Does Leaky Gut really exist?  Exploring the Scientific Basis

Intestinal permeability, commonly known as “Leaky Gut,” refers to the condition where the intestinal barrier becomes compromised.

This compromise permits microbes, their metabolites, toxins, and various other substances from the gut to traverse the barrier and gain entry into the body. Upon entering the bloodstream or reaching other organs and tissues, these antigens have the potential to activate immune responses. Bacterial metabolites, labeled as “pathogen-associated molecular patterns” (PAMPs), are capable of provoking the immune system. Consequently, mounting evidence establishes a growing connection between leaky gut and chronic diseases as well as autoimmune disorders [1].

Various autoimmune diseases, metabolic disorders, and mental health issues are associated with leaky gut. Patients with these conditions exhibit signs of leaky gut, including celiac disease [2], type 1 diabetes [3], inflammatory bowel disease [4], multiple sclerosis [5], ankylosing spondylitis [6], type 2 diabetes [7], insulin resistance [8], autism [9], schizophrenia [10], depression [11], and various cancers [12-13]. Additionally, 38% of children with eczema have leaky gut, and there is a correlation between leaky gut and stunted growth in children [14].

The intestines play a crucial role in both digestion and nutrient absorption, functioning as a barrier that delineates the body’s internal and external environments. Spanning up to 9 meters in length, the intestines need to facilitate the passage of nutrients into the bloodstream while simultaneously upholding a secure barrier to shield the body against infections and microbial intrusion [15]. During meals, our food carries not only nutrients but also a variety of bacteria and other components, including “endotoxins”, which refer to metabolites of bacteria.

The protective lining in your intestines takes in the good nutrients and gets rid of waste and other stuff using squeezing motions called peristaltic movements. The contents inside the intestines are not truly “inside” the body; rather, the intestine acts like a tunnel, allowing vehicles (nutrients) to pass through, but the tunnel walls (intestinal lining) separate the vehicles from the surrounding river (body). Similarly, the intestinal contents or remnants are not considered “inside” the body; the intestinal lining separates them from the body, only allowing necessary nutrients to pass through.

The intestinal barrier consists of multiple layers of protection [16], with the foremost being the “microbial barrier”. The intestinal surface is covered with mucus, forming the mucosal layer, which has an outer layer containing various microbial communities. When this outer layer is dominated by beneficial symbiotic bacteria, harmful bacteria struggle to establish themselves. However, an imbalanced gut microbiota due to an unhealthy diet can compromise the microbial barrier.

The inner layer of the mucosal layer is close to the epithelial cells of the intestinal wall and contains numerous antimicrobial proteins, such as defensins and lysozymes. This region is less suitable for intestinal microbes, earning it the name “biochemical barrier”, as the various antimicrobial proteins act as the body’s biochemical defense mechanisms. Despite being an inner layer, the mucosal layer is not directly against the intestinal wall cells; propelled by peristaltic waves, the mucus continually pushes bacteria towards the large intestine.

Beneath the mucosal layer are single-layered epithelial cells forming the intestinal wall. While most are nutrient-absorbing cells, there are also different subtypes responsible for secretion. For instance, the mucus in the mucosal layer is secreted by goblet cells, and the collective epithelial cells of the intestine form the “physical barrier” or “epithelial cell layer”.

Underneath these epithelial cells are numerous immune cells, including macrophages, immune T and B cells. When these immune cells encounter antigens that shouldn’t be present, they trigger immune responses, releasing inflammatory or anti-inflammatory cytokines and immunoglobulins to combat harmful microbes and antigens. This region is referred to as the “immune barrier” .  

If these barrier layers are breached, bacteria or antigens can enter the bloodstream, potentially spreading to other organs or inducing more severe immune reactions through the lymphatic and circulatory systems.

Substances within the intestine can traverse the intestinal barrier via two distinct pathways: the “transcellular pathway” and the “paracellular pathway.” Molecules such as fats, mineral ions, and select nutrients typically opt for the transcellular pathway, where they are absorbed into cells and then proceed through the intestinal lining. Conversely, larger molecules must take the paracellular pathway, navigating the spaces between intestinal epithelial cells. The transcellular pathway involves protein transporters secreted by cells, lipid penetration, or endocytosis into epithelial cells before crossing. As an example, lipopolysaccharides (LPS), a component found in bacterial cell walls, can access the bloodstream through the transcellular pathway using chylomicrons. Specifically defined, the term “leaky gut” pertains to the paracellular pathway, wherein substances traverse the gaps between adjacent epithelial cells.

In order to hinder the passage of foreign substances, junctional proteins establish connections between epithelial cells. These proteins primarily encompass “tight junction” (TJ) proteins, “adherens junction” proteins, and “desmosome” proteins. Among them, tight junction proteins serve as the initial line of defense, and disruptions at this juncture can result in leaky gut, prompting significant scientific attention. Tight junction proteins manifest various subtypes, including “claudin,” “occludin,” and “junctional adhesion protein.” Analogous to distinct forms of “windows” within the intestinal lining, these proteins, when frequently ajar, contribute to leaky gut. To maintain stability, these “windows” require anchoring to the wall’s “frames,” which are represented by “zonula occludens” (ZO) proteins. Instability within the “frames,” even when the “windows” are shut, can also precipitate leaky gut.

Summary

Leaky gut occurs when the integrity of the intestinal barrier is compromised. This compromise permits the entry of microbes, endotoxins, and other antigens into the body.

This breach in the intestinal barrier can trigger immune responses, and there is growing evidence linking leaky gut to chronic diseases, mental health issues, and autoimmune disorders.

What can cause leaky gut? How is it diagnosed? And, more importantly, how can it be improved? I will delve into these topics in upcoming posts.