Source-stratified gut-extraintestinal organ crosstalk in sepsis-associated acute gastrointestinal injury and paralytic ileus: the gut as both driver and target.

Sepsis-associated acute gastrointestinal injury and paralytic ileus are common but underrecognized manifestations of systemic critical illness and are closely linked to feeding intolerance, barrier failure, secondary infection, and progression to multiorgan dysfunction. However, the gut in sepsis should not be viewed solely as a passive target of distant organ injury. Owing to its unique microbial burden, highly specialized epithelial-immune barrier, and central role in host-microbe and metabolic homeostasis, the gut may function either as an initiator of injury amplification or as a vulnerable downstream target, depending on the infectious source and disease stage. In this review, we propose a source-stratified framework for gut-extraintestinal organ crosstalk in sepsis-associated acute gastrointestinal injury and paralytic ileus. In enterogenic sepsis, the gut more commonly serves as an injury driver through barrier disruption, microbial translocation, dysbiosis, and propagation of inflammatory and metabolic stress signals. In extraintestinal sepsis, the gut more often emerges as a susceptible target of systemic inflammation, microcirculatory failure, neurohumoral dysregulation, and organ-to-organ injury transmission, while subsequent gut dysfunction may in turn amplify remote organ damage. These distinct starting points ultimately converge into a self-reinforcing loop involving epithelial and endothelial barrier failure, immune dysregulation, mitochondrial dysfunction, immunometabolic reprogramming, regulated cell death, extracellular vesicle-mediated signaling, and bidirectional organ injury amplification. We further summarize how these shared mechanisms shape the gut-lung, gut-brain, gut-liver, gut-kidney, and gut-heart axes, and discuss their implications for biomarker development, bedside phenotyping, source-based risk stratification, and mechanism-guided therapeutic strategies. By reframing the gut as both driver and target within a source-dependent network of organ crosstalk, this review aims to provide a more integrative pathobiological model for sepsis-associated gastrointestinal dysfunction and to inform future translational and clinical studies.