Intestinal Permeability and Gut Barrier Function

Intestinal Permeability, Gut Barrier Function  and Related Diseases

The gastrointestinal tract has always been considered as food in and food out, digestion and absorption of nutrients. The walls of the intestines acting as a barrier controlling what enters the bloodstream to be transported to your organs. Through it’s ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. (3)  (21)

Gastrointestinal Function

 In recent years a lot has been discovered about the structure, function and regulations of the gut. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self-antigens. (10)

The gut barrier is a functional unit, organized as a multi-layer system, made up of two main components: a physical barrier surface, which prevents bacterial adhesion and regulates paracellular diffusion to the host tissues, and a deep functional barrier, that is able to discriminate between pathogens and commensal microorganisms, organizing the immune tolerance and the immune response to pathogens. Other mechanisms, such as gastric juice and pancreatic enzymes, which both have antibacterial properties, participate in the luminal integrity of the gut barrier.

From the outer layer to the inner layer, the physical barrier is composed of

      1. Gut microbiota, hat compete with pathogens to gain    space and energy resources, processes the molecules necessary to mucosal integrity and modulates the immunological activity of deep barrier, 

2. Mucus, which separates the intraluminal content from more internal layers and contains antimicrobial products and secretory IgA,
3. Epithelial cells, which form a physical and immunological barrier and
4. The innate and adaptive immune cells forming the gut-associated lymphoid tissue, which is responsible for antigen sampling and immune responses. Disruption of the gut barrier has been associated with many gastrointestinal diseases, and also with extra-intestinalchronic conditions such as type 1 diabetes mellitus, allergic diseases or autism spectrum disorders. So the gut barrier is a functional unit organized as a multi-layer system and its multiple functions are crucial for maintaining gut homeostasis. Numerous scientific evidence show a significant association between gut barrier leaking and gastro-intestinal and extra-intestinal diseases and also mucus layer and the gut microbiota are involved intestinal homeostasis. 

The intestinal epithelium is the largest mucosal surface in the body, and it provides an extensive interface with the external environment. (4) (13)

Healthy, mature gut mucosa with intact tight junctions serve as the main barrier to the passage of macromolecules into the gut. (15) Intestinal permeability refers to how easily substances pass through the intestinal wall. Small gaps in the intestinal wall called tight junctions allow water and nutrients to pass through, while blocking the passage of harmful substances. When the tight junctions become loose, the gut becomes more permeable, which may allow bacteria and toxins to pass from the gut into the bloodstream. This is commonly referred to as "leaky gut." When this happens  bacteria and toxins enter the bloodstream, it can cause inflammation and possibly trigger a reaction from the immune system. Symptoms of leaky gut syndrome include bloating, food sensitivities, fatigue, digestive issues and skin problem.

 The Intestinal barrier

 Epithelial permeability results from increased paracellular transport, apoptosis (the death of cells which occurs as a normal and controlled part of an organism's growth or development.) or transcellular permeability. Stress disorders such as endurance exercise, non-steroidal anti-inflammatory drugs administration, pregnancy and surfactants (such as bile acids and dietary factors increase permeability. Dietary factors can also therefore reverse intestinal leakiness and mucosal damage in the stress disorders. (5)  (6)

When the integrity of the gut barrier is compromised as is seen during prematurity or exposure to radiation, chemotherapy, mucosal oxidative stress and  toxins leading to gut barrier dysfunction —an immune response to environmental antigens that cross the gut mucosa may develop, leading to inflammation and in some cases autoimmune diseases. (16) (20)

The functional state of the junction can be assessed by measuring the rate of movement of probes across the junction. This is what is referred to as gastrointestinal permeability testing and there are a variety of this can be measured either in vivo or in vitro. Barrier function can be tested with stool samples, in vivo using orally administered probe molecules such as mannitol or in vitro using mucosal biopsies from humans. (9)

To date, the available treatments for the maintenance and repair of gut barrier are limited. A better understanding of the gut barrier features and mechanisms in health and disease, and the development of new pharmacological approaches for the modulation of gut barrier components, are needed for the prevention and treatment of gastrointestinal and extraintestinal diseases associated with gut barrier impairment. (4)

Factors  which can alter permeability of the junction

Modern life may actually be the main driver of gut inflammation. We now recognise that the functional state of the tight junction which was once considered a static parameter, is in reality dynamic, with a functional state that is carefully regulated. Epithelial tight junctions open and close all the time in response to a variety of stimuli such as diet, humoral or neuronal signals, inflammatory mediators, mast cell products, and a variety of cellular pathways that can be affected by microbial or viral pathogens. (18) (3)

In recent years, evidence has accumulated to indicate that tight-junction permeability is regulated by the absorption of various nutrients. (21)

 

Autoimmune diseases

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs.Collectively, autoimmune disorders are among the most prevalent diseases, it is generally accepted that a common denominator in autoimmune disease is genetic susceptibility of the host immune system to misinterpret a benign environmental antigen as a threat. (4) It is well known that the interaction between genes and the environment is fundamental to the immune response, but increasingly, research is validating a new paradigm in which genetic susceptibility coupled with increased intestinal permeability sets the stage for a specific environmental trigger. The trigger then causes a break in immunological tolerance and the onset of an autoimmune cascade.(17) 

