The leaky gut and the gut microbiome in sepsis - targets in research and treatment

Abstract

Both a leaky gut (a barrier defect of the intestinal surface) and gut dysbiosis (a change in the intestinal microbial population) are intrinsic to sepsis. While sepsis itself can cause dysbiosis, dysbiosis can worsen sepsis. The leaky gut syndrome refers to a status with which there is an increased intestinal permeability allowing the translocation of microbial molecules from the gut into the blood circulation. It is not just a symptom of gastrointestinal involvement, but also an underlying cause that develops independently, and its presence could be recognized by the detection, in blood, of lipopolysaccharides and (1→3)-β-D-glucan (major components of gut microbiota). Gut-dysbiosis is the consequence of a reduction in some bacterial species in the gut microbiome, as a consequence of intestinal mucosal immunity defect, caused by intestinal hypoperfusion, immune cell apoptosis, and a variety of enteric neuro-humoral-immunity responses. A reduction in bacteria that produce short-chain fatty acids could change the intestinal barriers, leading to the translocation of pathogen molecules, into the circulation where it causes systemic inflammation. Even gut fungi might be increased in human patients with sepsis, even though this has not been consistently observed in murine models of sepsis, probably because of the longer duration of sepsis and also antibiotic use in patients. The gut virobiome that partly consists of bacteriophages is also detectable in gut contents that might be different between sepsis and normal hosts. These alterations of gut dysbiosis altogether could be an interesting target for sepsis adjuvant therapies, e.g., by faecal transplantation or probiotic therapy. Here, current information on leaky gut and gut dysbiosis along with the potential biomarkers, new treatment strategies, and future research topics are mentioned.

Keywords: faecal transplantation; gut dysbiosis; leaky gut; lipopolysaccharides; microbiome; sepsis.

Figure 1. The alteration of all organisms (bacteria, fungi and phages) involved in sepsis and gut immunity

Sepsis induces intestinal immunity defects, through intestinal hypoperfusion (vasodilatation and cardiomyopathy), immune cell apoptosis, the stress hormone (corticotropin)/enteric neuron-induced immune responses, and systemic inflammation, inducing gut dysbiosis (left side). In parallel, sepsis-induced gut dysbiosis, caused by intestinal immunity defect, antibiotics and alteration in fungi and phages, facilitates gut translocation of microbial molecules or viable organisms (leaky gut) causing systemic inflammation (right side) that worsen gut integrity and induce gut dysbiosis as a vicious cycle. Picture is created by BioRender.com.

Figure 2. The adjunctive therapy of prebiotics, probiotics and FMT in terms of intestinal permeability effects

All of these strategies improve the balance of gut microbiota with increased organismal diversity that is beneficial to the host through reduced pathogenic microbes, strengthens the gut barrier and induces gut epithelial reconstruction.Picture is created by BioRender.com