A review of gut failure as a cause and consequence of critical illness

In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of gastrointestinal dysfunction drive and then perpetuate multi-organ dysfunction syndrome. Despite the clear importance of maintaining gut homeostasis, there are very few reliable measures of gut function in critical illness. Further, while multiple therapeutic strategies have been proposed, most have not been shown to conclusively demonstrate benefit, and care is still largely supportive. The key role of the gut in critical illness was the subject of the tenth Perioperative Quality Initiative meeting, a conference to summarize the current state of the literature and identify key knowledge gaps for future study. This review is the product of that conference.

Key Points

1. Gut Homeostasis and Its Disruption in Critical Illness: In health, the gut epithelium maintains a balance between absorption, secretion, and microbial containment. In critical illness, increased epithelial apoptosis, reduced proliferation, and loss of barrier integrity contribute to systemic inflammation and organ dysfunction.
2. Gut Dysbiosis and Microbial Translocation: Critical illness leads to gut dysbiosis, characterized by a loss of microbial diversity and overgrowth of opportunistic pathogens. Bacterial translocation through a compromised gut barrier contributes to systemic inflammation, sepsis, and MODS.
3. Splanchnic Hypoperfusion and Ischemia: In critical illness, blood flow is diverted from the gut to vital organs like the brain and heart, leading to ischemic injury, further worsening barrier integrity and promoting bacterial translocation.
4. Inflammatory and Immune Dysregulation: Gut immune dysfunction results in simultaneous pro- and anti-inflammatory responses, contributing to tissue damage and increased susceptibility to infections. Neutrophil and macrophage activation exacerbates inflammation and worsens gut injury.
5. Neurological and Cardiovascular Implications: Gut failure has bidirectional communication with the brain and heart. Gut-derived metabolites influence neuroinflammation, and gut dysbiosis has been linked to sepsis-induced encephalopathy and cardiovascular instability.
6. Systemic Effects of Endotoxemia: Translocation of bacterial lipopolysaccharides (LPS) from the gut into circulation triggers systemic inflammation, leading to endothelial dysfunction, capillary leak, microvascular thrombosis, and MODS.
7. Lack of Reliable Gut-Specific Diagnostic Markers: Currently, there are no gold-standard biomarkers for gut failure in critical illness. Proposed markers such as citrulline, I-FABP, and zonulin have shown limited clinical utility.
8. Therapeutic Strategies Under Investigation: Efforts to mitigate gut dysfunction include optimizing enteral nutrition, restoring gut microbiota balance with probiotics, targeting immune dysregulation, and improving gut perfusion. However, clinical trials have yet to demonstrate conclusive benefits for many proposed therapies.
9. Challenges in Treating Gut-Related Sepsis: The gut is a major source of secondary infections in critically ill patients. Strategies targeting the gut microbiome, reducing gut-derived inflammatory mediators, and preventing bacterial translocation may improve outcomes.
10. Future Directions in Gut Failure Research: Further studies are needed to develop real-time gut function monitoring, define gut-specific sepsis phenotypes, and explore novel interventions such as microbiome-based therapies and precision medicine approaches.

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