A variety of pathological states have been associated with abnormal permeability. Many of these are a consequence of intestinal epithelial damage that is associated with disease but not involved in a causal manner in the genesis of disease. However, in several autoimmune conditions it appears that increased permeability is a constant and early feature of the disease process. It is becoming increasingly clear that in some conditions increased permeability is critical to the development of disease as if it is reversed the disease does not develop an example of this is in type 1 diabetes, Crohn's disease or coeliac disease.(22) Crohn’s disease and ulcerative colitis, collectively called inflammatory bowel disease (IBD), are immune-mediated conditions characterized by a chronic inflammation of the gut.  Increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD. (24)

This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases. (17)

 This is a complicated area:

• epithelial permeability of the gastrointestinal tract can be evaluated in a site specific manner;
• increased intestinal permeability is observed in association with several autoimmune diseases. It is observed prior to disease and appears to be involved in disease pathogenesis;
• there are new and novel therapies emerging directed at altering abnormally increased intestinal permeability and these may play a role in treating or preventing these diseases. (18)

The ecosystem

Approximately 95% of the symbiotic microbes in the human body are located in the gut. (22) In a homeostatic state, this highly diverse population of microbiota promotes overall health. (1) The human gut is an ecosystem consisting of a great number of commensal bacteria living in symbiosis with the host. Several data confirm that gut microbiota is engaged in a dynamic interaction with the intestinal innate and adaptive immune system, affecting different aspects of its development and function. Gut microbiota interacts with both innate and adaptive immune system, playing a pivotal role in maintenance and disruption of gut immune quiescence. A cross talk between the mucosal immune system and endogenous microflora favours a mutual growth, survival and inflammatory control of the intestinal ecosystem. Based on these evidences, probiotics can be used as an ecological therapy in the treatment of immune diseases. (14) (7)

More recently, intestinal microbial dysbiosis has been associated with a number of brain pathologies, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, suggesting a direct or indirect communication between intestinal bacteria and the central nervous system. Dietary changes, chronic alcohol consumption, stress, the use of antibiotics, and other environmental factors, as well as genetic factors, can lead to alterations in the microbiota, which in turn may induce intestinal inflammation and increase intestinal permeability. (1) (19) (22)

Many drugs or compounds used in the treatment of gastrointestinal disorders act through the restoration of a normal intestinal permeability. Several studies have highlighted the role of probiotics in the modulation and reduction of intestinal permeability, considering the strong influence of gut microbiota in the modulation of the function and structure of gut barrier, but also on the immune response of the host. (4)

Glutamine

Glutamine is an important amino acid with many functions in the body. It is a building block of protein and critical part of the immune system as well as having a special role in intestinal health. The body naturally produces this amino acid, therefore it is not an essential amino acid, however it is considered a conditional amino acid, it is also found in many foods.  In patients with Irritable Bowel  Syndrome (IBS) with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related endpoints. (11) Because glutamine is an important fuel for intestinal mucosal epithelial cells as well as  promoting intestinal mucosal cell differentiation and proliferation and improved intestinal barrier function. (12)

Additionally, studies suggest that glutamine supplementation may be an effective treatment, a 2018 study found that in patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related end points. This included a reduction of greater than 50 points on the Irritable Bowel Syndrome Severity Scoring System and changes in daily bowel movement frequency, stool form, and intestinal permeability. (26) ( 8)

Zonulin

Zonulin (haptoglobin 2 precursor), a protein that modulates the permeability of tight junctions between cells of the wall of the digestive tract. It is is a protein, synthesized in intestinal and liver cells, that reversibly regulates intestinal permeability.  There are potentially many triggers for zonulin release but two that  have been identified  so far   are bacteria and gluten. (10)

The Gut-Brain Axis and Systems Biology

Neurogastroenterology, a subspecialty of gastroenterology that overlaps with neurology, encompasses the study of the brain, the gut, and their interactions. It is a particularly fascinating area of research with a rapidly evolving knowledge base. Specifically, neurogastroenterology focuses on the functions, malfunctions, and the malformations of the sympathetic, parasympathetic, and enteric divisions of the digestive tract.

Modern science continues to accumulate evidence demonstrating what ancient healing traditions have known for centuries: the GI tract has a central role in chronic, systemic disease. Given the strong mind-body/brain-gut connection, it is clear that when the normal integrity of the GI tract is compromised, distant systemic complaints can result, even in the absence of overt GI symptoms. Integrative approaches may be helpful for reducing symptoms and reestablishing a healthy gut and a healthy mind. (2)

In 2017, UCLA researchers established an association between gut microbiota and brain regions involved in processing sensory information. The study showed that differences in gut microbial composition correlate with regional brain volumes in patients with irritable bowel syndrome (IBS). It also shed light on the connections between childhood trauma, brain development, and gut microbiome composition. (1)  In other  words the study found a trend for a greater history of childhood emotional trauma in IBS, and the study’s authors speculated that “brain driven disturbances of the gut microbial environment in early life may have a long lasting effect on gut microbial composition. (1) The correlation of microbial taxa with early adverse life events, and with distinct brain structural changes, suggests a possible role of gut microbes and their metabolites in the development and shaping of the gut-microbiota-brain axis early in life. (25)