils and indicate that while W20 accessibility is compromised in Aß fibrils it resides in a much less hydrophobic environment than W19.