Gastrointestinal axis in post-traumatic sepsis: from molecular mechanisms to translational perspectives.

Post-traumatic sepsis is the leading cause of late mortality in intensive care units. While the concept of "gut-origin sepsis" has evolved over the past three decades, the stomach has largely been overlooked as an active contributor. This review synthesizes current evidence and proposes a novel "Gastrointestinal Axis" (GIA) integrating gastric and intestinal dysfunction as interconnected drivers of post-traumatic sepsis, with gastric autophagy as a proposed regulatory node. The mechanistic data supporting this framework derive primarily from intestinal epithelial cells and general sepsis models; direct evidence for gastric mucosal autophagy in human post-traumatic sepsis remains limited, and the causal inference that gastric autophagy failure initiates downstream intestinal injury remains a hypothesis requiring further validation. A comprehensive literature search of PubMed, Web of Science, and Scopus was conducted to identify relevant peer-reviewed studies on gut barrier dysfunction, dysbiosis, autophagy, and immune responses in post-traumatic sepsis. The central mechanistic framework involves histone deacetylase 5 (HDAC5) upregulation silencing ghrelin, thereby impairing gastric autophagy-a proposed regulatory node in the GIA-which reduces E2F1-mediated NF-κB suppression and impairs intestinal barrier integrity. Parallel protective pathways include PLK1-mTOR-regulated autophagy and SIRT3-mediated mitochondrial protection. This gastric dysfunction may propagate to the intestine, where dysbiosis with loss of obligate anaerobes and overgrowth of Enterobacteriaceae creates a "pathobiome" that potentially amplifies systemic inflammation. Bidirectional communication occurs via lymphatic, humoral, cellular, and neural routes. Emerging biomarkers such as intestinal fatty acid-binding protein, D-lactate, citrulline, and the Acute Gastrointestinal Injury grading system enable multimodal risk stratification. Early enteral nutrition (OR 0.36) and synbiotics (RR 0.61) show promise; preclinical data support HDAC5 inhibitors, ghrelin restoration, and teprenone as promising adjuncts for preserving GIA integrity. The GIA concept reframes gastric and intestinal protection as an integrated therapeutic strategy and provides a new conceptual foundation for preventing post-traumatic sepsis and guiding biomarker-driven mechanism-based interventions.