Abstract Rationale Acute respiratory distress syndrome (ARDS) is an often-fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Methods Here, we use a combination of gnotobiotic mice paired with models of acute lung injury, cell culture experiments, de novo bacterial genome assembly, single-cell RNA sequencing from mice and patients with ARDS, and re-analysis of a large metabolomics dataset from critically ill patients. Results Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L-lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. B. adolescentis was capable of driving oxygen-induced pulmonary toxicity in a mouse model where it reduced alveolar fluid clearance, providing a key physiologic mechanism by which it contributed to disease severity. Furthermore, lactate was correlated with illness severity in patients with ARDS, and B. adolescentis induced mitochondrial genes were preferentially expressed in epithelial cells from the endotracheal aspirates of ARDS patients. Conclusions Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts. This abstract is funded by: K08HL165106
Upadhyay et al. (Fri,) studied this question.