The gut-lung axis in ARDS: beyond microbial translocation

The gut-lung axis has emerged as a pivotal pathway in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Disruption of the intestinal barrier, a common event in critical illness, facilitates the systemic dissemination of live microbiota, their pathogen-associated molecular patterns (PAMPs), and bioactive metabolites. This process critically depends on the integrity of the gut vascular barrier (GVB). The GVB is the endothelial layer underlying the gut epithelium. It serves as the final gatekeeper, restricting microbial products from entering the systemic circulation. Concurrently, intestinal immune cells, such as γδ T cells and innate lymphoid cells (ILCs), migrate to the lungs and amplify the inflammatory cascade. Emerging evidence links regulated cell death, especially pyroptosis, necroptosis, and ferroptosis, to disruption of both gut and lung barriers, fueling a self-amplifying cycle of organ injury. This review synthesizes current evidence on the cellular, molecular, and metabolic mechanisms underlying gut-derived lung injury. Furthermore, we critically evaluate several emerging gut-targeted therapeutic strategies aimed at restoring microbial homeostasis and mitigating ALI/ARDS, including fecal microbiota transplantation (FMT), probiotics, synbiotics, and mesenchymal stem cell (MSC) therapy. Deciphering the gut-lung dialogue holds promise for developing novel treatments for this devastating condition.