Unveiling Gut Homeostasis Disruption in Sepsis: Towards an Integrated Mechanistic and Translational Roadmap

ABSTRACT

Sepsis, a life‐threatening clinical syndrome precipitated by a maladaptive host response to infection, is associated with substantial morbidity and high mortality rates. Gastrointestinal injury has gained recognition as a pivotal factor driving sepsis progression. Pathogen invasion incites oxidative stress and inflammatory cascades, leading to compromised intestinal barrier integrity and dysregulated local immunity. This results in increased gut permeability and bacterial translocation, fostering a state that can be described as ‘enteric sepsis’. Moreover, multi‐organ crosstalk via the gut‐liver and gut‐brain axes substantially amplifies systemic inflammation. The pathophysiology of sepsis‐induced intestinal injury is not yet fully elucidated, and clinically applicable biomarkers or early diagnostic tools remain scarce. Targeted therapeutic strategies have yet to be validated in clinical practice. This article presents a comprehensive review of recent advances in the pathophysiology and underlying mechanisms of sepsis‐induced intestinal injury, focusing on the signalling networks that disrupt intestinal homeostasis and immune equilibrium. Particular emphasis is placed on identifying key pathways and candidate biomarkers for early diagnosis and intervention. Additionally, the therapeutic potential of targeted intestinal‐protective agents is evaluated, integrating insights from traditional Chinese medicine to propose a combined treatment strategy. Ultimately, this review aims to establish a translational framework to advance clinical management and therapeutic innovation for sepsis‐associated intestinal dysfunction.