Sepsis and the diverse organ-gastrointestinal tract axis

Abstract

Sepsis remains a leading cause of morbidity and mortality worldwide, driven by a dysregulated host immune response to infection that culminates in multi-organ dysfunction. Recent advances highlight the gut microbiota's pivotal role in modulating immune responses and influencing the pathophysiology of sepsis through the organ-gastrointestinal tract axis. This review synthesizes current evidence on the bidirectional interplay between gut dysbiosis and the dysfunction of major organ systems—liver, lungs, kidneys, brain, and heart—during sepsis. We explore how gut-derived factors such as microbial translocation, endotoxins, and altered metabolite production exacerbate systemic inflammation and organ injury. In particular, we emphasize the roles of short-chain fatty acids, uremic toxins, bile acids, and trimethylamine-N-oxide in mediating immune dysfunction across the gut-organ axes. Therapeutic strategies targeting the gut microbiota— including prebiotics, probiotics, synbiotics, and fecal microbiota transplantation— show promise in preclinical and early clinical settings. However, challenges related to patient heterogeneity, safety, and the lack of precise biomarkers persist. This review consolidates disparate findings to underscore the gut as a central modulator in sepsis and advocates for microbiota-based interventions as adjunctive therapies in sepsis management.

Keywords: Critical care; Gut microbiota dysbiosis; Multi-organ dysfunction; Organ-gut axis; Sepsis

Core Tip: This review underscores the critical role of gut microbiota in sepsis pathophysiology, revealing how gut dysbiosis exacerbates multi-organ dysfunction via organ-gut axes (gut-liver, gut-lung, gut-brain, gut-kidney, and gut-heart). Innovative microbiota-targeted therapies, such as probiotics, prebiotics, and fecal microbiota transplantation, show potential to restore microbial balance, reduce systemic inflammation, and improve outcomes. By synthesizing current evidence, this manuscript provides a foundation for integrating microbiota-based approaches into sepsis management frameworks, offering a novel perspective for mitigating the global burden of sepsis.