What is dysbiosis and leaky gut?

The intestinal mucosa is a heterogeneous entity composed mainly of tightly packed single layers of epithelial cells covering the external surfaces of our intestinal mucosa, and interacting with the surrounding environment.

The secretion of various molecules into the lumen reinforces the barrier function on the extra-epithelial side, while a variety of immune cells provide additional protection below the epithelial layer.

Mucus forms a layer that separates the bulk of the luminal contents from the intestinal epithelium and prevents bacterial adhesion. The intestinal mucosa represents an enormous interface (200 m2) that ensures adequate containment of undesirable luminal content (pathogenic microorganisms, toxins, pollutants) within the intestine while preserving the ability to absorb nutrients.

Intestinal permeability, together with luminal processing by enterocytes of toxins or other foreign substances (antigens), regulates molecular trafficking between the intestinal lumen and the submucosa, leading to the responses of the body against the non-self (foreign) antigens.

Intercellular tight junctions tightly regulate the antigen trafficking.

What is gut dysbiosis?

Tight junctions are extremely dynamic structures that operate in several key functions of the intestinal epithelium under both physiological and pathological circumstances. More than 150 proteins are parts of those structures, but zonulin is a protein which plays a key role in the modulation of the tight junctions, by increasing the gut permeability.

Gut dysbiosis causes inappropriate production of an increased amount of zonulin with subsequent loss of the gut barrier function. This leads to the passage of luminal contents across the epithelial barrier and may cause the release of pro-inflammatory molecules that themselves cause increased permeability. This establishes a vicious loop and leads to a massive influx of dietary and microbial antigens.

What is leaky gut?

The concept of ‘leaky gut’ is based on the translocation of the whole bacteria, bacterial products and bacterial wall components into the circulation and distant tissues, contributing to remote organ injury.

Although bacterial translocation is a physiological process that is crucial for the development of the host immunity, in the case of leaky gut, a ‘pathological translocation’ happens. Should this phenomenon occur repeatedly, there are many potential adverse consequences for human health.

In particular, both the pathological bacterial translocation and the release of pro-inflammatory molecules have been associated with the onset of many chronic diseases, such as obesity, diabetes mellitus, cardiovascular, gastrointestinal, neurological diseases, and cancers. However, differently from animal models, in human studies the role of organ–bacteria interactions in not fully defined yet.

At present, the available human data should be regarded as hypothesis generating. This means the leaky gut may be a cause or an effect of the disease, and there may be either normal or dysbiotic microbiota that lead to inflammatory or other consequences that have impact on the disease.

Therefore, the role of gut barrier function is important, but there are many unresolved questions as there are no validated drug treatments yet, and the impact of restoring barrier function to improve health in diseases is yet unproven.

Further reading

Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research 2020; 9:69

Chakaroun RM, et al. Gut Microbiome, Intestinal Permeability, and Tissue Bacteria in Metabolic Disease: Perpetrators or Bystanders? Nutrients 2020; 12:1082

Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut 2019; 68:1516-1526