The human gastrointestinal system, with its intricate intestinal barrier, plays a pivotal role in safeguarding our health. This critical defence system prevents the entry of harmful antigens while allowing the absorption of nutrients. When the intestinal barrier becomes compromised, as in the case of ‘leaky gut syndrome’, it can lead to various diseases, including autoimmune and metabolic disorders. The good news is that this condition is often reversible through strategies like probiotics, prebiotics, and a high-fibre diet, which support the restoration of the barrier’s integrity. Understanding the signifi ance of the intestinal barrier sheds light on the importance of maintaining a healthy gut for overall well-being.

In the vast and intricate world of our bodies, there exists a silent guardian known as the mucosal barrier.

The concept of the intestinal barrier and its significance in health and disease dates back to early observations by scientists in the 19th century. Initial understanding was primitive, focusing primarily on the physical barrier provided by the intestinal epithelium. However, as research methodologies advanced, the discovery of tight junctions between epithelial cells in the 1960smarked a significant turning point, deepening our understanding of the barrier’s selective permeability. Recent decades have seen exponential growth in our knowledge, propelled by molecular biology and genomics, revealing the complex interplay between the gut microbiota, the immune system, and the intestinal barrier in maintaining health and contributing to disease pathogenesis.

The human gastrointestinal (GI) system, often referred to as the digestive system, is a marvel of biological engineering that plays a pivotal role in sustaining life and maintaining overall health. This intricate system comprises a series of organs and tissues, working together to break down food, absorb essential nutrients, and eliminate waste products. At the heart of this complex process lies the intestinal barrier, a critical line of defence that separates the contents of our digestive tract from the rest of the body. In an average lifetime, around 60 tons of food passthrough the human GI tract, along with a large number of microorganisms from the environment, which can threaten the integrity of the gut.¹

The intestinal barrier comprises a layer of epithelial cells that are tightly connected by structures called tight junctions, and mucus. Tight junctions act like gatekeepers, regulating the passage of substances between the cells.³ The intestinal barrier blocks the entry of diverse exterior antigens including food antigens, bacteria, pathogens, and toxins while absorbing nutrients and acting as a lubricant.⁴'⁵ This barrier also provides important components for bacterial growth, adhesion, and protection. The gut microbiota and mucosal barrier have a symbiotic relationship, where the mucosal barrier helps the bacteria thrive, and the gut microbiota contributes to the health of the mucosal barrier.⁶ The multifaceted intestinal barrier system has physical, biochemical, and immunological components that prevent the entry of most pathogens, as seen in Figure 3.⁴

WHAT IS GUT PERMEABILITY?

Gut permeability refers to how porous the intestinal barrier is ‒ how easy it is for different antigens to pass through the barrier. When the intestinal barrier functions normally, the tight junctions are held tightly together to maintain the barrier and prevent the entry of extracellular antigens and pathogens. When there are abnormalities in the membrane; the tight junctions are loosened, there is less mucus present, and as a result, the junctions are less effective in keeping the membrane together – causing it to be more porous. This can contribute to dysbiosis and then evolve into ‘leaky gut syndrome’ where exterior antigens from the gut lumen are able to enter the host.³

WHAT ARE THE CONSEQUENCES OF A POROUS GUT BARRIER?

A leaky gut can increase the local and systemic (throughout the body) immune responses. Disruptions in the function of the mucosal barrier have been associated with the rise or exacerbation of multiple diseases.⁴ These diseases include autoimmune diseases such as inflammatory bowel disease, coeliac disease, autoimmune hepatitis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus.⁴ Metabolic diseases such as type 2 diabetes and obesity have also been associated with leaky gut syndrome.³

The initiation and development of autoimmune diseases are influenced by a complex interaction between genetic predisposition, environmental factors, and the condition known as leaky gutsyndrome. Individuals with certain genetic markers are more susceptible to autoimmune conditions, as these genes affect the immune system’s functionality and regulation. Environmental triggers, including dietary factors, infections, and stress, can modify the expression of these genes through epigenetic changes, without altering the DNA sequence itself. This genetic susceptibility, combined with external influences, plays a crucial role in the development of autoimmune diseases.¹⁰

Leaky gut syndrome, characterised by increased intestinal permeability, allows undigested food particles, bacteria, and toxins to enter the bloodstream, leading to an immune response. Overtime, this chronic immune system activation may result in it attacking the body’s tissues, a hallmark of autoimmune diseases. The interaction between a compromised gut barrier and genetic predisposition, exacerbated by environmental triggers, underscores the complex aetiology of autoimmune conditions. Although the concept of leaky gut contributing to autoimmunity requires further research, strategies focusing on improving gut health and avoiding known triggers are considered beneficial for individuals at risk or suffering from autoimmune diseases. ¹⁰

A leaky gut leads to ‘metabolic endotoxemia’, which is a diet-induced 2-3 fold increase in gut-derived plasma lipopolysaccharide (LPS) level. This may cause low-grade systemic and tissue inflammation, which can contribute to the metabolic disease phenotype. Metabolic endotoxemia is indicative of leaky gut syndrome because it allows undesirable luminal immunogens, such as LPS, bacterial DNA and RNA and some bacteria to cross the barrier and enter the blood and lymphatic system. This is further proved by the high levels of gut-derived bacterial products detected in the blood of people with obesity and diabetes.⁸

WHAT FACTORS AFFECT GUT PERMEABILITY?

The image below highlights factors that affect gut permeability. Click here to learn more about the factors which affect gut permeability.