Gut integrity in intensive care: alterations in host permeability and the microbiome as potential therapeutic targets

Abstract

Background: The gut has long been hypothesized to be the "motor" of critical illness, propagating inflammation and playing a key role in multiple organ dysfunction. However, the exact mechanisms through which impaired gut integrity potentially contribute to worsened clinical outcome remain to be elucidated. Critical elements of gut dysregulation including intestinal hyperpermeability and a perturbed microbiome are now recognized as potential therapeutic targets in critical care.

Main body: The gut is a finely tuned ecosystem comprising ~ 40 trillion microorganisms, a single cell layer intestinal epithelia that separates the host from the microbiome and its products, and the mucosal immune system that actively communicates in a bidirectional manner. Under basal conditions, these elements cooperate to maintain a finely balanced homeostasis benefitting both the host and its internal microbial community. Tight junctions between adjacent epithelial cells selectively transport essential molecules while preventing translocation of pathogens. However, critical illness disrupts gut barrier function leading to increased gut permeability, epithelial apoptosis, and immune activation. This disruption is further exacerbated by a shift in the microbiome toward a "pathobiome" dominated by pathogenic microbes with increased expression of virulence factors, which intensifies systemic inflammation and accelerates organ dysfunction. Research has highlighted several potential therapeutic targets to restore gut integrity in the host, including the regulation of epithelial cell function, modulation of tight junction proteins, and inhibition of epithelial apoptosis. Additionally, microbiome-targeted therapies, such as prebiotics, probiotics, fecal microbiota transplantation, and selective decontamination of the digestive tract have also been extensively investigated to promote restoration of gut homeostasis in critically ill patients. Future research is needed to validate the potential efficacy of these interventions in clinical settings and to determine if the gut can be targeted in an individualized fashion.

Conclusion: Increased gut permeability and a disrupted microbiome are common in critical illness, potentially driving dysregulated systemic inflammation and organ dysfunction. Therapeutic strategies to modulate gut permeability and restore the composition of microbiome hold promise as novel treatments for critically ill patients.

Keywords: Barrier; Claudin; Critical care; Dysbiosis; Intestine; Microbiota; Occludin; Pathobiome; Sepsis; Tight junction.

Fig. 1

Schematic representation of gut barrier dysfunction in critical illness. Under basal conditions, TJs, composed of key proteins such as members of the claudin family, occludin, ZO-1, and JAM-A, and the perijunctional actin-myosin ring, maintain gut integrity and prevent the translocation of harmful substances. Activation of MLCK enhances the phosphorylation of perijunctional myosin light chains, ensuring cytoskeletal contraction and the subsequent opening of TJs. During critical illness, TJs are compromised, leading to increased gut permeability through three distinct pathways. The pore pathway allows passage of small ions and water, while the leak pathway allows larger molecules such as lipopolysaccharide (LPS). Additionally, the TJ-independent unrestricted pathway occurs at areas of epithelial damage enabling the translocation of whole bacteria. These changes are often accompanied by a shift in the microbial community towards dysbiosis with invasive pathogens. The disruption of barrier function increases the chance of microbes and microbial-derived products having distant effects, potentially triggering systemic inflammation through mucosal immune activation and leading to organ dysfunction

Fig. 2

Potential therapeutic interventions modulating gut permeability and targeting the microbiome in critical illness. Pharmacological approaches such as EGF, MLCK inhibitors, and caspase inhibitors, can potentially modulate gut permeability by strengthening epithelial TJs and preventing apoptosis (left side of figure). Microbiome-targeted therapies, including probiotics, FMT, and SDD can also potentially restore a healthy microbiome (right side of figure)