The interaction between airway microbiome and host in chronic obstructive pulmonary disease (COPD) is poorly understood. Here we used a multi-omic meta-analysis approach to characterize the functional signature of airway microbiome in COPD. We retrieved all public COPD sputum microbiome datasets, totaling 1640 samples from 16S rRNA gene datasets and 26 samples from metagenomic datasets from across the world. We identified microbial taxonomic shifts using random effect meta-analysis and established a global classifier for COPD using 12 microbial genera. We inferred the metabolic potentials for the airway microbiome, established their molecular links to host targets, and explored their effects in a separate meta-analysis on 1340 public human airway transcriptome samples for COPD. 29.6% of differentially expressed human pathways were predicted to be targeted by microbiome metabolism. For inferred metabolite–host interactions, the flux of disease-modifying metabolites as predicted from host transcriptome was generally concordant with their predicted metabolic turnover in microbiome, suggesting a synergistic response between microbiome and host in COPD. The meta-analysis results were further validated by a pilot multi-omic study on 18 COPD patients and 10 controls, in which airway metagenome, metabolome, and host transcriptome were simultaneously characterized. 69.9% of the proposed “microbiome-metabolite–host” interaction links were validated in the independent multi-omic data. Butyrate, homocysteine, and palmitate were the microbial metabolites showing strongest interactions with COPD-associated host genes. Our meta-analysis uncovered functional properties of airway microbiome that interacted with COPD host gene signatures, and demonstrated the possibility of leveraging public multi-omic data to interrogate disease biology.

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.

Thrombocytopenia is common in critical illness. But there are no studies that focus on thrombocytopenia and platelet recovery in Sepsis-3 patients. We employed a large database to identify sepsis based on Sepsis-3 criteria. Patients were grouped by nadir platelet count during ICU, propensity score matching was used to eliminate covariates imbalance, multivariable cox proportional hazard model was used for evaluating mortality. A total of 9709 patients were enrolled based on Sepsis-3, 1794 (18%) patients developed thrombocytopenia, with 858 (8.8%) exhibiting thrombocytopenia at ICU admission (prevalent), 891 (9.2%) developed thrombocytopenia during ICU stay (incident). In the incident thrombocytopenia group, survivors exhibited higher nadir platelet count, higher rate in platelet count recovery and shorter time to platelet recovery compared to non-survivors. Platelet recovery was not observed until 1 days (IQR, 1–2) after weaning of mechanical ventilation and 1 days (IQR, 1–3) after discontinuation of vasopressor in survivors of incident thrombocytopenia. Furthermore, thrombocytopenia was associated with longer duration of ICU length of stay, longer duration of mechanical ventilation and vasopressor use compared to no thrombocytopenia. Moderate (20–50 × 10⁹/L) and severe (<20 × 10⁹/L) thrombocytopenia group showed increased 28 days mortality compared to no thrombocytopenia, while the mortality rate between mild (51–100 × 10⁹/L) and no thrombocytopenia group (≥100 × 10⁹/L) showed no significant difference. Taken together these data revealed that thrombocytopenia occurred in 18% Sepsis-3 patients; platelet recovery occurred more frequent and earlier in survivors; platelet recovery was not observed until clinical improvement. Thrombocytopenia in Sepsis-3 demonstrated increased disease severity, and patients with platelet count <50 × 10⁹/L showed increased 28 days mortality.