Integrated mechanisms of the Gut-X axis and multi-organ injury in Sepsis

Sepsis is a life-threatening syndrome defined by infection-triggered dysregulation of the host response, and its persistently high mortality and marked clinical heterogeneity remain major barriers to early risk stratification and individualized management. While the gut is increasingly recognized as a key modulator of the systemic sepsis response, current evidence does not support a universal, upstream causal role for intestinal alterations in the initiation of multi-organ injury. In this review, we synthesize current evidence linking gut microbial dysbiosis and intestinal barrier dysfunction to the systemic dissemination and perturbation of microbial and host-derived signals in sepsis. We organize the downstream effects of individual gut-organ axes into three interconnected host-response domains. These domains are immune-inflammatory dysregulation, metabolic reprogramming, and neuroendocrine dysregulation. These domains overlap and have no established hierarchical order. The same signal may engage several domains simultaneously. We further classify intestinal alterations according to three analytical roles. These are prediction, mediation, and amplification. We also propose that heterogeneous organ phenotypes emerge from interactions between shared systemic signals and organ-specific susceptibility. Importantly, definitive evidence for a causal role remains scarce in human sepsis because the temporal sequence of these processes is incompletely defined and because infection source, antibiotics, nutrition, vasoactive support, secondary infection, and other intensive-care exposures substantially modify both the gut and distant organs. Ageing-related barrier vulnerability, immunosenescence, inflammaging, frailty, sarcopenia, and reduced physiological reserve may further modify these interactions. The Gut-X framework currently provides a model for organizing and generating mechanistic and longitudinal hypotheses. Its application to clinical stratification or patient selection for treatment remains unvalidated.