Microbial Determinants of Acute Respiratory Distress Syndrome Severity (MiDAS)

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PROJECT SUMMARY – ABSTRACT The Acute Respiratory Distress Syndrome (ARDS) is a serious form of inflammatory lung injury that disrupts the alveolar/capillary membrane leading to pulmonary edema and low oxygen levels. Despite advancements in understanding lung injury mechanisms, clinical trials for targeted pharmacologic therapies have shown limited efficacy, and care remains mostly supportive. Notably, most patients with ARDS do not die from hypoxemia but from multisystem organ failure, but the mechanisms of extrapulmonary organ damage are poorly defined. The clinical significance of ARDS was evident in the pre-pandemic era, accounting for 10% of ICU admissions, with up to 40% mortality and long-term sequelae to survivors, yet it has become a global emergency during the COVID-19 pandemic. Recent research has uncovered two reproducible ARDS subphenotypes (hyper- vs. hypo-inflammatory), with distinct profiles of systemic inflammatory biomarkers and divergent clinical outcomes. Despite the promise of this stratification framework for targeted therapeutics, ARDS subphenotypes are not currently used for therapeutic guidance and their biological underpinnings are unknown. Emerging work from our group highlights the lung microbiome as an underappreciated determinant of ARDS inflammation and clinical outcomes. Beyond the lungs, we have also discovered provocative associations between circulating, plasma microbial fragments (i.e. nucleic acids and cell-wall constituents) with host inflammation and outcome. Such microbial fragments may leak in the systemic circulation through the disrupted alveolar/capillary membrane and act as pathogen associated molecular patterns that stimulate innate immune cells. However, the extent and impact of microbial translocation in ARDS has not been thoroughly studied. In the proposed Microbial Determinants of Acute Respiratory Distress Syndrome Severity (MiDAS) study, we will leverage culture-independent methods of host-microbiota interactions in two body compartments (lungs and blood) in a well-phenotyped cohort of patients with and without ARDS, to accomplish the following specific aims: 1) To define the clinical and molecular determinants of lung microbiota translocation to the blood, and 2) To derive lung and blood compartment subphenotypes of host-microbiota interactions in ARDS. The MiDAS study will advance our understanding of the role of the lung microbiome in ARDS and clarify whether microbial translocation from the injured lungs of ARDS is an innocuous epiphenomenon or a significant pathogenetic contributor. With rapid and informative subphenotyping of ARDS patients by host-microbiota interactions, our approach has the potential to transform the practice of indiscriminate immunomodulatory therapies to timely, personalized regimens tailored to individual patients’ pathogens and inflammatory status.