Gut microbiota-immune-metabolic crosstalk in acute lung injury: integrating the gut-lung axis from mechanism to therapeutic targeting.

The gut is increasingly recognized as a central immunological organ that orchestrates host immune responses and modulates distant mucosal sites, particularly the respiratory tract. In critical illness, disruption of intestinal barrier integrity and microbial homeostasis facilitates the translocation of bacteria, endotoxins, and metabolites into the systemic circulation, thereby contributing to the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The "gut-lung axis" has emerged as a key mechanistic framework linking intestinal dysfunction with pulmonary inflammation and immune dysregulation. Both direct and indirect effects of the gut microbiota play pivotal roles in shaping host immunity. Microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune cell differentiation and function, particularly influencing the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells, which are critically involved in lung inflammatory responses. In addition, immune cells originating from the gut and bone marrow contribute to pulmonary immune activity, highlighting the systemic nature of gut-derived immune modulation. Conversely, alterations in lung microbiota can impact intestinal homeostasis, supporting the concept of bidirectional communication within the gut-lung axis. In this review, we comprehensively examine the pathophysiological mechanisms underlying ALI/ARDS across diverse etiological contexts from the perspective of gut-lung interactions, with a focus on immune cell dynamics and microbiota-derived metabolites. We further discuss emerging therapeutic strategies targeting the gut-lung axis, including microbiota modulation, fecal microbiota transplantation, and metabolic interventions. Elucidating these interconnected pathways may provide novel insights into the prevention and treatment of ALI/ARDS and advance the development of integrated organ support strategies in critical care medicine.