Gut barrier dysfunction and multidrug-resistant bacterial translocation in adult critical illness: Mechanistic insights from a systematic review

Abstract

BACKGROUND

The gastrointestinal tract plays an important role in host defence during critical illness. Disruption of epithelial integrity, microbiome imbalance, and immune dysregulation have all been linked to the translocation of multidrug-resistant (MDR) organisms from intestinal colonization to invasive infection. However, whether these associations reflect true causal mechanisms remains uncertain, and available human evidence has not been comprehensively synthesized using current methodological standards.

AIM

To systematically evaluate human evidence examining the relationship between intestinal barrier dysfunction, microbial colonization, and subsequent MDR infection in adult critical illness, with particular attention to study quality, heterogeneity, and potential confounding factors.

METHODS

This systematic review was conducted in accordance with PRISMA guidelines. A structured literature search was performed in PubMed, EMBASE, and the Cochrane Library (2000-2025) using predefined Boolean combinations and Medical Subject Headings. Prospective and retrospective cohort studies involving intensive care units (ICU) adults were included if they evaluated intestinal colonization, biomarkers of barrier dysfunction (citrulline and intestinal fatty acid-binding protein), microbiome alterations, or endotoxemia. Study selection and data extraction were undertaken independently by two reviewers, with disagreements resolved through discussion. Risk of bias was assessed using the Newcastle-Ottawa Scale and ROBINS-I tool. Owing to methodological and clinical heterogeneity, findings were synthesized using a structured narrative approach rather than meta-analysis.

RESULTS

Across the included studies, intestinal colonization with carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Klebsiella pneumoniae, Acinetobacter baumannii, and vancomycin-resistant Enterococcus was consistently associated with an increased risk of subsequent bloodstream infection. However, progression rates varied considerably across cohorts, likely reflecting differences in patient characteristics, antimicrobial exposure, and ICU practices rather than a consistent effect size. Biomarker studies showed reduced citrulline levels and elevated intestinal fatty acid-binding protein concentrations in patients with gastrointestinal dysfunction; however, these markers indicate enterocyte injury rather than directly measuring intestinal permeability or bacterial translocation. Microbiome analyses demonstrated reduced diversity and impaired colonization resistance, although the extent and timing of these changes were not uniform across studies. Taken together, the evidence supports a biologically plausible link between epithelial injury, dysbiosis, and infection risk, but does not establish a direct causal relationship, largely due to the observational design of available studies and the influence of confounding factors such as illness severity, antimicrobial exposure, and ICU environment.

CONCLUSION

Gut barrier dysfunction appears to contribute to the pathogenesis of MDR infection in critically ill adults; however, current evidence supports association rather than causation. Early recognition of intestinal colonization and strategies aimed at preserving mucosal integrity may offer potential clinical benefit, although their effectiveness requires confirmation in well-designed prospective and interventional studies.

Keywords: Gut barrier dysfunction; Tight junctions; Multidrug-resistant bacteria; Carbapenem-resistant Enterobacteriaceae; Bacterial translocation; Critical illness; Sepsis; Gut microbiome dysbiosis

Core Tip: Intestinal colonization with multidrug-resistant organisms often precedes bloodstream infection in critically ill adults. Findings from clinical cohorts, microbiome analyses, and biomarker studies indicate that disruption of epithelial barrier integrity and loss of microbiome-mediated colonization resistance may increase the risk of systemic infection. However, most available evidence is observational and remains susceptible to confounding, particularly from antibiotic exposure, illness severity, and intensive care units-related factors. This PRISMA-compliant systematic review brings together mechanistic and clinical evidence, with careful appraisal of study quality, and identifies gut barrier dysfunction as a plausible - though not definitively causal - contributor to antimicrobial resistance-associated infections, highlighting important directions for future research.